Israeli agricultural land use (km2) in the Kinneret watershed as documented in 2004.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3205",leadTitle:null,fullTitle:"Design of Experiments - Applications",title:"Design of Experiments",subtitle:"Applications",reviewType:"peer-reviewed",abstract:"This book is a research publication that covers original research on developments within the Design of Experiments - Applications field of study. 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\r\n\r\n\tPeople can be exposed to aflatoxins by eating contaminated plant products (such as peanuts) or by consuming meat or dairy products from animals that ate contaminated feed. Farmers and other agricultural workers may be exposed by inhaling dust generated during the handling and processing of contaminated crops and feeds.
\r\n\r\n\tAflatoxins pose a potential threat to human and animal health through the consumption, contact, or inhalation of foodstuffs and feedstuffs prepared from these commodities. As a result of the adverse health effects of mycotoxins, their levels have been strictly regulated especially in food and feed samples. Therefore, their accurate identification and determination remain a Herculean task due to their presence in complex food matrices. The great public concern and the strict legislation incited the development of reliable, specific, selective, and sensitive analytical methods for mycotoxins monitoring.
",isbn:"978-1-83969-304-5",printIsbn:"978-1-83969-303-8",pdfIsbn:"978-1-83969-305-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"34fe61c309f2405130ede7a267cf8bd5",bookSignature:"Dr. Lukman Bola Abdulra'uf",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10502.jpg",keywords:"Extraction, Chromatography, Health Risk, Carcinogenic, Chemical, Foods, Contaminations, Exposure, MRLs, Daily Intake Level, LD50, Toxicology",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 11th 2020",dateEndSecondStepPublish:"December 9th 2020",dateEndThirdStepPublish:"February 7th 2021",dateEndFourthStepPublish:"April 28th 2021",dateEndFifthStepPublish:"June 27th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Lukman Bola Abdulra’uf holds a Ph.D. degree in Analytical Chemistry from the University of Malaya, Kuala Lumpur, Malaysia. He is a member of the American Chemical Society and the Chemical Society of Nigeria.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"149347",title:"Dr.",name:"Lukman",middleName:"Bola",surname:"Abdulra'uf",slug:"lukman-abdulra'uf",fullName:"Lukman Abdulra'uf",profilePictureURL:"https://mts.intechopen.com/storage/users/149347/images/system/149347.jpg",biography:"Lukman Bola Abdulra’uf is a Senior Lecturer at the Kwara State University, Malete, Ilorin, Nigeria. He started his teaching career at the Kwara State College of Education, Ilorin, in 2006. He had his Ph.D. degree in Analytical Chemistry at the University of Malaya, Kuala Lumpur, Malaysia; MSc degree at the University of Ilorin, Nigeria; and his BSc degree at the Bayero University, Kano, Nigeria. His research focuses on the analysis of contaminants such as pesticide residues, mycotoxins, food additives, and veterinary drug residues in food samples using microextraction techniques. His current research interests focus on the synthesis of carbon nanomaterials, ionic liquids, and sol-gel for analytical applications and the use of graphene nanomaterials as electrochemical biosensors.",institutionString:"Kwara State University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Kwara State University",institutionURL:null,country:{name:"Nigeria"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53572",title:"Acting on Actin During Bacterial Infection",doi:"10.5772/66861",slug:"acting-on-actin-during-bacterial-infection",body:'The cell cytoskeleton is composed of three distinct protein families each of which is assembled from monomers to form polymer networks namely from actin, tubulin, or intermediate-filament proteins. Host and pathogens have developed intrinsic interactions with the cytoskeletal system, playing a central role in several stages of their life cycles. Deciphering the complexity of these interactions is revealing new insights about the mechanisms of bacterial pathogenicity but also on defining new host targets for alternative therapies to available antibiotics. Indeed, clarifying these bacterial mechanisms of host subversion has led to many discoveries about host cell biology, including the identification of new cytoskeletal proteins, regulatory pathways, and mechanisms of cytoskeletal function. Microorganisms exploit actin, microtubules, and intermediate filaments in diverse ways, however, it is mainly the actin cytoskeleton that appears to play a critical role in infection and is the topic of this chapter.
In host cells, actin is involved in the polymerization of stable filaments to assure the cell architecture; at the cell surface originates dynamic movements mediated via assembly and disassembly of microfilaments contributing to contour changes as well cellular locomotion, cell-to-cell adhesion, and signaling. In the cytoplasm, the actin skeleton provides tracks and tails to direct vesicle trafficking. Thus, the importance of the actin cytoskeleton for eukaryotic host physiology from cell movement, cell-to-cell adherence, endocytosis, vesicle trafficking, and cell signaling, among others, has provided pathogenic bacteria with a plethora of opportunistic chances to be exploited.
The roles of the actin cytoskeleton in host-pathogen interactions can be summarized according to groups of pathogens and how they interact with this system. Some promote attachment to the plasma membrane, forming specialized actin structures (pedestals), allowing strong adherence to host epithelial surfaces. Others induce actin polymerization to enter into nonprofessional phagocytic cells; while others prevent polymerization to avoid uptake by professional phagocytic cells. A few pathogens use the actin cytoskeleton to allow other specialized internalization processes to occur in phagocytic cells as an alternative or in addition to phagocytosis. Intracellular pathogens manipulate the cytoskeleton to prevent membrane trafficking or fusion events leading to the establishment of a niche inside a vacuole often avoiding delivery into the degradative environment of the lysosome. Finally, some pathogens escape from the phagosome vacuole to the cytosol and use the actin machinery to move within cells and to spread directly from the cytoplasm of one cell into the cytoplasm of an adjacent cell. Recently, actin dynamics during infection was related to innate immune responses that rely on activation of cytosolic pattern recognition receptors (cytosolic PRRs) for inflammasome or autophagy assembly and programmed cell death.
This chapter provides a comprehensive summary of various strategies used by both extracellular and intracellular bacteria to hijack the host actin cytoskeleton (Figure 1).
Schematic diagram of host cell actin rearrangements during bacterial infection. In red: actin filaments and actin polymerization promoting Rho GTPases. In brown: cell responses to bacterial infection. In blue: bacteria hijacking mechanisms of the host actin cytoskeleton.
Pathogens often have to overcome epithelial barriers to gain entry into the host cells. The first of which is the epithelial mucosae and a few pathogens, along their evolution, have developed strategies to overcome these barriers by means of active invasion mechanisms. Therefore some intracellular pathogens have evolved strategies to induce or modulate their uptake into these nonprofessional phagocytic cells. Alternatively, as a barrier circumventing mechanism, they may use the cells of the immune system (professional phagocytic cells such as macrophages, neutrophils, and dendritic cells) that patrols those epithelia. Here pathogens may or not play an active role in host cell internalization. Usually professional phagocytes recognize pattern signatures of pathogens (e.g., lipopolysaccharides: LPS), or opsonized bacteria (e.g., complement C3 or IgGs), by means of surface receptors. Likewise phagocytes play an active role in bacteria internalization. As part of the immune system these cells are equipped with a series of insult mechanisms designed to clear pathogens (as the proteolysis at low pH in the phagolysosome). Likewise, extracellular pathogens modulate the host cell plasma membrane for attachment and inhibition of phagocytosis in order to survive. In contrast, intracellular pathogens developed strategies to circumvent the bactericidal mechanisms of immune cells via establishing a protective vacuolar niche.
Several actin dependent mechanisms exist for allowing the establishment of infection: (1) Conventional phagocytosis meaning the entry into professional phagocytes by bilateral membrane pseudopodia formation that tightly encloses the bacteria. Phagocytosis always involves close contact between particle and plasma membrane by multivalence receptor-ligand interactions following morphological changes assembling a zipper mechanism. The host plays a central role for the internalization event while no action is required from the pathogen; (2) induced phagocytosis, a process of active induction of internalization into nonprofessional phagocytes such as epithelial cells, by pathogen manipulation of the host cell contractile system; both the host and the pathogen have active roles in the event. Mechanistically the process occurs by strong interactions between bacterial ligands with cell receptors as in conventional phagocytosis; (3) macropinocytosis: here there may be no direct contact between ligand-pathogen and cell-receptors. Literally, macropinocytosis means—cell drinking—and always involves extensive signaling (e.g., via EGF receptor, a type of tyrosine kinase receptor) that induces pseudopodia unilateral formation surrounding large amount of extracellular volume. So particles including bacteria go in passively along with extracellular fluid. Conventional macropinocytosis may occurs in several types of cells including professional and nonprofessional phagocytes leading to the formation of a large vacuole, the macropinosome; (4) induced macropinocytosis involves pathogen manipulation of the host cell cytoskeleton through growth factor induced signaling or directly using secretion systems that injects virulence factors into the cytosol. While referred classically as trigger phagocytosis, according to the type of morphological changes (with multiple ruffles at the cell surface), there is no direct connection between pathogen and plasma membrane. Finally, (5) an unconventional form of phagocytosis may be used for the establishment of infection via actin cytoskeleton. This is termed as coiling phagocytosis and involves single folds of the phagocyte plasma membrane wrapping around microbes in multiple turns (Figure 1).
Phagocytosis is a universal phenomenon involving the recognition and binding of a particle (over 0.5 μm in diameter), in a multivalence receptor-dependent manner, to its internalization and degradation within the phagocytic cell [1]. Mechanistically the process of particle internalization from the plasma membrane is clathrin independent and requires actin polymerization [2]. Phagocytosis of one particle does not signal or permit the indiscriminate phagocytosis of other particles bound to the cell surface. In fact particle ingestion is not automatically triggered by initial particle binding, but requires the sequential recruitment of cell surface receptors into interactions with the remainder of the particle surface. The forming phagosome conforms to the shape of the particle as a close-fitting sleeve of plasma membrane, held in place by interactions between surface receptors and the particle surface, much as teeth hold a zipper together [3]. Phagocytosis can be broadly categorized into three steps: particle binding (along with receptor-cell signaling), internalization (i.e., phagosome formation and invagination) and phagosome maturation (i.e., biogenesis of the degradative compartment: the phagolysosome).
The phases prior to the establishment of interactions between bacterial ligands and phagocytic receptors may involve pathogen fishing by cell structures—this process is also dependent of filamentous actin (F-actin), filopodia extensions (Figure 1). Filopodia serves differently in pathogens and immune cells: pathogens will use it to approach cell membranes for invasion while macrophages will take advantage of these structures for fishing surrounding molecules in order to patrol the environment for possible invaders [4].
Phagocytosis was first discovered in the lower eukaryote amoebae that use it for feeding. In higher organisms, phagocytosis is fundamental for host defence against invading pathogens and contributes to the immune and inflammatory responses [5] including turnover and remodeling of tissues and disposal of dead cells. All cells may to some extent perform phagocytosis [6]. However in mammals, phagocytosis is the hallmark of specialized cells including macrophages, dendritic cells, and polymorphonuclear neutrophils—these cells are collectively referred to as professional phagocytes [6]. In certain circumstances, other cell types, such as fibroblasts engulfing apoptotic cells and bladder epithelial cells consuming erythrocytes, are able to perform conventional phagocytosis as efficiently as professional phagocytes [6].
Professional phagocytes express a series of cell surface receptors which recognize a variety of microbial ligands. Receptors on the surface of the phagocytic cell orchestrate a set of signaling events that are required for particle internalization. However, most pathogens possess many different ligands on their surface. Their phagocytic uptake occurs via multiligand interactions, which induce the engagement of many receptors at the same time.
Two major categories of receptors involved in pathogen recognition are opsonic receptors and nonopsonic receptors (pattern-recognition receptors: PRRs) [1]. Receptors for opsonins such as IgG antibodies and the complement fragment C3bi engage FcγRs and complement receptors (CR), respectively. PRRs include toll-like receptors (TLRs) and other receptor families as C-type lectins receptors that recognize sugar residues as mannose or fucose and lipopolysaccharides (LPS). TLRs often function as coreceptors in phagocytosis by their discrimination of a broad range of microbial products, including LPS and peptidoglycan. The role of TLRs in accelerating and modulating phagosome maturation is still a matter of debate [7].
Bacteria opsonized by complement C3b, by IgG or having lipoarabinomannans at the cell wall surface will be recognized by complement receptors such as CR1 and CR3/4, Fc receptors or Man-6P receptors respectively, each triggering phagocytosis without stimulating a strong superoxide burst. The entry via these phagocytic receptors leads to the maturation of the forming phagosome into a very degradative lysosomal compartment that will destroy microbes [8]. All these receptors will be downregulated during phagocyte activation either through bacterial proinflammatory components as in the case of LPS or cytokines as IFNγ [8].
Activated macrophages will in turn reprogram their expression profile in order to increase the ability to kill pathogens via oxidative bursts and decrease protein digestion extension from amino-acids to small peptides, for antigen presentation [9].
Phagocytosis uses the actin cytoskeleton to construct a cup and close the cup by contractile activities [10]. Latter along phagosome maturation the actin cytoskeleton is also utilized for vesicle trafficking and fusion along the endocytic pathway [11]. The induced polymerization of filamentous actin (F-actin) from globular actin (G-actin) beneath the site of attachment of the particle is the driving force behind ingestion and proceeds from signal transduction downstream of the phagocytic receptors [1]. The precise signaling cascades linking activated receptors to actin polymerization are not fully understood yet it is well known that Rho GTPase family plays critical roles in controlling these cytoskeletal rearrangements [1]. These, RhoA, Rac1, and cell division cycle 42 (Cdc42) act as molecular switches in controlling actin dynamics by regulating the actin-related protein 2/3 (Arp2/3) complex [12]. Arp2/3 requires activation by nucleation-promoting factors, such as the Wiskott-Aldrich syndrome protein (WASP) family. Nucleation-promoting factors exist in an autoinhibited conformation until activated by Cdc42 and Rac1, as well as by phosphoinositide (PI) signaling (discussed latter in this chapter). Effectors such as Cdc42 and the phosphoinositide 4,5-bisphosphate PI(4,5)P2 (PIP2) synergize to activate WASP homolog N-WASP which triggers actin polymerization via Arp2/3 [13]. As the newly formed actin branch grows, the plasma membrane is forced out, extending the membrane as pseudopodia (Figure 1).
Various extracellular and intracellular cues including those from pathogens stimulate Rho GTPases, leading to actin-mediated membrane manipulation. RhoA, Rac1, and Cdc42 have all been shown to accumulate at the nascent phagosome cup. These proteins are preferred targets for bacterial toxins that in turn modulate the organization of the actin skeleton allowing invasion into nonprofessional phagocytic cells and preventing phagocytosis into professional phagocytes. These toxins modify the activity of Rho GTPases through covalent modification or regulation of the nucleotide state. Toxins such as Clostridium difficile toxin A and B modify Rho leading to inactivation of its function. This bacterium and the toxin it produces are a global health problem especially affecting the elderly who need to be prescribed prolonged doses of antibiotics. In fact extracellular bacteria, such as Clostridium spp., release toxins that glycosylate Rho GTPases in order to disorganize actin to reduce immune cell migration and phagocytosis and also to break down epithelial cell barriers [14].
Another group of toxins regulates the nucleotide state and thus the function of various Rho GTPases by acting as GTPase-activating proteins (GAPs). Yersinia spp. an enteropathogenic group of bacteria have secretion systems that inject a type of these Rho GAP toxins, Yop virulence factors leading to actin filamentation blocking and consequently to inhibition of phagocytosis in all host cells to where a contact is established with either professional or nonprofessional phagocytic cells [15].
Pseudomonas has the capacity to inactivate all Rho GTPases [16]. Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that causes life-threatening infections in cystic fibrosis patients, individuals with burn wounds, and the immuno-compromised. P. aeruginosa pathogenicity involves cell-associated and secreted virulence factors as ExoS one of four type III cytotoxins injected into the cytosol. In vivo the Rho GAP activity of ExoS stimulates the reorganization of the actin cytoskeleton by inhibition of Rac and Cdc42 and stimulates actin stress fiber formation by inhibiting of Rho [16]. The consequences are the prevention of phagocytosis. Moreover, the perturbation of F-to G-actin content together with cytosolic stress is sensed by the PRR pyrin triggering caspase 1 and inflammasome assembly leading to inflammation and cell death by pyroptosis.
Many intracellular bacterial pathogens have evolved to survive and even proliferate within immune phagocytic cells. Depending on the route of entry, the fate of intracellular bacteria varies significantly. Some opsonized bacteria as Brucella, the agent of brucellosis, for example, are destroyed efficiently within macrophages while the nonopsonised survive [17]. An essential feature of the pathogenicity of Salmonella is its capacity to cross a number of barriers requiring invasion of a large variety of phagocytic and nonphagocytic cells (reviewed in Ref. [18]). Virulent Salmonella enterica serovar Thyphimurium infection of macrophages triggers cell lysis while opsonized noninvasive mutants do not thus reinforce the idea that distinct overcomes depend on the internalization route [19]. The cytotoxicity of serovar Typhimurium is related to the capacity of this organism to invade cells. Mutants lacking invasion proteins encoded by the salmonella pathogenicity island 1 genome region (SPI-1) failed to induce cell lysis in murine macrophages [20]. This is an important step of salmonella infection allowing the pathogen escaping to macrophages to reach the basolateral membrane of the gut cells for invasion.
The uptake of Mycobacterium spp. by phagocytes has been intensively studied since these cell types, especially macrophages, are the preferred targets of this successful pathogen. An important class of Mycobacterium pathogens includes tuberculosis bacilli. This intracellular facultative pathogen controls the bacterial load during macrophage internalization by interfering with actin polymerization at the phagocytic cup [21]. This is a necessary step in virulence for preventing apoptosis and therefore to prevent pathogen intracellular killing [22]. For this, during early phases of Mycobacterium infection, the microRNA 142-3p is overexpressed in response to phagocytosis and interferes with the expression of N-WASP and consequently with the Arp2/3 complex required for actin nucleation at the cell membrane [21]. Therefore, a low bacterial load is accomplished intracellularly, preventing the apoptosis of the infected cells. In addition, recently, miR-142-3p was shown to directly regulate protein kinase Cα (PKCα), a key gene involved in phagocytosis [23].
The heterodimeric host surface receptor complement-receptor 3 (CR-3), mediates uptake of opsonized and nonopsonized mycobacteria. Interestingly, CR-3 is targeted by other intracellular pathogens, such as Coxiella burnetii, the Q-fever agent, in order to avoid phagocytosis. This strategy is based on ensuring a spatial location of CR-3 outside the pseudopod extensions [24].
Lipid modification by receptor signaling creates the potential for radiating signals that can affect large areas of the plasma membrane. Phospholipid kinases, lipid phosphatases, and hydrolases are activated during phagocytosis. Classes of phospholipids typically found on the inner face of biomembranes include phosphatidylinositol (PI). The generation of phosphoinositides derived from PI via phosphorylation events will generate classes of important lipids enrolled in cell signaling and phagocytosis as example of phosphatidylinositol (4)-phosphate (PI(4)P=PIP), PI(5)P, PI(4,5)P2 (PIP2), PI (3,4)P2, and PI(3,4,5)P3 (PIP3). As mentioned previously in this chapter, these phosphoinositides, especially PIP2 and PIP3, are capable of binding and increasing the activity of proteins that modify membrane chemistry and the actin cytoskeleton. As an example, PIP2 increases the activity of WASP, a protein that stimulates actin polymerization via Arp2/3.
This class of PIs in addition to their relevance in particle internalization is important during the phase of phagosome maturation into a degradative compartment, the phagolysosome. In phagosomal membranes PIP2 activates the actin nucleators of the Ezrin, Moesin, and Radixin family inducing polymerization of F-actin and therefore phagosome maturation [11]. This will be addressed later in this chapter in the context of the manipulation of the actin cytoskeleton by pathogens in order to establish an intracellular niche.
Classically, the manipulation of the actin cytoskeleton by invasive pathogens was classified into two general mechanisms according to the type of morphological changes that occur in the host cell—the zipper and trigger phagocytosis [3]. Entry of uropathogenic Escherichia coli, Yersinia, Helicobacter, Listeria, and Neisseria into epithelial cells is reminiscent of the classical model of zipper phagocytosis. The trigger model will be addressed as macropinocytosis in the next section of this chapter as it is not in fact a phagocytosis event. Moreover, the zipper mechanism may also be triggered actively by pathogens.
Adherence to nonprofessional phagocytic cells, epithelium by a pathogen is necessary to avoid mechanical clearance and is the first step of colonization by for example enteropathogens. Thus bacterial pathogens exhibit a large variety of cell surface adhesins, including fimbriae (pili) and afimbrial adhesins some of which participate in the internalization step. Likewise, in this type of entry, a bacterial adhesin binds to a host cell surface receptor involved in cell-to-cell adhesion and/or activates regulatory proteins that modulate cytoskeleton dynamics. Moreover, adherence and internalization into epithelial cells looks to be a strategy used by pathogens to escape destruction by immune cells as described below.
Most type I pili expressed by pathogenic E. coli bind to host mannose-containing glycoproteins some expressed in gut epithelial cells including M cells (microfold cells of Payer’s Patches) [25]. Others such as FimH from uropathogenic E. coli can bind to β1 and α3 integrins and thereby promote bacterial internalization following a process that to date has only been described in urinary bladder epithelial cells. Uropathogenic E. coli (UPEC) cause the majority of community-onset urinary tract infections (UTI). Early in acute cystitis, UPEC gains access to an intracellular niche that protects a population of replicating bacteria from arriving phagocytes [26]. Transition bacillary forms of UPEC (1–2 μm in length) are readily engulfed, while filamentous UPEC resist phagocytosis, even when in direct contact with neutrophils and macrophages. Despite these strong host defenses, a subpopulation of UPEC is able to persist for months in a quiescent reservoir state which may serve as a seed for recurrent infections [27].
Yersinia spp. such as Yersinia enterocolitica and Yersinia pseudotuberculosis invades gut mucosae at the ileum terminal end and multiplies in the underlying lymphoid tissue. Invasin and YadA (Yersinia adhesion A) are crucial for yersinia adherence via β1 integrins and matrix components, respectively. β1 integrins exist on the basolateral face of enterocytes and on the apical surface of the epithelia derived M cells. The coalescence of integrins following bacteria invasin linkage will lead to yersinia internalization by a “zipper mechanism”. Binding of invasin to β1 integrin activates focal adhesion tyrosine kinase and triggers a complex cascade implicating Rac1-Arp2/3 pathways but also phosphoinositide-3-kinase (PI3K) leading to the closure of the phagocytic cup. In contrast, YadA binds diverse extracellular matrix components, such as collagen, laminin, and fibronectin, thus indirectly mediating integrin binding [28]. Yersinia species also hijack host cell phosphoinositide metabolism for their uptake. Rac-1 recruits, and Arf6 activates the type I phosphatidylinositol-4-phosphate-5-kinase (PtdIns(4)P(5)Ka), which forms PIP2 at the entry site, and this lipid may regulate phagocytic cup formation by coordinating membrane traffic and controlling F-actin polymerization [29].
Helicobacter pylori is another example of pathogen that adheres to mucosa via β1integrins and invades nonphagocytic cells. Efficient infection of cultured epithelial cells seems to be restricted to certain H. pylori strains. This pathogen uses a type IV secretion system (T4SS) targeting β1 integrins to translocate the virulence factor CagA into the cytosol. The adhesin CagL present in the T4SS pilus surface bridge activates the integrin on the basolateral membrane of gastric epithelial cells. In all cases, however, invasion of H. pylori seems to involve a typical zipper-like entry process. Both PI3-K and PKC are required for bacterial uptake and induction of cytoskeletal rearrangements [30]. Curiously preinfection of cultured gastric cells with yersinia expressing Yop virulence factors that interfere with the same signaling events impaired phagocytosis of H. pylori [30]. Internalized H. pylori was shown to be located in tight phagosomes and in close association with condensed actin filaments and localized tyrosine phosphorylation signals. Similar to UPEC in bladder epithelial cells, invasion of epithelial cells by H. pylori may constitute one of the evasion strategies used by this pathogen to circumvent the host immune response and persist in stomach.
Curiously the vaccinal strain for tuberculosis Mycobacterium bovis BCG has been used as the more effective treatment for bladder cancer [31]. The bacillus induces phagocytosis in tumor cells via their surface fibronectin attachment protein (FAP) to β1integrins. After phagocytosis a strong cytotoxic effect is displayed via T-helper CD8 stimulation leading to antitumor activity.
Listeria monocytogenes is a food-borne Gram-positive bacterium that makes use of two surface proteins, Internalin A (InlA) and B (InlB), to engage, in a species-specific manner, to host adhesion molecules E-cadherin and hepatocyte growth factor receptor Met respectively, to induce its internalization [32]. Only InlA is critical for invasion of the gut epithelial cells. The specific engagement of E-cadherin initiates activation of the adherens junction machinery inducing the recruitment of β-catenin, Rho GAP protein ARHGAP10, α-catenins to the site of the entry. Internalization is then further mediated by Rac- and Arp2/3-dependent actin polymerization. In contrast to this, InlB is essential for Listeria uptake by most nonphagocytic cell types, such as hepatocytes, endothelial cells, fibroblasts, and certain epithelial cell lines. Additionally, it is known that ActA, a Listeria protein required for actin-tail formation and intracellular cytosolic movement, can also mediate Listeria uptake by epithelial cells [32]. Recently a new phagocytic process was characterized that allows human endothelial cells to internalize listeria independent of all known pathogenic bacterial surface proteins. Here bacteria adhesion is mediated by Rho kinase and the control of the internalization step is coordinated by formins (as FHOD1 and FMNL3) a class of actin nucleation proteins. The overall control of the event is mediated by cytoskeletal proteins usually enrolled in cell shape and locomotion including Rho, focal adhesions, and PI kinases [33].
Neisseria gonorrhoeae, is an exclusive human pathogen that primarily infects the urogenital epithelia, causing the sexually transmitted disease gonorrhoea. Entry of N. gonorrhoeae into human epithelial cells is multifactorial. Initial attachment is mediated by pili (a T4SS), followed by tight adherence via the phase-variable colony opacity (Opa) proteins. These are a family of 11 outer membrane proteins variably expressed at the surface of the bacterium. However, only OpaA confers invasion into epithelia [34]. This entry is mediated by heparan sulfate proteoglycan (HSPG) receptors of the syndecan family expressed on the target cell surface. Pilus engagement has also been demonstrated to play a role in host cell cytoskeletal rearrangements inducing microvilli formation at the cell surface to surround the bacteria for a zipper mechanism of internalization [35].
In endothelial cells, the T4SS-pilus-mediated adhesion of Neisseria meningitidis induces the formation of membrane protrusions similar to microvilli leading to bacterial uptake. These protrusions result from a Rho- and Cdc42-dependent cortical actin polymerization, and from the activation of the ErbB2 tyrosine-kinase receptor and the Src kinase, leading to tyrosine phosphorylation of cortactin, an activator of Arp2/3 [36]. Adhesion of N. meningitidis to endothelial cells promotes the local formation of membrane protrusions reminiscent of epithelial microvilli structures that surround bacteria and provoke their internalization within intracellular vacuoles.
Unique molecular properties associated with the process of macropinocytosis are beginning to be elucidated. Because of their size and the fact that they may be formed without activation by ligands, the large vacuoles (macropinosomes) formed during this pinocytosis event can contain extracellular fluid and pathogens. At the mechanistic level, phagocytosis and macropinocytosis present many similarities including the involvement of phosphoinositol phosphate signaling and actin cytoskeleton reorganization. During macropinocytosis it is not observed a direct connection between bacteria/cargo and multiple receptors but it was demonstrated the relevance of tyrosine kinase receptors involved in responses to growth factors as the epidermal growth factor and platelet-derived growth factor. The consequence of intensive actin remodeling results in ruffling protrusions at the cell surface, or in unilateral large pseudopodia formation leading to the formation of large macropinosomes. Activated receptor tyrosine kinases, as well as the Src family kinases, are clearly observed on newly formed macropinosomes. Therefore in concert with the morphological definition provided by Lewis in 1931 based on ruffling formation, and elevation in response to growth factor stimulation can be used to define macropinocytosis [37].
Macropinocytosis has been observed in professional phagocytes as well in epithelial cells. Immature dendritic cells and activated macrophages display high levels of constitutive macropinocytosis [38]. The consequent internalization of large volumes of extracellular solute that accompanies macropinocytosis facilitates their capacity to continuously survey the extracellular space for foreign material. In fact, this increased levels of macropinocytosis upon encounter with the antigen/pathogen enhances both antigen capture and antigen presentation by dendritic cells as well as the complete clearance of pathogens after macrophage activation by inflammatory stimulus [38].
In epithelial cells, an induced form of macropinocytosis was observed after infection with pathogens such as Shigella, Salmonella, enterophatogenic E.coli (EPEC), and Mycobacterium tuberculosis. Therefore, individual pathogens have developed a range of strategies to modulate the host’s normal macropinocytic pathways both to invade the host cells and to manipulate the lipid and protein composition of the encapsulating macropinosome to promote cell uptake and then survival. A few virulence factors secreted by pathogens are able to induce ruffling similar to the growth factors named above. The closure of ruffles back to themselves will entrap pathogens into a large vacuole (micropinosome) incorrectly named in distinct publications as “spacious phagosome”.
Invasive enteropathogens, such as Shigella flexneri and S. enterica serovar Typhimurium, use the trigger mechanism of invasion in epithelial cells to induce membrane ruffles and macropinocytosis. This is a phenomenon dependent on a type III secretion system encoded by both bacteria. The T3SS effectors activate host Cdc42 and Rac1 albeit via distinct cellular relays. In Salmonella, SopE acts as a guanyl-nucleotide-exchange factor for Rho [39]. This induced Rho GTPase perturbation is recognized in the cytosol by PRRs (NOD1 sensor) inducing a proinflammatory response and innate immune responses. SigD/SopB is another protein secreted by the SPI-1 T3SS of Salmonella to invade nonphagocytic cells. The phosphatidyl-inositol phosphatase activity of SigD/SopB induces rapid disappearance of PIP2 from invaginating regions of the cytoplasmic membrane leading indirectly to Rho activation and macropinocytosis. Once inside the host cell, Salmonella induces the recovery of normal cytoskeleton dynamics via SptP, a SPI-1 effector with Cdc42 and Rac1 GAP activity that returns these proteins to their nonactivated state.
In comparison, the effectors IpaC, IpgB1, and VirA of Shigella bind to initiate a focal adhesion structure required for internalization via a process that recruit Rho isoforms [40]. Consequently, the injection of the effectors IpaC, IpgB1, and VirA by S. flexneri induces Rac1/Cdc42-dependent actin polymerization. Finally, the translocated effector IpaA binds vinculin and enhances its association to actin filaments, thus mediating the localized depolymerization of actin, which is required to close the phagocytic cup [40].
S. flexneri invasion has been classically described as a macropinocytosis-like process, however the role of macropinosomes in intracellular bacterial survival remains elusive. There is evidence that bacterial entry and membrane ruffling are associated with different bacterial effectors and host responses during S. flexneri invasion. Rho isoforms are recruited differentially to either entering bacteria or membrane ruffles, and entry has been proposed to occur initially via effector mediated contact of S. flexneri to specific receptors suggesting entry is akin to receptor mediated phagocytosis. In fact, the host surface molecules β1-integrins and CD44 (hyaluronic acid receptor) are needed for Shigella entry [40].
Recently, the mechanism of Shigella invasion of epithelial cells was observed using advanced large volume correlative light electron microscopy (CLEM) indicating a combination of induced phagocytosis and macropinocytosis [41]. Here, the macropinocytic event instead of being the major effector for internalization was in fact shown to be required for release of the bacteria from the phagosome and cytosolic escape later in phagocytosis. Macropinocytic vesicles formed at the invasion site are functionally involved in vacuolar rupture. This unique and surprising pathogenic strategy stands in stark contrast to other invasive pathogens that induce direct lysis of their surrounding vacuole via the action of destabilizing bacterial proteins.
S. enterica is an invasive, T3SS-employing pathogen and shares many common host entry characteristics with S. flexneri. It was hypothesized that salmonella containing vacuole and macropinosomes may be distinct, as they are sorted into different intracellular routes [42].These evidence suggest that pathogen induced enhanced uptake of extracellular fluid in S. enterica serovar Typhimurium-infected epithelial cells is an event related to the invasion mechanisms used by this pathogen but not the major mechanism for bacteria internalization as referred in most published data.
Surface-adherent pathogens, such as enteropathogenic or enterohaemorrhagic E. coli (EPEC or EHEC, respectively), use their T3SS to secrete a transmembrane receptor into the host membrane to stimulate actin polymerization and generate cellular extensions called pedestals. EPEC uses the T3SS apparatus to inject the intimin receptor (Tir). Tir acts as a cell receptor of host kinases activating N-WASP and the actin nucleator Arp2/3 resulting in actin polymerization and pedestal formation at the site of the attachment. While stabilizing bacteria connection to epithelial cells the actin pedestal formation promotes T3SS mediated injection of additional effector proteins able to subvert other host pathways. Where bacteria are attached, microvilli are lost; the epithelial cells form cup-like pedestals upon which the bacteria rest. The underlying cytoskeleton of the epithelial cell is disorganized, with a proliferation of filamentous actin. Although EPEC have traditionally been considered to be noninvasive, accumulating evidence casts doubt on this assumption. From the earliest published electron micrographs of EPEC infection, bacteria have been observed within epithelial cells at the sites of attaching [43]. The virulence factor dependent on Tir signaling EspG contributes to the ability of EPEC pathogens to establish infection through a modulation of the host cytoskeleton involving transient microtubule destruction and actin polymerization in a manner akin to the S. flexneri VirA protein [28, 44].
Patients with inflammatory bowel disease exhibited an increased number of mucosae-associated E. coli with invasive properties. The adherent-invasive E. coli (AIEC) uses M cells to reach macrophages of Payer’s Patches where they survive and replicate inside large macropinosomes that share features of phagolysosomes. To survive, these bacteria, inside the vacuoles, adapted to the harsh acidic environment that is the key signal to activate virulence genes. In fact infected macrophages with AIEC secrete large amounts of tumor necrosis factor alpha leading to local granuloma formation. Those macrophages will subsequently aggregate and fuse releasing bacteria that then will reach the basolateral domain of gut epithelial cells for invasion. Epithelial cell invasion is a key virulence factor only for EIEC, which may lead to a dysentery-like illness similar to that caused by S. flexneri [45].
Alveolar macrophages constitute the main defense against M. tuberculosis infection. However, tuberculosis bacilli resist phagocytic cell bactericidal mechanisms and replicate within them. Although M. tuberculosis survives within phagocytic cells, this bacterium may also bind and invade alveolar epithelial cells [46] and endothelial lymphatic cells [47]. Infection of epithelial cells was concomitant with large lamellipodia projections (ruffles) similar to macropinocytosis. Likewise, Mycobacterium can induce formation of macropinosomes however; this does not depend on a bacterial secretion system, as the culture media in the absence of pathogen was sufficient to induce this process. Since nonviable bacteria fail to induce macropinocytosis in opposition to live bacteria, the most prominent candidate to induce ruffling is pointed as being secretory products actively produced by life bacilli. There are no requirements for bacteria to attach directly to the plasma membrane. In endothelial cells, scanning electron microscopy (SEM) micrographs show that mycobacteria were internalized by characteristic phagocytosis-like and macropinocytosis events [47]. However the mycobacterial determinants leading to actin reorganization and pathogen active internalization are not clarified. It is very likely that the invasion and survival in epithelial and endothelial cells contributes to the one-third of the human population latently infected with this microorganism.
Coiling phagocytosis is an actin dependent endocytic event, morphologically accompanied by a typical pseudopodia that looks like whorls or wrapps around the bacteria in several turns (Figure 1). A definition of the phenomena is complex as it presents similarities to macropinocytosis and conventional phagocytosis: for the first due to the large pseudopodia; for the second due to cargo specific entrapment. In coiling phagocytosis, the single pseudopodia do not trap fluid droplets but enclose microbes; however, the multiple pseudopod whorls have largely self-apposed surfaces instead of those that are microbe-apposed surfaces. Legionella pneumophila and Borrelia burgdorferi the agents of Legionellosis and Lyme disease, respectively, use this form of endocytosis for establishment of the infection within macrophages. It was demonstrated that coiling phagocytosis is an active and selective process of the phagocytes, initially triggered by heat- and aldehyde-insensitive moieties of the microbial surface [48], suggesting that coiling and conventional phagocytosis are very closely related, most likely starting from the same phagocytosis-promoting receptor(s). The lack of difference between viable and killed microbes indicates that coiling phagocytosis is actively driven by the phagocytes and not by the microbes. This distinguishes coiling phagocytosis from nonclassical uptake mechanisms such as the induced phagocytosis or macropinocytosis. In this respect, the identification of granulocyte macrophage colony-stimulating factor (GM-CSF) and phorbol esters such as PMA as coiling-promoting substances may be a clue as to the regulatory mechanisms involved in coiling phagocytosis [48]. On the side of the phagocytes, coiling phagocytosis obviously is clearly a regulated mechanism, because the monocytes used it selectively for certain spirochetes, which is inconsistent with simply an accidental trapping of pericellular microbes.
In summary, deciphering the players that induce or prevent phagocytosis in one infection context may be used as strategies to clear pathogens in other context. It is an interesting observation that preinfection of cultured gastric cells with yersinia expressing Yop virulence factors that interfere with the same signaling events, impaired phagocytosis of H. pylori. This may be a potential starting strategy to fight gastric cancer due to this pathogen.
Define what receptors stimulate to induce a more bactericidal response of infected cells, how to control bacterial load that is internalized to induce apoptosis, as is the case of microRNAs that control WASP in tuberculosis context; how to neutralize factors that prevent Rho family of GTPases to modify actin in order to induce phagocytosis of extracellular pathogens, these are a few targets to explore deeply. Other relevant area to act is how to neutralize bacterial adhesins, secretion systems or their access to surface receptors as integrins to prevent epithelia invasion. It is imperative to decipher what are the virulence factors that mimics or induce growth factors that leads to induced macropinocytosis. In addition, it is important to find how to neutralize secretion systems that reorganize the actin cytoskeleton for macropinosome formation and therefore for pathogen invasion of epithelial and endothelial cells, important reservoirs of latent infections.
In addition to particle binding and internalization, phagocytosis includes the process of phagosome maturation leading to pathogen destruction in the acidic hydrolytic environment of the phagolysosome. These events are important innate immune mechanisms. Indeed a consequence of phagosome maturation is the activation of the antigen presentation machinery. Macropinocytosis culminates in the appearance of a large vacuole that, indeed follows the fate of the phagosome. Some pathogens have evolved to establish sustained infection in professional phagocytes preventing phagosome maturation as is the case of M. tuberculosis and S. enterica. Other’s diverts the endocytic pathway into a distinct vacuole more similar to the secretory pathway (e.g., Legionella pneumophila associates with the endoplasmic reticulum). By doing this, pathogens establish an intracellular niche were they survive, escape the immune bactericidal responses and have access to nutrients. Finally, a group of pathogens are able to escape the endocytic pathway by lysing the vacuole and move to the cytosol (e.g., Mycobacterium marinum within macrophages; M. tuberculosis within endothelial cells; Shigella, listeria within epithelial cells) (Figure 1).
The material in endosomes or phagosomes that is destined for lysosome degradation by endocytosis or phagocytosis reaches this compartment by fusing with the organelle. Critical for this is the membrane composition of the correct repertoire of lipids, membrane-bound proteins, and also proteins that shuttle on and off membranes. The manipulation of the phagosomal membrane by pathogens may block the ability of fusion with lysosomes leading to a vacuole that may be trafficked apart from the endocytic route. In alternative, the vacuole may be arrested from maturation along the endocytic pathway by pathogen membrane manipulation leading to continuous transient fusion events with upper compartments.
Phagosome maturation is known to be influenced by the lipid species present on the outer and most likely inner membrane, and published studies have focused mostly on kinases that generates PIP, and PIP2, which binds actin nucleation proteins [49]. Additionally, the ability to nucleate actin leading to F-actin polymerization from phagosomal membranes was associated to the formation and availability of actin tracks for organelles to move towards the actin-nucleating source, increasing vesicle trafficking, fusion events, and phagolysosome biogenesis (Figure 1) [50]. Identifying key roles for PIP and PIP2 opened the door for the analysis of several other lipids that interconnected with these phosphoinositides in the actin assembly process, as well as sphingolipids and fatty acids favouring phagosome maturation [11, 51]. Examples of F-Actin stimulatory factors includes the eicosanoide omega 6 arachadonic acid, ceramide and sphingosine-1-phosphate.
Several groups have explored the role of actin cytoskeleton during Mycobacterium late phases of phagocytosis. Pioneering work by de Chastellier and co-workers shows that Mycobacterium avium a pathogen common in AIDS patients, disrupt the macrophage actin filament network highlighting here the target for the bacterium that allows sustained intracellular survival. It was demonstrated that in contrast to nonpathogenic mycobacteria, pathogenic M. tuberculosis prevents actin polymerization on phagosomal membranes [11, 52]. Therefore, the enrichment of M. tuberculosis phagosomal membranes with classes of lipids that leads to PIP2 was shown to induce F-actin tracks from the vacuole membrane. This is concomitant with an increase of fusion events, phagolysosome biogenesis and, consequently M. tuberculosis intracellular killing [11]. Drug-induced manipulation of the pathogen actin nucleation-induced blockade represents interesting alternative therapies for tuberculosis.
Another pathogen that blocks phagosome maturation is Salmonella. Several hours after bacterial uptake into different host cell types, Salmonella induces the formation of an F-actin meshwork around the Salmonella-containing vacuole (SCV), which is a modified phagocytic compartment. SCV integrity is closely linked to a surrounding meshwork of actin that in contrast to what happens during mycobacteria infection, acts as a barrier that prevents membrane contact and, therefore vacuole fusion with other endocytic organelles [53]. This process does not require the Inv/Spa type III secretion system or cognate effector proteins, which induce actin polymerization during bacterial invasion. A second T3SS, the salmonella pathogenicity island 2 (SPI2), translocate effectors from the phagosomal membrane to the cytosol. The consequence of this event is the induced polymerization of actin around the SCV that will allow salmonella intravacuolar survival. The spv virulence locus will express the SpvB protein and ADP-ribosyl transferase that will promote actin depolymerisation in latter stages of infection. Treatment with actin-depolymerizing agents significantly inhibited intramacrophage replication of salmonella. Furthermore, after this treatment, bacteria were released into the host cell cytosol, whereas SPI-2 mutant bacteria remained within vacuoles [53]. In conclusion, while during M. tuberculosis infection actin assembly is prevented or F-actin is disrupted to allow the establishment of an intracellular niche, in the case of salmonella infection the generation of an F-actin induced mesh is required to maintain and position a vacuole that sustains bacterial growth.
Early after host invasion some pathogens escape lysosomal destruction and antigen presentation by escaping into the cytosol. Thereafter, actin polymerization is manipulated by several cytosolic pathogens such as L. monocytogenes, S. flexneri, Burkholderia pseudomallei, Rickettsia spp., and M. marinum. These generate and use actin tails to move within and between cells.
When intracellular moving bacteria reaches the plasma membrane, they push out long protrusions that are taken up by neighboring cells, facilitating the infection to spread from epithelial cell to cell in the absence of immune surveillance. At the cell-to-cell cytoplasmic membranes sites, the cytosolic actin-based moving pathogens induce the formation of surface protrusions that force the internalization from the infected cell into noninfected neighbor cells. The process of engulfment is called paracytophagy and involves internalization of a double membrane containing pathogen: the inner from the donor cell and the outer from the recipient cell (Figure 1) [54, 55]. At this point the pathogen may escape again to cytosol to start a new infection process.
In the case of enterophatogenic E. coli EPEC it was found that some actin pedestal of the attached EPECs also translocate along the cell surface, reaching speeds of 0.007 μm/s allowing bacteria to spread between attached cells [34] (Figure 1). While this model shares similarities with the Listeria or Shigella systems, the main difference is the presence of a membrane between the pathogen and the cell cytoskeleton (Figure 1: as in the case of filopodia fishing compared to paracytophagy). The actin polymerization system Arp2/3 complex has been manipulated by several pathogens differently. Some mimics the Wiskott-Aldrich syndrome protein (WASP) family [56], while other’s recruit WASP directly to activate Arp2/3 [57]. Examples of the first include the actA protein of listeria and RickA of riquetsia. For the second examples exist as is the case of IcsA of S. flexneri and nondetermined factors of M. marinum but dependent on the ESAT-6 secretion system 1 [57]. M. marinum is a water-borne bacterium that naturally infects fish and amphibians and is an opportunistic pathogen for humans causing tuberculosis while Rickettsia conorii belongs to the spotted fever group of Rickettsia species transmitted by ticks [55].
The actin-based motility of B. pseudomallei the causative agent of melioidosis occurs by a mechanism distinct to that used by other intracytoplasmic pathogens. In fact, the actin tails induced by this pathogen contains Arp2/3 components but it is not clear in the enrollment of the intracellular motility of B. pseudomallei [58]. The overexpression of Scar1 a cellular actin nucleating promoting factor that in the context of S. flexneri, L. monocytogenes and R. conorii, blocks actin tail formation and motility, during B. pseudomallei infection as no effect on actin-based motility [58].
The predominance of a membrane surrounding vacuole during the infection of most intracellular pathogens looks to be related to immune protection from the defensive mechanisms that exist in the cytosol. The arrival of a pathogen or their PAMPs to the cytosol could “wake up” several patrol mechanisms that include cytosolic PRRs. The sensing by cytosolic innate receptors leads to an inflammatory response by secretion of proinflammatory cytokines and chemokines or a interferon type I response that overall leads to antimicrobial response; the stress in the cytosol induce inflammasome assembly [59].
Therefore, the arrival of the pathogens in the cytosol establishes a bridge to the innate immune response by contact of the pathogen-associated molecular patterns (PAMPS) with PRRs, such as NLRPs (Nod like, similar to Toll like receptors- TLRs on cell membranes). Additionally, and by causing cytosol stress, PAMPS will activate (via PRRs) the inflammasome, a complex structure of proteins similar to the apoptosome [60]. Inflammasome assembly will lead to pro-Interleukin1β (pro-IL-1β) and pro-IL-18 inflammatory cytokine activation via caspase 1 and to the programmed cell death dependent on caspase 1, as it is pyroptosis and pyronecrosis [22]. This is a natural immune response in gut and respiratory epithelial cells but not in endothelial vascular and lymphatic cells that lakes these cytosolic receptors and constitutes important host niches for intracellular pathogen survival [33, 47].
Rickettsiae possess a tropism to endothelial cells, a tissue that usually serves as barrier to intravascuolar blood from surrounding tissues. This tropism leads to the endothelial cell injury associated with complications of the disease. RickA (mentioned previously in this chapter) is a protein present in the pathogenic species R. conorii, but absent in Rickettsia thyphi [56]. This absence is responsible for an erratic actin-based motility of R. thyphi leading to the hypothesis of existence of multiple actin-polymerization mechanisms in pathogenic rickettsia. A consequence of this erratic movement may be the delayed spread from cell to cell and continuous replication of thyphi species leading to bacterial overload and necrotic cell lysis [56].For R. conorii paracytophagy cell-to-cell-spread is the common mechanism for pathogen dissemination [55].
Macrophages, in contrast to endothelial cells, possess NLRs and other PRRs families. During M. tuberculosis as well as for M. marinum infection phagolysosomal rupture and bacteria escape to the cytosol usually leads to necrotic cell death [61, 62]. The existence of a functional RD1 region expressing ESAT-6 is relevant for the activation of the inflammasome, the necrotic cell death and the secretion of proinflammatory cytokines IL-1β [21]. In endothelial cells, however, the tubercle bacilli survives [47].
The detection of cytosolic LPS, as a consequence of disruption of replication vacuoles harboring Gram-negative bacteria was shown to trigger the activation of murine caspase-11 that leads to the assembly of a noncanonical inflammasome [63]. Caspase-11 (Casp-4 in humans) is also crucial for clearance of bacteria that escape the vacuole, such as Burkholderia. In addition, detection of sdhA mutants of Legionella and sifA mutants of Salmonella activate caspase-11-dependent pyroptosis [63]. Detection of cytosolic pathogens thus leads to caspase-1- or caspase-11-mediated pyroptosis and restricts bacterial growth.
Another potent host defense mechanism that restricts intracellular pathogens is autophagy. Some intracellular bacteria cause the formation of ubiquitinated aggregates around either bacterial structures or replication vacuoles, and the autophagic machinery can recognize these. The process of bacterial clearance by selective autophagy is called xenophagy. Listeria moves within the host cytoplasm through actin-based motility, promoted by the bacterial ActA protein, which is important for avoiding recognition by autophagy [64]. In contrast to the ActA protein, the Shigella IcsA protein that also promotes actin-based motility from one pole of the bacterium binds to the autophagy protein Atg5 thus targeting the bacterium to a phagophore. Shigella uses two different mechanisms to escape the host autophagic response: first, it secretes IcsB, a protein that competitively binds to IcsA and prevents its recognition by Atg5 thus preventing LC3 recruitment and the process of autophagy [65].
All together these findings let us to postulate that important strategies to fight pathogens will pass by control their life cycle in the cytosol. Either addressing the linkage of actin tails to Arp2/3 or WASP proteins or neutralizing the bacteria actin nucleators to prevent motility and spread to neighbor cells; either to induce death of the infected cell by apoptosis, pyroptosis, or necrotic lysis; either by exposition of pathogen signatures that leads to xenophagy; altogether these are a few potential strategies to address in the future.
During evolution, higher eukaryotic organisms have developed epithelial barriers and phagocytic immune cells to resist and fight infections. The discovery of antibiotics in the early part of the last century led to predictions that bacterial infections would be kept under tight control via natural systems and treatment with drugs. But the capacity of bacteria to evade natural protective systems and rapidly develop resistance to antibiotics had led to the current situation of bacteria posing major health problems in both the developed and underdeveloped world. There is now a major requirement to find alternative treatments to fight bacterial pathogens. Over the years, various studies have elucidated the mechanisms by which bacterial PAMPs, adhesins, and secretion systems together with their translocated effectors target and alter the host actin dynamics. Targeting the host actin machinery is important for the survival and pathogenesis of several extracellular, vacuolar, and cytosolic bacteria. Studying the manipulation of host actin by pathogens has vastly improved our understanding of various basic cell biological processes in host cells while giving key insights into both bacterial pathogenesis and host innate immunity. Together this opens a new and exciting field of research with the objective of discovering new classes of antibiotics that directly or indirectly interfere with this actin-modulating mechanism.
The Lake Kinneret and its Drainage Basin had been widely investigated [1–6] aimed at enhancing basic scientific knowledge as well as ensuring submission of management recommendation to responsible national authorities. Vast majority of the studies were aimed at ad-hoc tracking ecological and anthropogenic changes. Insufficient attention was given to predictive design of systems sustainability. Anthropogenic management interventions are aimed at both, protection, and sustainable maintenance of the ecological structure and services. Nevertheless, ecosystem structures highly depend on the utilization trait. If a natural structure of an ecosystem is not threatened by anthropogenic intervention and/or by natural constrains, protection is smoothly implemented. Global climate change, increase of human population density, and consequently increasing demands for food production while tackling acute water scarcity became critical over larger global zones. Global promotion of desertification (decline of soil fertility) and afforestation amplified human intervention in natural ecological structure. Therefore, ecological management became a critical parameter which has a significant impact on human society. The ecosystems of Lake Kinneret and its watershed are subject for national and international concerns as sources for water supply, agricultural development, commercial fishery and aquaculture, territorial land for living (population dispersal), and more. During the last 80 years, natural and anthropogenic modification were accurately carried out over these ecosystems and consequent management operations were implemented aimed at efficient utilization of the natural resources of land and water while ecosystems sustainability will be preserved. A survey of the history and implementation of achievements which accompanied the ecological modifications in lake Kinneret and its watershed to ensure undamaged and sustainable ecosystem functionality is presented in this paper.
\nLake Kinneret watershed is part of the Northern segment of the Syrian-African great rift Valley. The Lake Kinneret Watershed area (2730 km2, of which 73% is an Israeli territory), from Kinarot Valley in the south to Upper Galilee (northeastern Israel) and southern Anti-Lebanon in Lebanon is 110 km long [1, 2, 3, 4]. The Total area of the Kinneret drainage basin is 2730 km2. It is divided into sub- units: (1) Northern: The River Jordan drainage; (2) Eastern: The southern part of the Golan Heights; (3) Western: The drainage area of Tzalmon and Amud rivers; (4) South-Eastern and South-Western minor sections. Versatile vegetations cover, soil and geological formations characterized the Kinneret watershed. Surface mean slope of the Kinneret Watershed is 2.8%. The following major events during the Anthropocene period were: The Lake Kinneret South Dam construction; The drainage of Old Lake Hula and swamps resulted a change of the regional Hydrological conditions; Regional population emigration and immigration; Governmental resolution of Lake Kinneret as major source for water supply and the construction of the National Water Carrier (NWC). These achievements established the long-term national policy of land use and water supply and geo-political boundary [3].
\nThree major headwater rivers (Hatzbani, Banyas and Dan) flow southerly downstream from the Hermon mountain region [2, 3, 5, 6, 7, 8, 9, 10, 11]. The Hula drainage changed the hydrological conditions: Jordan river crossing the Hula Valley splitting into two canals which joint at the south end of the Hula Valley flowing southerly downstream into Lake Kinneret maintains its Water Level (WL). Long-term (1926-present) record of WL daily monitor indicates maximal amplitude of 6.67 m (208.20–214.87 MBSL). The upper limited legislation of WL (208.8 mbvsl) was aimed at prevention of damage to previously constructed housing. The lower limit is flexibly affected by the location of the intake of the NWC (215 mbsl) and precaution of water quality impact. Since 1972 the hydrological management of the entire headwater resources was achieved by precipitation range, national water demands and NWC capacities and obviously by the south dam operation. [3]. Maximal lake water storage was achieved by close Dam limited by WL altitude. These were the management rules when 60% of national domestic water supply were originated from the Kinneret. Nevertheless, ecosystem sustainability aimed at water quality, mainly salinity, might be threatened if dam is closed and major withdraw is done through NWC [1, 2, 3, 5, 12]. Before Dam construction nutrient rich winter inflows crossed the lake through the upper water layers due to their higher temperature than that of the Epilimnion and naturally flew out through an open outlet. After Dam construction (1933) the outflow became human controlled aimed at water storing, and enhancement of salt and pollutants removal [1, 2, 3, 5, 12]. The final decision was a combination of actual conditions: precipitation-discharge range, desalinized water volume availabilities and lake water quality.
\nThe territorial part of Israel within the Kinneret watershed is 2000 km2 which is 73% of the total of 2730 km2. The agricultural land use in the Kinneret watershed area is given in Table 1 [3, 7, 13, 14, 15].
\nType of land cover | \nArea (km2)\n | \n
---|---|
Field Crops | \n180 | \n
Orchards | \n197 | \n
Fishponds, reservoirs, Agmon, Lake Kinneret | \n171 | \n
Natural Forest and Grove | \n266 | \n
Not Cultivated land | \n1067 | \n
Other | \n111 | \n
Total | \n1992 | \n
Israeli agricultural land use (km2) in the Kinneret watershed as documented in 2004.
The total legislated water consumption for agriculture and domestic usage (source: National water authority) indicates the following: Until late 1990’s it was ranged between 100 and 120 mcm (106 m3) per year of which 99% for agricultural irrigation: 42% -grooves’ 48% - field crops, 7% -fish ponds, and 1% - human domestic supply. Later on, restriction was instructed to 85 mcm/y and further to 68 mcm/y were implemented with additional supply from Lake Kinneret to the Golan Heights of 19 mcm/y [8, 9] (Tables 2 and 3).
\nGeographical region | \nSurface area (km2) | \nAnnual rainfall (mm/y) | \nAnnual rain volume (mcm/y) | \n
---|---|---|---|
Eastern-Northern Galilee | \n542 | \n800 | \n434 | \n
Jordan-Hermon | \n788 | \n900 | \n709 | \n
Hula Valley | \n200 | \n450 | \n90 | \n
Golan Height | \n580 | \n900 | \n522 | \n
Western Basin | \n450 | \n450 | \n202 | \n
Small Southern Basins | \n170 | \n450 | \n77 | \n
Total | \n2730 | \n(Mean: 658) | \n2034 | \n
Used-cover type | \n1949 | \n1958 | \n1976 | \n1986 | \n2010 | \n
---|---|---|---|---|---|
Water | \n24% | \n0 | \n0 | \n2% | \n2% | \n
Swamps | \n54% | \n7% | \n7% | \n3% | \n7% | \n
Flooded | \n22% | \n0 | \n0 | \n0 | \n0 | \n
Field Crops | \n0 | \n59% | \n79% | \n58% | \n68% | \n
Uncultivated | \n0 | \n17% | \n— | \n14% | \n5% | \n
Other | \n0 | \n8.5% | \n3% | \n10% | \n7% | \n
Orchards | \n0 | \n0 | \n3% | \n8% | \n9% | \n
Fish ponds | \n0 | \n8.5% | \n8% | \n5% | \n2% | \n
How does agricultural management accept such constraints of natural drought and the followed legislation of water supply restriction? The answer was given in [15]: During 20 years (1990–2010) the efficiency of water utilization aimed at the beneficial revenue of agricultural production increased from 41,100 to 81,420 US$ per ha. It was the result of improvement of agricultural technology.
\nBefore Hula Drainage the Valley was mostly (6500 ha) covered by natural wetlands (Peat soil) and old Lake Hula (1300 ha), Hula drainage, converted natural wetland into agricultural land [7, 15, 17, 19]. It was an infrastructure development for an agricultural income source for the local immigrated residents. Between 1960 and 1990 the Peat-Land area cultivation has yielded economically sufficient products. Nevertheless, contributed nutrient to Lake Kinneret threatened its water quality. It was resulted by inappropriate irrigation methods. The outcome was peat soil destruction and subsidence, dust storms which blocked the drainage canals, underground fires and rodent population outbreaks. Agricultural crops were damaged and Kineret water quality became threatened. A reclamation project (Hula Reclamation Project, HRP) was consequently discussed and implemented. A shift of 500 ha Peat-Land from agriculture to eco-tourism usage was achieved. The HRP concept was aimed at ecosystem sustainability and therefore based on anthropogenic intervention combined with the introduction of natural plants. Reconstruction of the hydrological drainage system of the entire valley was renovated. The critical need for soil structure protection by maintenance of its moisture was achieved by implementation of irrigation method of moveable sprinkle line [14, 17].
\nThe major significant variable of regional water balance is obviously rainfall contribution. Although a major part of the regional rainy waters input is transformed into runoff, flowing downstream into Lake Kinneret, significant volume of is migrated into unknown underground spaces in the Hula Valley. When climate is changed, and therefore, water consumption and possibly land use policy reduces, it will have an impact on lake water level. The second level of water consumption is due to Evapo-transpiration (ET). This variable of the regional water balance is strongly affected by climate conditions, land plant cover, water availability and soil properties. Dryness conditions enhance soil moisture reduction, which is affected by land use policy of slow down crops cultivation (plant coverage restriction) and, therefore, reduce regional evaporation capacity. The management of the Kinneret watershed is a good example of protection of sustainability of an ecological ecosystem where natural and anthropogenic interests are together combating dryness in the hula Valley (Figure 1) [7, 13, 14, 15, 17].
\nAnnual Total Hula Valley region average of ground water table (GWT) (m below surface).
As a result of enhanced dryness and water supply limitations, the national policy of water pricing was reordered. Consequently, cost account of water consumption in the Hula Valley became more expensive. Nevertheless, as part of the National Water Authority recognition of ecosystem sustainable management, a formal confirmation was carried out of the special status of the Hula valley. Followed by legislated water price reduction accompanied by stakeholders’ commitment to irrigate fields despite being bare in summer. Nonprofitable expenses were compensated by the lowering of water pricing. The difference between the National and the reduced tariff was dedicated to a stakeholder’s managerial foundation to cover those irrigation expenses.
\nResults in Table 4 indicate a reduction of Water-Swampy-Flooded area from 100% to less than 5% surface cover. As a result of enhanced dryness (water scarcity) driven by climate change during the recent 15 years field crops area in the watershed was restricted by 35% and Fishponds by 43%. Although agricultural land-use in the Watershed was reduced as well as water availability (from 110 mcm/y to 68 mcm/y) crops and revenue per areal unit were improved simultaneously. This was resulted by technological improvements and land beneficial significance. In other words, natural constrains of water scarcity were achieved by water and land utilization efficiency aimed at sustainability maintenance.
\nWL range (mbsl) | \nNumber of months (%) | \n
---|---|
Below 214 | \n32 (6) | \n
214–213 | \n65 (11) | \n
213–212 | \n89 (15) | \n
212–211 | \n104 (18) | \n
211–210 | \n144 (24) | \n
210–209 | \n125 (21) | \n
Above 209 | \n30 (5) | \n
Number of months with monthly means of WL with respect to 1 m WL interval in Lake Kinneret (1970–2018).
Since mid-1980’s precipitation decline in the Kinneret Drainage Basin was documented (Figures 2–6). During 2013/14 and 2015/16 seasons rainfall was 47% and 68% respectively below the multiannual mean. Major contributors to the Jordan discharge are Dan and Banias rivers. The discharge of Dan and Banias during 2014 (2.67 and 0.16 m3/s respectively) were the lowest since recent 22 years in comparison with the maximum discharges of 12.8 and 7.4 m3/s respectively [8, 9]. The annual discharges of those rivers declined by 63 and 14 mcm/y respectively. As a result, annual availability of lake water (inflow minus evaporation) during 1985–2016 indicates a decline from 470 to 225 mcm/y. As the result of promoted trend of dryness, the hydrological dynamics of the Lake Kinneret ecosystem was modified. The Input reduction accompanied by water level decline and elimination of pumping together with close Dam policy eliminated exchange level and prolongation of RT from 5 to 7 to a range of 15–>20 years. Evaluation of SPI (Standard Precipitation Index) values from 87 years precipitation record has indicated 11 and 17 negative indexes (aridity level) during1927–1970 and 1970–2014 respectively, which is an indication of climate change toward dryness. River discharge reduction initiated also changes of the phytoplankton community structure in Lake Kinneret. The Nitrogen supply was diminished resulted Peridinium decline which was replaced by Cyanobacteria dominance.
\nGroups of decade (10 years) averages of monthly means of water level in Lake Kinneret. Trend of changes, periodical means, and anthropogenic events are indicated.
Fractional polynomial regression between annual (1940–2018) precipitation and years.
Fractional polynomial regression between annual Jordan discharge (mcm/y) (left panel) and rainfall (mm/y) (Dafna Station, right panel) during 1969–2018.
Fractional polynomial regressions between rainfall (left panel, Dafna Station), and annual means of WL (mbsl) (right panel), and years.
Fractional polynomial regressions between annual means of daily maximum (left panel) and minimum (right panel) air temperature measured in Dafna Station and years during 1940-2020.
Decline of rainfall and Jordan River discharges during the last 40 years and historical deficiency of aquifers storage in the Israeli Northern Basin for 100 years were documented by the Israel Hydrological Service [1, 5, 8, 9]. During 2013/14 and 2015/16 rainfall was 47 and 68% respectively below the multiannual average. The Rivers Dan and Banias discharge during 2014 (2.67 and 0.16 m3/s respectively) were the lowest since recent 22 years. Major contributors to the Jordan flow are Dan and Banias rivers. The annual discharges in those rivers declined by 63 and 14 mcm/y, respectively. A decline from 470 to 225 mcm/y of availability of Kinneret waters (mcm/y) was indicated during 1985–2016.
\nThe records of daily Maximum and Minimum of air temperatures measured at the Meteorological Station Dafna (northern part of the Hula Valley) indicates an increase since mid-1980s. The air temperature record indicates [13, 14, 17, 19] an annual maximum and minimum elevation by 2.7 and 1.5°C, respectively. Studies on regional water balances confirmed enhancement of water loss not only as precipitation and runoffs but also in the underground preferential cavities in the peat soil. Dryness processes of the Hula Valley soil confirm the potential loss of water during dryness periods. Therefore, it was recommended to prevent decline level of soil moisture by suitable irrigation method. Recommended Optimal management is, therefore, moisture enhancement especially during summer time. Climate change and consequent dryness constrains initiated a special legislation, the Peat Soil Convention, which ensured summer water supply for irrigation.
\nThe obvious direct relation between Kinneret WL and precipitation regime in the watershed was documented widely in previous studies. Historical (9000 years before present) data of the Kinneret WL was investigated by two different methods [20, 21] and indicated an amplitude of 20 m (197–217 mbsl) WL fluctuations. Monthly means of daily WL measurements has indicated that during 48 years only 97 months (17%) WL was lower than the legislated bottom line of 213 mbsl occurred mostly during recent 18 years (Table 4) [1, 3, 10, 16, 18, 19, 20, 21, 22, 23] .
\nResults in Table 4 and Figure 2 indicate that during most of the time (83%) the Kinneret WL was not lower than 213 mbsl and, before 2000th, WL was higher than the minimal legislated altitude. The decline of WL below the instructed WL bottom- line (213 mbsl) was recorded during years of exceptional decline of rainfall: 2000–2002, 2008–2011, and 2016–2018, which consequently resulted in significant restriction of agricultural water allocation by the National Water Authority.
\nThe discussion about dependence relations between phytoplankton and nutrients presented here emphasize the paradigm of an everlasting dilemma: Between phytoplankton composition and nutrient concentrations, who is the boss? (Figures 7 and 8) Algal community structure responds to the concentration of the nutrients or the contrary: does the nutrient concentrations is primary or secondary result of the algal density [6, 11, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]? Nitrogen input is defined as predictor of algal domination in Lake Kinneret: Peridinium or Cyanobacteria. A decline of epilimnetic TN standing stock was documented during 1969 to 2001 accompanied by decline of Peridinium biomass while the biomass of Cyanobacteria increased. TN decline initiated Nitrogen deficiency, which is favored by Cyanobacteria [32] due to their ability of maintain the fixation of atmospheric Nitrogen by the enzyme of Nitrogenase. Earlier studies suggested two elements as key factors for the Peridinium bloom formation: Copper (Cu) and Selenium (Se) [6, 23, 29, 30, 31, 32, 33]. The study of the Cu impact was not thoroughly developed but that of Se did it thoroughly. It was confirmed that Se is a limiting factor of Peridinium growth. Before Hula drainage, the chemical conditions of the peat soil were mostly reductive but presently more oxidative and, therefore, limitation of Se is not impossible. Earlier Studies [29, 30], suggested that precipitation and runoff discharges are an important source of bioavailable Se (Selenites and Organic Se) and high availability of Se in surface waters of Kinneret watershed might be a significant supporter of the Peridinium heavy blooms. Therefore, it is suggested that in addition to Nitrogen deficiency, Se input decline affected the decline of Peridinium biomass. Conclusively, the replacement of Peridinium by Cyanobacteria is mostly due to change of nutrients dynamic resulted by climate change. The depletion of Nitrogen supply is based on a long-term record and the recorded data about Se dynamics is partial.
\nFractional polynomial regressions between annual averages of Epilimnetic loads (ton) of Total nitrogen (TN) (left), Total phosphorus (TP) (right) inputs through Jordan inflow and years.
Fractional polynomial regressions between annual averages of phytoplankton biomass (g/m2) (Peridinium, Cyanophyta) and years.
Open or Not to Open (ONO) the South Dam when WL is high? That is the question for Sustainability by hydrological managers [23, 34, 35]. Regional trends of climate change and dryness process were recorded: Standard Precipitation Index (SPI) enhancement precipitation decline, air and lake water temperature increase, river discharges and restriction of lake input volumes and consequent decline of WL, elongation of RT duration. The decline of water availability for domestic and agricultural supply created a national concern accompanied by increase of Lake water salinity, epilimnetic Nitrogen deficiency and Phosphorus sufficiency which enhanced biomass replacement of Peridinium by Cyanobacteria [28]. These natural ecological modifications were accompanied since 2010 by replacement of the lake as principle supplier of drinking water by desalinization of mediterranean waters. The following additional parameters made the ONO dilemma more significant. Multi-annual (1933–2020) daily record of WL indicates an average annual increase of 1.6 m. Nevertheless several annual exceptions of higher and/or lower of it are common. These exceptions are critical for decision makers with regard to the dynamics and management policy of water supply which was dependent of pumping rate and Dam management: high WL indicate pumping potential enhancement and low WL dictate withdraw restrictions. Several cases which represent not common conditions are: During fall 2001 WL was lowered to the lowest altitude ever recorded since 1933–214.87 mbsl and pumping was exceptionally restricted; during winter 1969 WL increased up to 208.2 mbsl and the dam was maximally opened; Five hydrological years (October–September next year) 2013/2014–2017/2018 were a drought sequence in a row when the annual increase of the WL varied between 0.35 and 1.58 m. At the end of this drought period the epilimnetic salinity was 325 ppm Chloride which was even predicted to increase higher if dryness trend would be continued. Three years earlier (2011–2013) the WL annual elevation varied between 1.75 and 2.58 m. After five drought seasons (2014–2018) heavy rain winters came and WL elevation was 3.41 in 2019 and 3.0 m in 2020. In December 2019 when WL was 211.89 mbsl, salinity was measured as 325 ppm. chloride. Later on in winter 2019 the heavy input discharges during January – mid-March when dam was closed dilution effect resulted salinity decline to 273 ppm chloride, (52 ppm decline). It is likely that enhanced water exchange (RT shortening) by open dam might cause higher decline of salt concentration. Moreover, it is also predicted to enhance nutrients and Microcystis biomass removal which enhance improvement of water quality. Since late 1990’s the phytoplankton assemblages are dominated by Cyanobacteria, mostly due to the toxic Microcystis spp. The recent lake situation is therefore creating a dilemma for future management of sustainability: Water supply is done by desalinization, while salinity and Microcystis are enhanced supported by close dam and RT elongation water quality is therefore deteriorated. It is likely that, within future design for sustainability other than hydrological factors must be included. For example, salinity, nutrients and toxic Cyanobacteria biomass Consequently, during rainy winter a partial open of the dam is recommended aimed at quality improvement.
\nThe salinity of Lake Kinneret water was a critical parameter when supply for agricultural utilization was actually required. The major supply of salt to the lake are fluxed through the lake bottom through two major process: surface infiltration (superficial) and welling up. Salts’ contribution through rivers and tributary inflows are much lower in comparison the sub-lacustrine sources. The salinity of River Jordan (65% of total inflows) is more than 10 times lower than that of the lake. Nevertheless, until late 1950’s about 25% (total about 160000 tons annually) of salt input came through the runoff of two hot-salty springs located close to the north-western lake shoreline. Those two springs were diverted (1967) and about 40,000 tons of salt were eliminated from the lake budget. As a result of this anthropogenic implementation accompanied by the heavy floods during the winter of 1968–1969 (25% of lake water were exchanged) lake water salinity declined from 400 to 210 ppm Chloride. Historical information indicates Chloride concentration range before the 1950’s between 290 and 325 ppm. A critical question is therefore arise: why salinity was increased during 1948–1968 from 280 to 400 ppm Chloride when negligible consumption of lake water was supplied for domestic and agricultural usage and the only one management tool, Dam operation (NWC was not in use yet) was available? The WL record indicates an increase of more than 2 m during 20 years (1948–1968). It is therefore suggested that Dam operation policy was aimed at long-term water accumulation causing WL elevation accompanied by Salt accumulation which resulted significant concentration increase of Chloride by more than 100 ppm. It has to be noted that during 1948–1968 there was also a sequence of several drought seasons in a row. Conclusively, for 20 years, the water exchange was low resulting elongation of Residence Time duration. The 1948–1968 event is a case study example for future consideration of sustainability design. The case study of 1948–1968 was not the only one for future consideration. Two other closely related cases which continued only one winter each are relevant: During two winters with heavy rain, in 1968/69 and 1991/92 similar inputs of 1 × 109 m3 were fluxed into the lake during 2 months. The difference between the two winters was the Dam operation [23, 34]: During the first winter the Dam was maximal open and during the second winter completely closed. It has to be considered that the input of low salinity river waters into the much higher salt concentration of lake water create a dilution effect in winter and salt concentration in the lake decline but the level of the decline is dependent on two parameters: input volume and water replacement dynamic and the level of replacement is the dependent of open Dam policy. Results indicated that open Dam operation enhanced water replacement (exchange) which is in fact Residence Time shortening. Therefore during the winter of 1968/69 the Chloride concentration declined by 64 ppm while in the winter of 1991/92 the decline was smaller – 39 ppm. It is therefore recommended to enhance water exchange (shorter Residence Time) through open Dam or pumping regime to remove salt and other pollutants (including biomass of Cyanobacteria) if water storage for supply is not critical resulted by desalinization supply.
\nResidence Time prolongation (Water exchange reduction) affected also Nitrogen and Phosphorus dynamics (Figures 9–11). The process of Peridinium decline and Cyanobacteria enhancement was also supported by RT prolongation. The climate change initiated a linkage of chain events. Discharge decline and water scarcity (dryness) resulted WL decrease, RT prolongation and nutrient supply reduction accompanied by the modification of algal community structure. Normally, the higher the discharge is the faster is the increase of the WL and the shorter is the RT. and vice versa. The decline of discharge and Nitrogen input was accompanied by decline of epilimnetic TN stock and decrease of TN/TP mass ratio. Optimal Ecosystem management is aimed at protecting sustainability and the operation tool is through hydrological control: desirable ranges of pumping, WL fluctuations, nutrient dynamics preventing water quality deterioration resulting adequate water quality. Before 2010 the majority of domestic water supply originated from Lake Kinneret but essential climate change condition constrains created the need for the construction of alternative water source - Desalinization. The decline of discharge and insufficient Nitrogen input caused the phytoplankton community change. The newly created ecosystem structure enforced management adaptation for sustainability protection. When water budget is positive accompanied by appropriate withdraw (pumping and/or open Dam options) RT become shorter and water exchange is high. Decline of Nitrogen availability accompanied by Phosphorus enhancement caused the decline of TN/TP mass ratio [23, 35]. Hydrological management of Lake Kinneret is creating a dilemma for future implementation: Water supply is done by desalinization, salinity and Microcystis are enhanced as supported by close dams that enhance RT prolongation and water quality deterioration. It is therefore likely that recently, WL regime is not the management key factors and other parameters should step forward on the scale of priorities such as: salinity, nutrients and toxic Cyanobacteria biomass. For example, during heavy rain a partial open of the Dam is recommended to remove salt, phosphorus and Cyanobacteria biomass while water supply is not critical.
\nFractional polynomial regression between annual means of monthly residence time (RT in years) and years.
Fractional polynomial regression between RT length (years) and algal (Peridinium, Cyanophyta) biomass (g/m2).
Fractional polynomial regression between RT length (years) and monthly changes of water level (m).
Monthly changes of epilimnetic TN stock were found to be related to the length of Residence Time (RT; the ratio between inflows rate and Lake Volume): higher TN stock accompanied longer RT [23, 27, 28]. Lake Volume increase and shorter RT are correlated with the epilimnetic load decline of TN an increase of epilimnetic TP loads during January–April and gradual decline later on until December was correlated with the Hydrological parameters: RT elongation during January–September, became shorter later; The decline of TN/TP Mass ratio is respective to RT prolongation: The higher the RT value is, the lower is the Epilimnetic TN/TP mass ratio [24, 26, 27] . The biomass of Peridinium contributes Phosphorus and the headwater input are carriers of Nitrogen. The shortest RTs were recorded during the Peridinium bloom onset and later when RT length declines, P-mediated Peridinium dissipates, and Epilimnetic stock diminishes. Shortest RT’s were recorded during winter, and later in the year RT becomes longer. Conclusively, external hydrology (water discharge) contribute Nitrogen and Peridinium bloom in addition to dust deposition, external inputs, and bottom sediments by microbial activity contribute Phosphorus. When Nitrogen supply was declined Peridinium bloom was deleted and Phosphorus fluxes were shortened and TN/TP mass ratio was lowered. The final result was enhancement of Peridinium replacement by Cyanobacteria [28].
\nElongation of RT corresponds to the reduction of the Peridinium biomass. The RT elongation is a signal of Nitrogen availability deficiency. A slight increase of Peridinium biomass documented during the longest RT, is probably attributed to Nitrogen input by fixation carried out by Cyanobacteria.
\nA prominent increase of the Cyanophyta Biomass (from 1.9 to 6.3 g/m2) was documented in response to RT elongation of 1 to 15 years accompanied by decline of Nitrogen availability. It is likely that the Nitrogen deficiency in lake water was compensated by Nitrogen fixation maintained by Cyanobacteria. It is assumed that the minor decline of Cyanobacteria biomass observed during the longest RT is due to the lack of Phosphorus when Peridinium is absent.
\nThe Fishery management in Lake Kinneret is aimed at both, commercial income and water quality protection and ecosystem sustainability [34]. As a result, stocking of exotic fish species was confirmed just of those which cannot reproduce in the lake, their feeding habit improve water quality and their contribution to commercial fishery is essential. Final confirmation was given after a thorough investigation which confirm the implementation of those three objectives. The Tilapia Sarotherodon galilaeus was indicated as an optimal species target: the species is native, feed intensively on the bloom forming Peridinium and have a high commercial value. Therefore, fishing efforts are mostly aimed at this fish and the lake population is enhanced by commercial fingerlings production. Results in Table 5 summarized annual landings of S. galilaeus [36, 37, 38, 39, 40].
\nPeriod | \nTrend of change | \nPeriodical averaged landing (t/year) (SD) | \n
---|---|---|
1959–1970 | \nStable | \n175 (28) | \n
1970–1990 | \nIncrease | \n248 (112) | \n
1990–2010 | \nDecline | \n231 (154) | \n
2011–2016 | \nIncrease | \n184 (99) | \n
Respective data of other stocked species indicates the followings: The stocking of Oreochromis aureus which is not pure native species in the lake was eliminated due to food competition with preferred S. galilaeus; Until the mid-1990s, stocking of Silver Carp (Hypophthalmichthys molitrix) was not recommended aimed at enhancement of zooplanktonic algal grazers whereas later on when Microcystis replaced Peridinium its stocking was recommended due to its efficient consumption of this algae. Three Gray mullet species (Marine origin) are successfully stocked because of ecological adaptation to improve water quality, not able to reproduce in Lake Kinneret and has high commercial value. Another 7 other species of exotic species were totally deleted from stocking program. Conclusively, stocking resources are invested toward fish species that has positive impact on water quality, fishermen income, and the exotics are unable to reproduce in the lake. The fishery (landing and stocking) management policy contribute strengthening of ecosystem sustainability. Peridinium was the major food source for Sarotherodon galilaeus. Several other constraints created additional pressures on the fish population: Increased population of the migratory fish predator, Great Cormorant (Phalacrocorax carbo), reduction of stocked S. galilaeus fingerlings, usage of illegal fishing gill-nets mesh size, the elimination of Bleaks (Sardine: Mirograx terraesanctae terraesanctae, Acanthobrama lissneri) fishing, enhanced piscivory of S. galilaeus by Clarias gariepinus and outburst of Viral diseases, which infected mostly Tilapias. Ecological structure with complicated interactions require informative record long enough to ensure appropriate management decision in response to actual and unusual developed changes. Inappropriate alerted conclusions were followed a fishery crisis in Lake Kinneret when annual landings of S. galilaeus in 2007–2008 were less than 10 tons while normally its varied between 100 and 300. Simultaneously, documentation of the total number of fish (>90% Bleaks) was gradually increasing between 1987 and 2005. A recommendation of a three-year total fishing ban in Lake Kinneret was concluded. This decision was alternatively replaced by a recommendation of normal continuation of fishing. The fishing ban decision was canceled, and fishing continuation was confirmed formally. During 2010–2016, the population of S. galilaeus and consequently their landings were recovered and came to its normal level. During 2007–2008, Tilapia fishery in Lake Kinneret collapsed [18, 19]. A governmental decision of 3 years total commercial fishing ban was undertaken. Nevertheless, as part of ecological sustainability clarification of potential reasons the resolution was canceled and within 3 years the T. galilaeus population recovered. [36, 39]. The changes of the Phytoplankton composition were also accompanied by a modification of the fish feeding habits. During its dominance, Peridinium spp. was the major food component of the most valued native fish (Sarotherodon galilaeus) in the lake. Zooplankton was the major food constituent of the endemic Bleak cyprinids (Acanthobrama terraesanctae terraesanctae, Acanthobrama lissneri). To ensure water quality, it is important to maintain high grazing pressure of zooplankton on nano-phytoplankton. Removal of the unwanted Bleaks by intensified fishery management and the introduction of the exotic Silver Carp (Hyphophthalmichthis molitrix), an efficient consumer of Microcystis, is therefore beneficial. Zooplankton biomass in Lake Kinneret declined from 1970 to the early 1990s but increased thereafter. Both, the biomass and size frequency of cladocerans were affected by fish predation. Under the modified food web structure, Tilapia became a competitor with Bleaks on Zooplankton consumption. Information given in previous studies including the long-term record of the Kinneret zooplankton [1, 2, 3, 6] distribution, population dynamics and physiological trait was re-evaluated in the present paper.
\nThe Zooplankton compartment within the Kinneret ecosystem exemplify the necessity for multi targeted maintenance evaluation [1, 2, 5, 6]. The complex interaction relationships require a comprehensive implementation. Long term (1969–2001) averages of zooplankton biomass (WW) density in Lake Kinneret is given in Table 6 as averages and ranges (Max-Min) of annual means.
\nGroup | \nAverage (g(ww)/m2) (%) | \nMax-min range (g(ww)/m2) | \n
---|---|---|
Copepoda | \n9.0 (33) | \n2.3–17.7 | \n
Cladoceraa | \n15.9 (59) | \n8.8–25.1 | \n
Rotifera | \n2.1 (8) | \n0.9–5.2 | \n
Total | \n27.0 | \n12–48 | \n
Averages of annual (1969–2001) means and max-min ranges of zooplankton groups (Copepoda, Cladocera, Rotifera, Total) WW-biomass (g(ww)/m2).
A deeper insight into the Zooplankton temporal distribution indicates long term decline since mid-1980s accompanied enhancement of Bleak populations. The Bleaks population increase was resulted by decline of fishing pressure. Therefore, a recommendation was submitted and accepted to subsidize Bleak fishing. The concept of sustainability included reduction of cascaded top-down pressure on algal grazers to improve water quality. Nevertheless, ecosystem sustainability protection requires a comprehensive approach of which only fishery was accounted. To achieve water quality improvement by algal biomass reduction in oligotrophic deep lakes Phosphorus removal is ultimately required. Because Phosphorus removal was excluded Sustainability protection was only a partial success: zooplankton biomass was recovered but algal biomass was not reduced [36, 37, 38, 39]. The suppression of the enhanced population winter migratory fish consumer Cormorants in Lake Kinneret became essential as a protector of ecosystem sustainability [36, 37, 38, 39]. The deportation of Cormorant from Lake Kinneret is a useful implementation of water quality protection. The number of Great Cormorant (Phalcocorax carbo) wintering (from the end of October through March) in the Lake Kinneret Region is approximated as 6000 (5000–7000). The predation rate of the Cormorants indicates a daily ration varying between 300 and 1000 grams per bird with the more common value of 700 grams per bird [37, 38]. Six thousand Great Cormorants preying daily at 500 g fish per bird during 100 days removed 300 tons of sub-commercial-sized Tilapia (Mostly S. galilaeus) from the lake. However, we have to take into account that the fishes preyed on are below the commercial size of 100 g per fish, that is to say that the potential damage is bigger (legal size >200 g/fish). Individual Tilapia preyed on weighted 50-70 g; if not preyed on they might grow up to commercial size within 5–6 months to be marketed. Consequently, the commercial value of such losses is between 1.5 and 3.0 million US$. Such a damage to fishermen’s income and ecologically to the system can be reduced by aggressive deportation of the Cormorants from Lake Kinneret and simultaneously from their night station site. The ecological contribution of Tilapia to the ecosystem aimed at water quality protection is done through the consumption of Peridinium biomass gradually reappeared recently. The recommended accompanied operation is Bleaks removal aimed at releasing zooplankton food biomass to S. galilaeus. Predictive recommendations include, among others, is a practical design which is presently under consideration aimed at achieving reduction of fish predation by Cormorant without violating accepted legislations. In other words to protect nature items together with improvement of fishery and water quality in Lake Kinneret.
\nThe lake shallows/beach interface is a contradiction between public and eco-limnological services. The surface area of the inundation zone is about 11 km2 according to: Annual WL fluctuates between 209 with lake bottom area is 168.9 km2, and 213 mbsl with lake bottom area of 161.4 km2, lake shoreline length is 55 km and adjacent beach belt width is 50 m. This nearby water beach area is potentially open for recreation service entitled “Aquatic Recreation Belt” (ARB) [41]. Nevertheless, under temporal long-term inundation regime the ARB allocation is not precisely predictive. During heavy precipitation season WL is high and major part of the ABR area is shrunk while after low rainfall season ABR area is wider and immediately covered by beach aquatic vegetation. The fast grower aquatic plants create a nuisance for aquatic recreational activities such as water access and favored environmental conditions for unwanted animals like Venomous Snakes. Fox, Mongoose, Jackal, etc. Moreover, next year the aquatic plants would be flooded and decomposed forming optimal conditions for Mosquitoes reproduction accompanied by accumulation of rotten bad smell organic matters. Reasonable solution might be mowing of those plants which on the other hand probably create shortage of spawning ground for S. galilaeus [10]. The Kinneret shoreline length is 55 km of which only 12.7 km (23%) are legal open public beaches. So far, prognosis of damage is practically negligible while enhancing S. galilaeus population biomass is possible by commercial production of fingerlings. Conclusively, partial mowing of beach vegetation and S. galilaeus reproduction would not be interfered. These objectives are due to the high (212–213 mbsl) WL regime. A recent computation of lake water surface area in respect to WL obviously indicates close positive significant linear regression when WL was below 210 mbsl. Under higher WL the relation was insignificant. It is because WL came the Bethsaida lagoons altitude. Resulting lower elevation of WL with respect to wide flooding area. The Beteicha lagoons densely covered by aquatic plants (Tamarix spp.,\nTypha spp., and Phragmites spp.) are known as an optimal spawning ground, YOY care treatment for S. galilaeus. Conclusively [10], beach vegetation mowing as a compromise between fish reproduction interference and human recreation is relevant when WL altitude is lower than 212 mbsl.
\nSince 1993 flocks of migratory Cranes (Grus grus) stay during 4 winter months in the Hula Valley. The Crane wintering provided the most attractive target for Eco-tourism [42]. The winter migrating of app. 50,000 Cranes in the Hula Valley during 4 months are very attractive, and the touristic visits were enhanced significantly from about 50,000 during the early 1990’s to almost half a million presently. The Crane wintering flocks created severe difficulties, including damage of agricultural crop and nutrient (excretions) sources in Lake Agmon-Hula and further downstream into Lake Kinneret. It might be risky for the stability of the Kinneret Sustainable trait: 50 × 103 Cranes excrete 5.24 gP/Ind./day during 170 days produce approximately 44.5 tons of TP [42] beside other TP sources in the Hula Peat soil, agricultural fertilization and ecological processes in Lake Agmon.
\nProtection of aquatic Ecosystem sustainability require anthropogenic control throughout the entire watershed. The social, agricultural, hydrological and ecological activities of development in the Hula Valley justify a careful approach., The Crane case, among others, require a significant consideration. The Hula Valley contribute above 50% of the external nutrient inputs into Lake Kinneret and the agricultural management has an impact on nutrients merit to the lake. Ecotouristic management including Crane wintering as visitors’ attraction is part of reasonable entire Valley management and Kinneret water quality protection. Therefore collaborative management by the farmers and tourism managers is vital. A collaborative solution between farmers, nature authorities, water managers, land owners, and regional municipalities was budgeted and implemented. Money was allocated for the renting of a 40 ha field block in the valley dedicated as “Feeding Station” where purchased Corn seeds are given to the cranes twice a day. Feeding start in late December and continue until early March when the Cranes fly back to Europe for breeding. Cranes which land prior to Mid-December are deported aimed at reducing number of potential feeders, prevention damage and reduction of the cost of Corn seeds. This achievement initiated benefits for both the landowner farmers by income resource as half a million bird visiting watchers (priced entrance) while the Hula Valley effluents were not significantly deteriorated.
\nIt is suggested that Cranes do not contribute a significant addition of TP to lake Kinneret and the Epilimnion increase is the result of internal sources. Moreover, positive regressions were indicated between River Jordan discharge and nutrient inflow loads which is r2 = 0.596, (p < 0.0001) for TP. Independently, the discharges in the Jordan River were declined since the mid-1980’s from 15 to <10 m3/s caused by precipitation decline.
\nThe reconstruction of the old Hula native Flora and Fauna indicated approximately 300 bird species 12 fish species, 40 plant species observed in the Hula Valley.
\nThe Eco-Touristic Crane Project was designed to be a part of a comprehensive objective aimed at establishment of watershed and lake Kinneret ecosystems sustainability.
\nThe Hula Reclamation Project was aimed at ensuring sustainability of modified eco-systems by bridging over the conflict between agriculture development, Kinneret water quality protection and nature conservation. The tension between farmers, water managers, nature preservation was reduced, and collaboration came instead. The outcome of the HP was renewal of an ecosystem, which has become a tourist attraction including enriching the biological diversity.
\nThe management of Lake Kinneret and its watershed require a national attempt to ensure their sustainability. These ecosystems are crucial for the nation and their protection is the national concern. Their functional efficiency can be achieved by long term managerial operation conducted by principles of sustainability. The outcome of this paper evaluations are the following recommendations: Lake Management: (1) Shorter length of residence time to enhance water exchange and input of desalinized waters and together with pumped withdraw for supply and Dam open policy and lowering of WL are accepted options; (2) Recommended WL range between 208.8 and 213 mbsl with annual fluctuated amplitude of 1.5 m; (3) Enhance nitrogen supply to the epilimnion to encourage Peridinium bloom renovation; (4) Stocking of Sarotherodon galilaeus and Hypophthalmichthys molitrix and implementation and enforcement of fishery regulations; (5): Renewal bleaks fishery; (6): Mowing of aquatic vegetation in public beaches; Management of the Watershed: Enhance peat soil moisture through continuation of the “Peat Soil Convention”; agricultural maintenance accompanied by eco-tourism with reasonable population size of cranes and regulated number of visitors.
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