Protein with anti-inflammatory properties produced in different strains of bacteria.
\r\n\tThis book will aim at serving as a complete and updated reference for a broad audience, including, students, orthotics, optometrist and ophthalmologist. The book will describe in detail general myopia features as well the most recent diagnostic techniques (e.g. OCT and visual field) which occupy a more and more relevant position in early myopia complications detection. It will explore the connection between myopia and other, popular disorders such as glaucoma, choroidal neovascularization, and retinal detachment: highly myopic eyes tend to have a retina and choroid thinner than normal and, then, the assessment of myopic eyes is far from being a simple task even with the most advanced imaging techniques. In the light of such observations, the book will give a special mention to pharmacological and surgical treatments currently available along with rehabilitation procedures and optical devices.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"41ca0f616bfa2745783b652b87ebedc3",bookSignature:"Prof. Felicia M. Ferreri",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8705.jpg",keywords:"Myopia of prematurity, Retinal detachment, Intraocular pressure, Myopia and glaucoma, Myopic macular degeneration, Ocular motility,Visual rehabilitation, Clinical treatment, Retinal sensitivity, Visual Electrophysiology response, Visual Field, Ultrasonic Biometry",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 3rd 2018",dateEndSecondStepPublish:"December 24th 2018",dateEndThirdStepPublish:"February 22nd 2019",dateEndFourthStepPublish:"May 13th 2019",dateEndFifthStepPublish:"July 12th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"32442",title:"Prof.",name:"Felicia M.",middleName:null,surname:"Ferreri",slug:"felicia-m.-ferreri",fullName:"Felicia M. Ferreri",profilePictureURL:"https://mts.intechopen.com/storage/users/32442/images/system/32442.png",biography:"Felicia M. Ferreri graduated summa cum laude from University of Messina, Italy in 1998 and completed her ophthalmology residency at the Policlinico Universitario, Messina in 2002. She was interned at San Raffaele Hospital in Milan (Corneal Section) and at Hospital Careggi in Florence (pediatric ophthalmology diseases). She spent research periods in Seville ('Virginio del Rocio' hospital), Madrid ('San Carlos' hospital), Manchester ('The 'Bolton Hospital') and Rio de Janiero (Universidade Fluminense).\r\nShe served as co-investigator for many national and international clinical trials. Since 2002, she is an Assistant Professor in Ophthalmology at the University of Messina. Her research interests are in the areas of glaucoma, neuro-ophthalmology, pediatric ophthalmology, and cataract. She authored more than 50 scientific papers.",institutionString:"University of Messina",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Messina",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"191",title:"Ophthalmology",slug:"medicine-ophthalmology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@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, copy-editing 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. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6786",title:"Optic Nerve",subtitle:null,isOpenForSubmission:!1,hash:"b21864e6a0b3b316480d18efda1e18ee",slug:"optic-nerve",bookSignature:"Felicia M. Ferreri",coverURL:"https://cdn.intechopen.com/books/images_new/6786.jpg",editedByType:"Edited by",editors:[{id:"32442",title:"Prof.",name:"Felicia M.",surname:"Ferreri",slug:"felicia-m.-ferreri",fullName:"Felicia M. 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\nThe intestine encompasses a broad variety of microorganisms (bacteria, archaea, eukarya, and viruses) [2] from more than 3500 different species [3, 4] that coevolved with the host in a mutually beneficial relationship [5, 6]. The composition and density of bacterial populations in adult individuals differ considerably over the GIT. The area of the GIT that has highest microorganism abundance is the colon (1014) followed by dental plaque (1012), ileum (1011), saliva (1011), and skin (1011) [7]. However, low concentrations (up to 102–107 cells/mL) and bacterial diversity are found in the upper GIT (stomach, duodenum, jejunum) [3, 4], since the presence of acid, bile salts, and pancreatic secretions hinders the bacterial colonization [8], so that there is no nutritional competition between the microbiota and the host [9]. Thus, both function and structure of microbial communities are significant and are closely related. However, function could be the more important measure of microbiome health, since bacterial ecology suggests that analogous ecosystems have similar function although they have moderately diverse composition [10, 11].
\nThe importance and the specific functions that gut microbiota has in human nutrition and health are well settled. The attributed functions can be classified in three classes: metabolic, protective, and trophic [12]. The gene diversity of the microbial community provides a variety of enzymes and biochemical pathways, specific to the host, able to contribute to short-chain fatty acid (SCFA) production by carbohydrate fermentation and production of some vitamins such as K, B12, biotin, folic acid, and pantothenate. These factors added to synthesis of amino acids from ammonia or urea contributing to the metabolic function of the microbiota [13, 14].
\nThe gut microbiota’s protective function is related to barrier effect, once the resident bacteria generate a resistance line which avoid pathogens/opportunistic bacteria and maintain normal mucosal function. The activity of some bacteria to secrete antimicrobial substances, such as bacteriocins, is able to inhibit the growth of other bacteria and nutrient competition [15, 16].
\nRegarding trophic functions of gut microbiota, the interaction between resident microorganisms has influence in differentiation and proliferation of epithelial cells [17], as well as in the development and regulation of the immune system by numerous and varied interactions between microbes, epithelium, and gut lymphoid tissues [18].
\nIt is important to highlight that the interactions between the gut microbiota and the host immune system are required to preserve the gut homeostasis [19, 20, 21]. When this relationship is affected, alterations in bacterial function and diversity lead to the imbalance in the composition of the resident microbiota, favoring either the growing of pathogenic bacteria or the decreasing in beneficial bacteria in a process known as dysbiosis [22], which appoint a great threat to gut integrity and is intrinsically related to the development and progression of several diseases, such as inflammatory bowel diseases.
\nOne of the most well-characterized chronic inflammatory diseases that mainly affect the digestive tract is inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD). The exact etiology of IBD is still unclear, but the strict relation between genetic and the environmental factors, such as enteric immune dysregulation and alterations in the intestinal microbiome [23, 24], is broadly known. Besides, these diseases generate substantial morbidity and have a high prevalence in developed countries (5 in 1000 individual are affected) they remain to increase in developing nations [25].
\nBoth diseases, UC and CD, present different pathogenesis, symptomatology, inflammatory profiles, and gut microbiota composition. CD is characterized by the irregular transmural inflammation (extending deeply into the submucosal regions) which can affect any portion of the GIT and often made difficult by strictures, abscesses, and fistulae. On the other hand, the inflammation presented in UC is restricted to the superficial layers of the intestinal mucosa characterized by mucosa erosion and/or ulcer, generally localized in the region of the gut most colonized by bacteria, the colon [26, 27]. In addition, regarding the immune response associated with these diseases, it is possible to relate CD with an increased IL-12, IL-23, IL-27, interferon γ (IFN-γ), and tumor necrosis factor-α (TNF-α) production, all associated with Th1 and Th17 immune responses, different from UC which is correlated with a Th2 immune response, with high levels of IL-5 and transforming growth factor-β (TGF-β) production [28].
\nIt is important to highlight that the principal cause of death in IBD patients is colorectal cancer (CRC) [29]. Frequent episodes of inflammatory process in the intestinal mucosa are related to development of this disease, which is the second most frequently identified cancer in females and the third in males.
\nThere are increased evidences that environmental factors such as lifestyle and diet alterations have effect in CRC incidence [30]. This effect has been documented because there is evidence showing an essential relationship between dietary antigens and antigens of commensal bacteria with the regulatory T cells (Tregs), which maintain the immune tolerance and, consequently, reduce the risk of tumorigenesis associated with inflammation [31].
\nIn this context, it was reported that the higher consumption of diet rich in grains and vegetables decreases the incidence of CRC. This effect involves different mechanisms such as the diminution in the fecal transit time due to the increase in the stool bulk, and consequently, it reduces the contact of carcinogen with colon cells and the fermentation of these fibers of colonic components [14, 32]. In addition, significant reduction in concentration of acetate, propionate, and butyrate with increase in fecal pH [33] and the decrease in the number of obligate anaerobe microorganisms have been reported in individuals with colon cancer [34] when compared with healthy people. Thus, intestinal environmental alterations are the keys to evolution toward adenoma and afterward to CRC progression [35].
\nIt has been also reported that up to 30% of patients with UC need surgical management such as the restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) [36]. This procedure removes the entire colon and rectum while preserving the anal sphincter and, hence, normal bowel function and fecal continence, therefore acting as an internal pelvic place for intestinal contents [37]. Around 50–60% of UC patients with following IPAA develop inflammation in the ileal pouch, generating the condition called “pouchitis.” The reported incidence of pouchitis is variable, generally because of the diagnostic criteria that have been used to define this syndrome [38, 39]. In addition, although its pathogenesis is uncertain, the main hypothesis for the mechanism by which the disease occurs is the break in the mucosal barrier generated by dysbiotic microbiome in susceptible patients, generating an unusual mucosal immune activation [40]; still the disease typically responds to antibiotics.
\nCorresponding to the increased attention given to the role of the intestinal microbiota in a variety of diseases, there has been an intense exploration of potential means to manipulate the intestinal microbiome either by probiotic administration or fecal microbiota transplant (FMT) for therapeutic effect [41].
\nIn this context, a randomized clinical trial based on a 1-week treatment with anaerobically prepared donor FMT, compared with autologous FMT, resulted in a higher probability of remission in 8 weeks for patients with UC, revealing that stool administration from healthy donors to UC or CD patients is an intervention that seeks to restore a healthier balance of gut microbes and control IBD [42]. Data on FMT for Crohn’s disease is rather more limited than for UC, but it has been shown that single standardized FMT resulted in a clinical remission sustained for more than 9 months in CD patients [43]. However, the authors suggest that further studies are needed to enhance the knowledge about the use of stool transplantation for IBD treatment.
\nAlteration in the gut microbiome composition with increase in some groups of microorganisms, such as Clostridium and Fusobacterium, was also reported in patients with pouchitis [44, 45]. In this context, literature evidences indicate that the probiotic administration such as VSL#3 is effective in the chronic pouchitis prevention [46]. On the other hand, FMT to pouchitis treatment did not report the same beneficial results. Only three reports with this approach [47, 48, 49] exposed that neither clinical remission nor any adequate response was observed in the evaluated patients suggesting that the efficacy of FMT for pouchitis after proctocolectomy is limited [49]. The importance of standardization of this procedure needs to be highlighted to improve its efficacy, since frequency, route of administration (e.g., endoscopy, nasogastric tube, colonoscopy), and the criteria of choice of healthy donor are very important parameters to be considered.
\nDifferent chemotherapy regimens such as FOLFOX (5-fluorouracil and oxaliplatin), FOLFIRI (5-fluorouracil and irinotecan), and triple FOLFOXIRI regimen (5-fluorouracil, oxaliplatin, and irinotecan) [50, 51] are adopted for different types of cancer but with a broad range of collateral effects.
\nMucositis is the most common side effect in patients undergoing chemotherapy/radiotherapy treatments, which consist in an inflammation and/or ulcers in the gastrointestinal tract [52] with consequent loss of cells from the epithelial barrier of the GIT. Many symptoms are related to gastrointestinal mucositis, such as diarrhea, severe abdominal pain, bleeding, fatigue, malnutrition, dehydration, electrolyte imbalance, and infections, with potential fatal complications which can conduce to reduction or interruption of antitumor treatment [53] and consequently leads to longer hospitalization.
\nThis pathology occurs due to cytotoxic effects of anticancer drugs/radiotherapy that cause damage at the DNA of stem cell (epithelial cell progenitors) with intense oxidative stress and consequent cell death. This apoptotic process is exacerbated affecting the absorption by shortening the villi structure of enterocytes and causing the loss of epithelial barrier with an invasion of inflammatory cells (neutrophils, eosinophils, and macrophages) leading to an increased production of inflammatory mediators at the mucosal area with consequent epithelial erosion and ulceration. The progressive destruction of mucosal integrity causes the rupture of the tight junctions proteins, leading to an increase in the intestinal permeability with subsequent penetration of commensal microbiota to the submucosal layer generating bacteria translocation which exacerbates the inflammatory process and intensifies the symptoms [53, 54, 55, 56, 57]. Besides, the intestinal microbiota composition is also modified by the chemotherapeutic drugs and radiotherapy action [54, 58, 59] resulting in dysbiosis. After the end of treatment, recovery and restoration of the GIT structure occur [60].
\nBesides IBD and mucositis, it has been reported that intestinal microbiota has an intrinsic effect on metabolism, potentially contributing to several features of the pathophysiology of metabolic syndrome [61, 62]. The metabolic syndrome is an accumulation of various risk factors (glucose intolerance, hyperinsulinemia, hypertension, as well as dyslipidemia) which can often be associated with insulin resistance, hypertension with abdominal fat accumulation, and obesity [63, 64, 65].
\nThe etiology of metabolic syndrome is not well-defined; however there are evident characteristics and life habits that could contribute to its development such as unbalanced diet, smoking, lack of physical activity, and the genetic predisposition [66]. These factors directly increase the risk of cardiovascular disease and chronic diseases as type 2 diabetes mellitus and obesity, and the interaction between components of both the clinical and biological phenotypes of the syndrome contributes to the development of a pro-inflammatory state [67].
\nThe inflammatory process observed in MS is directly associated with increased oxidative stress. The reactive oxygen species (ROS) are capable of mediating symptoms of diabetes mellitus, such as insulin resistance and decrease in insulin secretion, and attend as precursors for the formation of LDLox (oxidized low-density lipoproteins), responsible for a large part of the development of atherosclerotic lesions, and the increase in circulating cholesterol fractions and glucose [68, 69]. In addition, chronic diseases are directly related to changes in the intestinal microbiome [70, 71], and they are also associated with elevated circulating levels of pro-inflammatory cytokines such as TNF and IL-6 [72].
\nThe probiotic use in attenuating symptoms of different inflammatory diseases is widely reported in the literature. Among the commercial probiotics studied for treatment of these diseases, only a few products have been extensively tested in clinical trials in patients with MS, in order to demonstrate an effective result on weight loss, lipid metabolism, and reduction of inflammatory markers.
\nStudies performed with Lactobacillus strains have shown the ability of these probiotics in reducing the lipid accumulation in adipose tissues, as well as in inducing the subexpression of lipogenic genes [73, 74]. Animals that received diets with high concentrations of lipids and then treated with L. gasseri SBT2050 had shown lower intestinal permeability and bacterial translocation, as well as reduction of inflammatory parameters, suggesting that this strain improves the intestinal barrier function [75, 76, 77, 78]. In addition, L gasseri BRN17 was studied to treat animals with MS caused by the carbohydrate-rich diet consumption. This strain reduced the accumulation of adipose tissue in mice, and it has a beneficial effect on weight loss [79, 80, 81]. Another important approach with associated probiotics (Bifidobacterium, Lactobacillus, and S. thermophilus) for treatment of overweight patients has shown an improvement in lipid profile, as well as insulin sensitivity [82]. Besides, recently Hsieh e collaborators [83] demonstrated that administration of live Lactobacillus reuteri ADR-1 and killed Lactobacillus reuteri ADR-3 strain ameliorated type 2 diabetes mellitus in a clinical trial. The results indicated that the consumption of ADR-1 displayed a reduction effect on serum glycated hemoglobin (HbA1c), triglyceride, and cholesterol levels. On the other hand, the intake of ADR-3 showed a beneficial effect on blood pressure reduction. Besides, a reduction in the levels of pro-inflammatory cytokines (IL-1β), increase in antioxidant enzyme (superoxide dismutase), and the changes in intestinal microflora composition (increase in intestinal level of Lactobacillus spp. and Bifidobacterium spp. and decrease in Bacteroidetes) were observed. Thus, these strategies highlight the beneficial and potential effect of interventions targeting gut microbiota modulation by the use of probiotic strains to treat components or complications of metabolic syndrome.
\nThe human being for more than 4000 years has been consuming fermented products, by the fermentation process. At the beginning this practice was done to preserve foods from either physical, chemical, or microbial alterations. The microorganisms participating in this process are the lactic acid bacteria, extensively widespread in nature and also belong to the GIT communities, able to convert the sugar in lactic acid as well as produce other metabolites which contribute to food modifications, either sensorial or nutritional value. Thus, the terminology “functional food” was attributed to food with health benefits to the consumer including nutritional and physiological function [84, 85, 86].
\nDuring the fermentation, these bacteria can contribute to improving the digestion of nutrients (lactose, proteins, small peptides, and polysaccharides); providing essential micronutrients (vitamins) as well as bioactive compounds (metabolites) with potential health benefits to the host, such as prevention against enteric inflammation [87, 88]; providing antimicrobial, antihypertensive, hypocholesterolemic, immunomodulatory, antioxidant, and anticancer effects [46, 85, 89, 90, 91, 92]; showing ability to regulate the immunity; and, consequently, improving host quality of life [93].
\nTherefore, the gut communities and the microbial-derived molecules present in the gut lumen have been strongly influenced, either qualitatively or quantitatively, by consumption of dairy products [94] such as yogurts, cheeses, and fermented milk, among other fermented products using probiotic bacteria. Thus, the microbiota manipulation by functional food, probiotics, and prebiotics are evaluated as a beneficial option for treatment of GIT diseases [95].
\nThere is a constant interaction between the host and the bowel commensal bacterial community in order to maintain the homeostasis [3, 96, 97, 98]. However, when this mutualist relationship is compromised, the intestinal microbiota may cause and/or contribute to either the establishment or the progression of inflammatory diseases [96, 97, 98, 99]. In this context, the search for therapeutic strategies that minimize the development and progression of pathologies caused directly and indirectly by the unbalance of the commensal microbiota has grown. The consumption of probiotic bacteria is one of these strategies, as they present several effects, such as ability to improve the intestinal barrier, stimulate the systemic and mucosal immune system, regulate the composition of the intestinal microbiota, and provide essential micronutrients (such as vitamins and SCFAs) and other bioactive compounds (metabolites) with potential health benefits for the host [100, 101, 102, 103].
\nProbiotics are defined as “live microorganisms that offer host health benefits when administered in adequate amounts” [104, 105]. The majority of the studied probiotics belongs to the group of lactic acid bacteria. However, other microorganisms with probiotic properties also deserve attention, such as yeasts (Saccharomyces spp.) and bacteria of the genus Bifidobacterium and Faecalibacterium, among others [106, 107, 108].
\nLAB, which include, mainly, species from the genus Lactobacillus, Leuconostoc, Lactococcus, Pediococcus, and Streptococcus, constitute a group of Gram-positive, anaerobic or aerotolerant, nonspore-forming, nonmobile, and highly low pH-tolerant microorganisms. However, the main characteristic of this group is its ability to produce lactic acid as the final product of the fermentation of carbohydrates [109, 110, 111].
\nLAB are often present in the human gut but also can be introduced by the ingestion of fermented foods, such as yogurt and other fermented milk products and fermented cured meat by-products [103], having the generally recognized as safe (GRAS) status by the Food and Drug Administration (FDA). Lactobacillus spp., Streptococcus spp., and Lactococcus spp. are the major LAB species with probiotic effects, and they have been used in therapeutic applications for treatment and prevention of various intestinal disorders [112, 113].
\nScientific evidence reveals that the mechanisms by which probiotic bacteria ameliorate inflammatory bowel damage are heterogeneous, strain specific, and dependent on the number of available bacteria. Thus, administration of probiotic bacteria, specially LAB, improves intestinal inflammatory responses by (i) modulation and normalization of perturbed intestinal microbial communities; (ii) competitive exclusion of pathogens such as Staphylococcus aureus and Salmonella typhimurium, among others; (iii) bacteriocin and SCFA production; (iv) enzymatic activities related to metabolization of a number of carcinogens and other toxic substances; (v) adhesion to mucosal cells, cell antagonism, and mucin production; (vi) intestinal permeability reduction by tight junctions protein modulation (e.g., zonulin, claudin, occludin, junctional adhesion molecule); (vii) modulation of the immune system by stimulating Tregs cells, IgA production by B cells, and NF-kβ signaling pathway inhibition; and (viii) interaction with the brain-gut axis via the generation of bacterial metabolites (\nFigure 1\n) [103, 114, 115, 116, 117, 118].
\nA schematic diagram about potential action mechanisms of probiotic bacteria.
In order to potentialize the beneficial effects of probiotic strains, research has been conducted over the last decades, based on genetic engineering techniques, especially those related to DNA manipulation. Thus, modern methods of genetic engineering open the new opportunities to design and create genetically modified probiotic strains with the desired characteristics or to exclusively target a specific pathogen or toxin to be used either as a vaccine or for drug delivery [119, 120]. Since most of the probiotic strains are part of the LAB group, most of the genetic manipulation studies are carried out with species that belong to this group, such as Lactococcus and Lactobacillus genera. Consequently, recombinant probiotics have been created for mucosal delivery of therapeutic and/or prophylactic molecules comprising DNA, peptides, single-chain variable fragments, cytokines, enzymes, and allergens [121, 122], leading to the concept of “biodrug” for the prevention and treatment of various diseases [123]. Thus, researches have emphasized the use of species of these genera in two different approaches: the first as producers of heterologous protein and the second as vehicle for delivery of DNA vaccines [124].
\nMany studies are carried out with Lactococcus lactis due to its economic importance in the production of cheese and its easy growth and manipulation. In addition, it was the first species of LAB to have its genome completely sequenced, which allowed a greater understanding of its genetic and physiological mechanisms, aiding in the development of technological packages for its genetic manipulation in a laboratory environment [124, 125, 126, 127, 128].
\nThere are several ways to make LAB produce heterologous proteins, and the most used form is through the insertion of a plasmid into its cytoplasm. Plasmids are elements of extrachromosomal DNA that are naturally found in prokaryotes. With the advent of the recombinant DNA technique, these elements have been manipulated to act as molecular vehicles that allow the production of proteins of interest by the bacterium [129].
\nThe first heterologous protein production system based on plasmid insertion in LAB was developed for L. lactis. These systems included both inducible and constitutive promoters, which ensure efficient expression of the antigen of interest under different conditions [130, 131]. Although it is possible to choose the type of promoter to be used in the vector, the vast majority of expression vectors present inducible promoters that allow controlled expression of the protein of interest by protecting against aggregation and protein degradation in the bacterial cytoplasm. On the other hand, these vectors present safety issues that need to be analyzed since it is necessary to introduce chemical compounds into the culture medium to induce protein expression prior to animal administration [132, 133, 134].
\nWith the improvement of cloning and expression techniques, several production systems were developed, specifically for LAB, allowing the production of different molecules of interest, including pathogen antigens, by a large number of LAB species [135, 136, 137, 138, 139]. The most commonly used regulation systems in LAB are the following:
\nAmong the heterologous production systems, the most widely studied is the nisin-controlled gene expression system. This system is based on the expression of three genes (nisA, nisF, and nisR) that are involved in the production and regulation of the antimicrobial peptide nisin, which is naturally secreted by different strains of L. lactis. In this system the membrane-located histidine kinase NisK senses the signal inducer nisin and autophosphorylates and then transfers the phosphorous group to the intracellular response regulator protein NisR which acts as a transcription activator of nisA/nisF and induces gene expression under pNis promoter. Depending on the presence or absence of the corresponding targeting signals, the protein is either expressed into the cytoplasm or the cell envelope or secreted into the external medium [140]. Thus, it has already been successfully used for the expression of different proteins of medical and biotechnological interest [141, 142].
\nIn 2004, Miyoshi and colleagues [143] developed the xylose-inducible expression system whose promoter is the xylose permease gene (pxylT) found in L. lactis NCDO2118. This system produces either cytoplasmic or secreted proteins being activated in the presence of xylose and strongly repressed in the presence of glucose, fructose, or mannose [143].
\nMore recently, the stress-inducible controlled expression system was developed using the L. lactis groESL promoter [134]. This system induces expression of proteins of interest via stress stimuli such as those found in the GIT (e.g., bile salt, acid pH, antimicrobial peptide, and heat shock proteins) [134, 144]. This system does not require the induction of bacterial culture or the presence of regulatory genes, being a good alternative in the delivery and production of therapeutic proteins at mucosal surfaces.
\nAmong the available approaches to stimulate efficient mucosal responses, the use of bacterial system for DNA delivery and its expression using the eukaryotic cell machinery have been extensively explored. Unlike the production of heterologous protein, in which the bacterium is responsible for the synthesis of the protein of interest, in the DNA vaccine platform, the bacteria only act as a delivery vehicle for prophylactic and therapeutic purposes [109, 145].
\nNew vectors had been developed to approach the DNA vaccine using LAB as live delivery vehicles [146, 147, 148, 149, 150]. These vectors present a series of common characteristics such as the presence of a eukaryotic promoter, which allows protein expression by eukaryotic cells; a prokaryotic region, which has a selection marker (usually antibiotic resistance); a multiple cloning site, where the open reading frame (ORF) of interest will be inserted; and a prokaryotic origin of replication, which ensures that the plasmid replicates only in prokaryotic cells [151]. Some molecules (IL-10, IL-4, and HSP65) have been cloned in these vectors to evaluate their effect, especially as a treatment approach in diseases related to the bowel [152, 153], as well as reporters (GFP and Cherry) which allowed the understanding of this platform in the mammalian body [148, 154]. Although further studies need to be conducted in order to elucidate whether the cloning of ORFs of interest in these vectors is really effective pointing to disease prevention and treatment, this approach is undoubtedly an important tool for the development of new techniques with potential in the medical clinic.
\nAmong the different techniques used to construct recombinant LAB strains, the most recent is associated with the use of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system, based on the use of a system present in several bacterial strains that works as part of the adaptive immune system of bacteria and archaea against the presence of external DNA, such as plasmids and bacteriophages [155, 156, 157, 158, 159].
\nAlthough this system has been studied for more than 30 years [160], it was only in 2013 that the first experiments were carried out emphasizing its use as a tool for genome editing [161, 162]. Evaluating the CRISPR databases, it is possible to observe that about 46% of all bacterial genomes presents the CRISPR-Cas system, and this percentage reaches approximately 63% of the sequenced Lactobacillus genomes [163]. The natural presence of this system in most of the LAB strains expands the possibilities of genetic manipulation of microorganisms of this group, including probiotic ones [164].
\nThe first gene editing experiment in LAB based on the CRISPR-Cas system was conducted by Oh and van Pijkeren [165] where they were able to edit three different regions of the genome, with efficiency up to 100% in the selected clones. After this pioneering work, few others were published focusing on LAB gene editing [166, 167, 168].
\nTherefore, the use of this technology is presented as a widely viable strategy to be applied in LAB, enabling the development of food-grade recombinant strains in order to allow their future use in the clinic [169].
\nThe use of recombinant L. lactis strains, as well as others recombinant LAB strains, using different systems has shown promising results in many studies as an alternative therapy to treat, especially, GIT inflammation and other diseases (\nTable 1\n).
\nMicroorganism | \nGene | \nExpression System | \nInflamation Condition | \nAnti-Inflamatory Properties | \nReferences | \n
---|---|---|---|---|---|
\nL. lactis MG1363 | \nMouse IL-10 | \nSICE | \nMouse model of DNBS-induced colitis | \nRestoration of intestinal architecture; IgA production and IL-6 reduction; Reduced tissue damage | \n[134] | \n
\nL. lactis MG1363 | \nMouse IL-10 and IL-4 | \npValac vector | \nMouse model of DSS/TNBS-induced colitis | \nDecreased IL-6, IL-12 and MPO activity Reduced tissue damage | \n[152, 153] | \n
\nL. lactis NZ9000 | \nMouse TGF-β1; IL-10 and leukocyte protease inhibitor Human Elafin | \nNICE | \nMouse model of DSS-induced colitis | \nReduced tissue damage Decreased pro-inflammatory cytokines | \n[174] | \n
\nL. lactis NCDO 2118 | \nHuman 15-lipoxygenase-1 | \nXIES | \nMouse model of DSS-induced colitis | \nReduced tissue damage | \n[175] | \n
\nL. lactis NCDO 2118 | \n\nM. leprae Hsp65 protein | \nXIES | \nMouse model of DSS-induced colitis | \nRestoration of intestinal architecture CD4+Foxp3+ and CD4+LAP+ regulatory T cells production | \n[176] | \n
\nB. bifidum BS42 | \nMouse IL-10 | \nBEST | \nMouse model of DNBS-induced colitis | \nReduced tissue damage | \n[177] | \n
\nL. casei BL23 | \nSuperoxide dismutase A from L.lactis MG1363 Catalase from L.plantarum ATCC | \npLEM415 vector | \nMouse model of TNBS-induced Crohn’s disease | \nReduced tissue damage Reduced microbial translocation Increase IL-10/INF-γ reduction | \n[180] | \n
\nS. thermophilus CLR807 | \nSuperoxide dismutase A from L.lactis MG1363 Catalase from L.plantarum ATCC | \npIL253 vector | \nMouse model of TNBS-induced colitis | \nReduced tissue damage Reduced microbial translocation IL-17 reduction | \n[181] | \n
\nL.lactis AG013 | \nHuman Trefoil Factor 1 (Htff-1) | \nThyA native promoter of L.lactis\n | \nHamster model of radiation-induced oral mucositis | \nReduced clicnical scores of oral mucositis | \n[186] | \n
\nL. lactis NZ9000 | \nHuman pancreatitis associated protein (Reg3A) | \nNICE | \nMouse model of 5-FU-induced intestinal mucositis | \nMicrobiota Regulation Villus architecture preservation Increased Paneth cells activity | \n[185, 187] | \n
\nL.lactis NCDO2118 | \n\nM. leprae Hsp65 protein | \nXIES | \nMice model of experimental encephalomyelitis | \nIncreased CD4+Foxp3+ regulatory T cells Reduced encephalytogenic CD4+ T cells | \n[184] | \n
\nL.lactis MG1363 | \nMouse IL-17 | \nSICE | \nMice model HPV-induced cancer | \nReduced tumor size Induced IL-6 and IL-17 secretion | \n[182] | \n
\nL.lactis NZ9000 | \n\nM. leprae Hsp65 protein and peptide derived of human Hsp60 protein | \nNICE | \nMice model of diabetes type 1 | \nReduction of insulitis Inhibition of T cell proliferation | \n[183] | \n
Protein with anti-inflammatory properties produced in different strains of bacteria.
To arrive at mucosa in sufficient quantities to exert their therapeutic effects, many LAB strains must survive, during their passage through the GIT, stressor factors such as pH, temperature, bile salt concentration, and the presence of antimicrobial peptides [170, 171, 172]. In this context, an interest approach was recently developed by Coelho-Rocha and colleagues [154] using an encapsulated recombinant strain (L. lactis pExu:mcherry) and tested it through the GIT at different times post-administration. They have shown that the microencapsulation process is an effective method to improve DNA delivery, guaranteeing a greater number of viable bacteria able to reach different sections of the bowel [154].
\nThe use of recombinant probiotics to improve therapeutic approaches has been widely studied using different systems with different molecules. As IBDs are a serious clinical topic, many strategies have been tested trying to improve previous results found with wild type strains.
\n\nL. lactis MG1363 strain carrying the pTREX1 vector expressing the mouse IL-27 protected mice against the inflammatory effects of dextran sulfate sodium (DSS)-induced colitis. This recombinant strain was able to reduce disease activity scores and pathology features of the large and small bowels and also led to reduced levels of inflammatory cytokines IL-1β, TNF-α, and IFN-γ in colonic tissue. In addition, reduction in the number of CD4+ and IL-17+ T cells in gut-associated lymphoid tissue and increase in IL-10 production were observed [173].
\nBesides, it was also demonstrated in a DSS-induced colitis mouse model that the oral administration of L. lactis NZ900 strain harboring the NICE system expressing either the anti-inflammatory cytokine IL-10, TGF-β1, secretory leukocyte protease inhibitor (SLPI), or elafin was able to ameliorate some clinical parameters in inflamed mice. Even though it was possible to observe the reduction of weight loss and diarrhea, microscopic colonic damage scores, colon thickness, and myeloperoxidase (MPO) activity, the authors reported that treatments with recombinant L. lactis strain delivering either SLPI or elafin were more efficient to reduce signs of colitis than treatments with anti-inflammatory cytokines. Altogether these recombinant strains display anti-inflammatory effects in inflamed mice [174].
\nApproaches using the invasive L. lactis MG1363 FnBPA+, by expressing the FnBpA protein at their surface and carrying the pValac eukaryotic expression vector coding either the IL-10 cytokine [rL. lactis FnPBA+ (pValac:il-10)] or the IL-4 cytokine [rL. lactis FnPBA+ (pValac:il-4)] in DSS or trinitrobenzenesulfonic acid (TNBS)-induced acute model of colitis, respectively, were also investigated. The administration of L. lactis FnPBA+ (pValac:il-10) recombinant strain was capable to reduce the intestinal inflammation by increasing IL-10 levels and sIgA production, accompanied by decreasing IL-6, as well as the restoration of intestinal architecture of mice colon [153]. Besides, the engineered L. lactis FnPBA+ (pValac:il-4) was able to slump the level of pro-inflammatory cytokine (IL-12, IL-6) and myeloperoxidase activity and increase levels of IL-4 and IL-10, consequently decreasing the colitis harshness [153].
\nThe human 15-lipoxygenase-1-producing L. lactis NCDO2118 harboring the xylose-inducible expression system (pXylt:CYT:15-LOX-1) was also effective in attenuating the symptoms of DSS-induced colitis in a murine model [175]. Its oral administration improved the body weight, decreased pro-inflammatory cytokines (IFN-γ and IL-4) while increasing the anti-inflammatory cytokine IL-10, and, consequently, ameliorated the macroscopic damage scores associated with the inflammation.
\nThe oral pretreatment with genetically modified L. lactis NCDO2118 able to secrete HSP65 protein from Mycobacterium leprae, using XIES system (pXylt:SEC:hsp65), prevented DSS-induced colitis in C57BL/6 mice [176]. This protection was associated with reduced pro-inflammatory cytokines, such as IFN-γ, IL-6, and TNF-α; it also increased IL-10 production in colonic tissue and expansion of CD4+FoxP3+ and CD4+ latency-associated peptide (LAP+) regulatory T cells in the spleen and mesenteric lymph nodes. Besides, the authors showed that this effect was dependent on IL-10 and toll-like receptor 2 (TLR-2) [176].
\nAlthough L. lactis represents an excellent candidate for a live mucosal vector delivery system, other bacteria have also been explored as promising live vehicles for molecule expression with therapeutic properties, such as Lactobacillus, Bifidobacterium, and Streptococcus. In this context, Mauras et al. [177] using the new Bifidobacteria Expression SysTem (BEST) allowing the production of IL-10 in Bifidobacterium bifidum BS42(pBESTExp4:il-10 and pBESTBL1181:il-10) demonstrated that the use of these recombinant strains in a DNBS-induced colitis model showed its ability to decrease local inflammation and confirmed therefore its potential for delivery of therapeutic molecules in the colon.
\nIt is well known that IBD is associated with oxidative stress by the increase in concentration of reactive oxygen species in the GIT and impaired antioxidant defenses [178, 179]. In this context, it has been shown that some probiotic LAB strains may play a protective role in IBD by expressing antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) [180, 181].
\nLeBlanc et al. and Del Carmen et al. [180, 181] showed, respectively, that L. casei BL23 and S. thermophilus CRL807 transformed with two different plasmids (pLEM415:mnkat; pLEM415:sodA) (pIL253:sodA and pIL253:mnkat) harboring the genes encoding catalase (CAT) or superoxide dismutase (SOD) antioxidant enzymes exhibited anti-inflammatory activities in a mouse model of Crohn’s and colitis disease induced by trinitrobenzenesulfonic acid (TNBS). The authors observed a reduction in weight loss, fewer liver microbial translocation, lower macroscopic and microscopic damage scores, and modulation of the IFN-γ/IL-10 [180] and IL-10/IL-17 [181] cytokine production in the large intestines of mice treated with either CAT- or SOD-producing lactobacilli/streptococci.
\nThe stress-inducible controlled expression (SICE) system represented by L. lactis MG1363 strain harboring the pLB333 plasmid was developed to avoid the external induction of culture before the host administration [134]. Several interesting molecules were cloned in this system such as IL-10 [134] and IL-17 [182], and the effect of L. lactis secreting them was evaluated in mice models. L. lactis (pSICE:il-10) was tested in a DNBS-induced colitis mice model, resulting in a significant reduction in colitis parameters with improvement in weight loss and a decrease in macroscopic scores [134]. The intranasal administration with L. lactis secreting IL-17A (pSICE:il-17), in a mice model of human papilloma virus (HPV)-induced cancer, was able to reduce tumor size and induce IL-6 and IL-17 secretion in reactivated splenocytes from mice challenged with the tumoral cell line [182]. Both works confirmed the potential use of L. lactis harboring the SICE system to deliver interesting molecules either to colitis or colon cancer patients [134, 182].
\nAlthough many studies have focused on the use of recombinant bacteria for the treatment of IBDs, as was previously discussed, the use of recombinant probiotic strains expressing/delivering therapeutic molecules has been explored for treatment or prevention of other diseases such as mucositis, cancer, obesity, multiple sclerosis, and diabetes [182, 183, 184, 185].
\nAn in vivo study reported by Caluwaerts et al. [186] showed that recombinant L. lactis AG013 secreting human trefoil factor 1(hTFF-1) was able to reduce the severity and course of radiation-induced oral mucositis. Carvalho et al. [187] also demonstrated that a recombinant strain of L. lactis NZ9000 using the inducible NICE system to express the human pancreatitis-associated protein (PAP) was able to prevent 5-FU-induced intestinal mucositis in a murine model. It was observed that this protein preserved villous architecture, increased Paneth cell activity [187], and suppressed the growth of Enterobacteriaceae during inflammation [185].
\nIt also has been shown that oral administration of a recombinant L. lactis NCDO2118 strain (pXylT:SEC:hsp65) prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice [184]. Mice fed daily with this recombinant strain increased the number of natural and inducible CD4+FoxP3+ and CD4+ latency-associated peptide (LAP+) regulatory T cells in the spleen, inguinal and mesenteric lymph nodes, as well as in the spinal cord. In addition, a reduction in the recruitment of encephalitogenic CD4+ T cells to the spinal cord was observed, which decreased IgG response against HSP65 and induced an anti-inflammatory cytokine profile (IL-17 reduction and IL-10 increase) during EAE development.
\nThe oral administration of recombinant L. lactis expressing HSP65 and tandemly repeated P277 (pCYT:HSP65-6P277) was also analyzed in a model of type 1 diabetes mellitus (DM1) [183]. The authors observed that oral administration of recombinant L. Lactis resulted in the prevention of hyperglycemia, improved glucose tolerance and reduced insulitis, and induced HSP65- and P277-specific T-cell immunotolerance, as well as antigen-specific proliferation of splenocytes, demonstrating to be an effective therapeutic approach in preventing DM1 [183].
\nAnother study using the E. coli Nissle 1917 strain engineered to secrete N-acylphosphatidylethanolamines (NAPEs) (pDEST-At1g78690 expression plasmid) demonstrated that this strain was able to reduce the obesity of mice fed with a high-fat diet when added to drinking water. N-acyl phosphatidylethanolamines are precursors to the N-acylethanolamine (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reducing food intake and obesity. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis than mice receiving standard water or control bacteria [188]. In addition, it was observed that changes on intestinal microbiota significantly decreased the abundance of Firmicutes and increased the abundance of Proteobacteria. Thus, these results provide evidence of the potential efficacy of this approach to inhibit the development of metabolic disorders and related diseases.
\nCurrently the association between disease progression, especially chronic inflammatory diseases, and intestinal dysbiosis has been more frequently observed. As a clinical strategy, the use of probiotic bacteria, which naturally benefit the host, has been increasingly used on the treatment of diseases related to the GIT. In view of the good results obtained with this approach, researchers have sought through bacterial genetic modification to increase the beneficial potential of probiotics, either through their use for heterologous protein production or as a vehicle for vaccinal plasmid delivery, by developing recombinant bacterial strains and by testing their action in different disease models. And while there are still a number of questions that need to be answered about the use of genetically modified organisms for health care, especially in human, the use of these strains has proven to be a potentially effective therapeutic alternative, so much so that clinical trials using recombinant lineages have already been authorized and conducted in humans.
\nThe medical, economic and social impact of the dual epidemics of human immunodeficiency virus (HIV) and tuberculosis (TB) will continue to remain one of the biggest public health challenges of the twenty-first century. According to the World Health Organization (WHO) Global Status Report, 11% of 10.4 million new cases of TB in 2015 were HIV-positive [1]. This is an increase in the number of new TB cases from 9.2 million in 2014 [1]. Sixty percent of the new TB cases are reported from India, Indonesia, China, Nigeria, Pakistan and South Africa [1]. It has been difficult to rein in the TB epidemic, and there are many reasons for it. One of the main reasons for spread of TB in low TB/HIV burden countries is the reactivation of latent tuberculosis. In high TB/HIV burden countries, the main factors are lack of accessible health facilities where timely and effective treatment of TB can be given and the burgeoning numbers of drug-resistant TB cases. Another significant factor in the failure of TB control programmes in the developing countries has been the ongoing HIV epidemic. HIV-infected patients are at increased risk of new TB infection as well as reactivation of latent TB infection (LTBI). Prevention of reactivation TB in those with LTBI is now considered as one of the key strategies of TB prevention and is one of the pillars for the WHO “End TB Strategy” [1]. The WHO aims to implement LTBI detection and treatment in the 30 high-TB burden countries first. In these countries, it has set out an ambitious target of bringing 90% of children under 5 years who are TB contacts and PLHA under the chemoprophylaxis programme by 2025 [1]. Biostatistical modeling shows that if 8% of persons with latent tuberculosis could be permanently protected each year, the global incidence in 2050 would be 14 times lower than incidence in 2013, with no other intervention needed [2].
Latent tuberculosis infection (LTBI) is a state of persistent immune response to Mycobacterium tuberculosis (Mtb) antigens without evidence of clinically manifested active TB [3]. In simpler terms, LTBI is infection with viable bacilli of Mtb complex but without symptoms of the disease. LTBI has great public health significance because a significant proportion of these people can develop active TB and contribute to spread and persistence of TB in the population. About 2–3 billion people, that is, one-third of the world’s population, has TB infection but no TB disease. Among the people with LTBI, the lifetime risk of developing TB disease is 5–15% [4, 5, 6]. In HIV-infected, the annual risk of developing reactivation TB is 5–15% [7]. The risk is similar in people on anti-TNF-α therapy, patients on dialysis and those undergoing solid organ or hematological transplant [3]. Another similar high-risk group is that of children under 5 years of age who are household contacts of pulmonary TB cases [3].
Operational constraints and unfounded fears of increased incidence of drug-resistant TB have been the two main reasons for the poor implementation of LTBI programme in high-TB burden countries. Only 87,236 children under 5 years age who were household contacts of TB cases were initiated on TB chemoprophylaxis in 2015 [1]. The best chemoprophylaxis coverage was from the Americas (67%, range 63–71%) and European Region (42%, range 40–44%). In high TB or HIV/TB burden countries, the figures ranged from 2.6% in Cameroon to 41% in Malawi. These numbers belie the actual magnitude of the problem. The total number of children on TB chemoprophylaxis (87236) is only 7.1% (range 6.9–7.4%) of the 1.2 million children who are eligible for treatment. PLHA have a higher coverage with TB chemoprophylaxis, especially in the African region. In 2015, TB chemoprophylaxis was being offered to PLHA enrolling for HIV care in 57 countries. These countries represent 61% of the global TB burden. These data are encouraging because in 2014 there were only 49 countries where TB preventive treatment was available. South Africa, Malawi, Mozambique and Kenya have the largest number of PLHA on TB chemoprophylaxis. Much more needs to be done. Of the 30 high TB/HIV burden countries, no preventive treatment was available in 21 countries. Even in nine that did report so, coverage of people newly enrolled in HIV care varied from 2% in Indonesia to 79% in Malawi. The National AIDS Control Organization (NACO) in India issued new TB management guidelines in 2016 [8]. TB care has now been integrated into the services provided by the ART centres and isoniazid preventive therapy (IPT) has also been included in it [8].
Ninety percent of people infected with Mtb are able to successfully contain the microbe and ward of clinical disease. It should be realized that Mtb infection cannot be eradicated but only contained even in healthy immune-competent people and a key pathological mechanism in this is formation of tubercular granuloma.
Mtb infection occurs via the respiratory tract and on entry, mycobacteria encounter alveolar macrophages in the airways and immediately infect them. Macrophages can provide an intracellular sanctuary for mycobacteria, and Mtb has evolved numerous mechanisms to survive within macrophages. A characteristic set of pro-inflammatory cytokines and chemotactic factors for macrophages are released and cause granuloma formation. The granuloma is composed of various cells including macrophages, lymphocytes, dendritic cells, neutrophils, and sometimes fibroblasts, often with a necrotic centre. This structure serves to contain the bacilli and acts as an immune microenvironment that limits M tuberculosis replication. However, formation of a granuloma is not enough to control infection, as it has been seen that persons with active TB can have multiple granulomas in the lungs and possibly other tissues. Instead, granulomata must have optimal immunologic function to contain or eliminate the bacilli [9]. When they fail to do so, they release anti-inflammatory cytokines which aim to prevent tissue destruction but at the same time trigger fibrosis.
Structural or functional disruption of the granuloma is likely to lead to reactivation of latent M. tuberculosis infection, dissemination, and active disease [9]. Research in HIV-TB has given insight into some of the mechanisms involved in reactivation of TB [10]. The cause of disruption can be understood as general and overlapping processes, including increase in the HIV viral load within involved tissue, a reduced number of CD4 T cells, a defective macrophage function, and perturbation of Mtb-specific T-cell function [9]. They can all lead to detrimental changes within granulomas.
Depletion of CD4 cell population leads to an inability to mount an effective cell-mediated immune response against Mtb. Studies on macaques infected with simian immunodeficiency virus (SIV) have shown that reactivation of LTBI is directly associated with depletion of CD4+ T cells [10, 11, 12]. Critical decline in the number of CD4+ T cells is associated with a decrease in the number of memory CD4+ T cells (CD27+ CDRO45+) that can recognize Mtb antigens, decrease in polyfunctional antigen-specific CD4+ T cells and a relative increase in interferon gamma + CD 8+ T cells [10, 11, 12]. Other mechanisms include suppression of cell-mediated responses of regulatory T cells (Tregs) and impairment of TNF-α- mediated apoptosis of Mtb-infected cells [13].
Prior to putting people on chemoprophylaxis for LTBI, active TB has to be first excluded by standard case finding methods. Latent tuberculosis infection (LTBI) is most often diagnosed by the tuberculin skin test (TST), and the Mantoux TST is the standard method of determining Mycobacterium tuberculosis infection. This test is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) (equivalent to 1 TU of PPD RT 23 or 2.5 TU of PPD- S) into the inner surface of the forearm. In India, PPD-RT 23 with Tween 80 of strength 1 TU and 2 TU are standardized tuberculins available which is supplied by the Bacillus Calmette-Guérin (BCG) vaccine Laboratory, Guindy, Chennai. CDC recommended strength is 5 TU of PPD-S. The injection is given intradermally with a tuberculin syringe, with the needle bevel facing upward. The injection should produce a pale wheal 6–10 mm in diameter and the skin test reaction should be read between 48 and 72 hours after administration. The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling) across the forearm (perpendicular to the long axis) and not the erythema (redness).
Classification of positive TST results
Induration size/Patient profile | ≥5 mm | ≥10 mm | ≥15 mm |
---|---|---|---|
HIV-infected persons
|
| Any person, including persons with no known risk factors for TB |
In interpreting a positive TST, it is important to consider much more than only the size of the induration. Rather, the TST should be considered according to three dimensions: size of induration, pre-test probability of infection and risk of disease if the person were truly infected [14]. There are two important causes of false-positive results: nontuberculous mycobacterial (NTM) infection and prior BCG vaccination [15]. NTMs are not a clinically important cause of false-positive TST results, except in populations with a high prevalence of NTM sensitization and a very low prevalence of TB infection [15]. The impact of BCG on TST specificity depends on when BCG is given and on how many doses are administered. If BCG is administered at birth or infancy and not repeated, then its impact on TST specificity is minimal and can be ignored while interpreting the results [15]. In contrast, if BCG is given after infancy (e.g., school entry) and/or given multiple times (i.e., booster shots), then TST specificity is compromised [15].
Tuberculin skin tests are subject to variability when repeated tuberculin tests are given. Chance variation should result in differences of less than 6 mm (representing two standard deviations) in 95% of subjects. This supports the adoption of 6 mm as a criterion to distinguish increases in reaction size due to random variation alone from true biologic phenomena, which could be either conversion or boosting [16]. Boosting is best distinguished from conversion on clinical grounds. One can attribute an increase in reaction size to boosting when the increase in reaction is seen after an interval of 1–5 weeks during which there has been no possibility of exposure, such as pre-employment testing of a health care worker [16]. Conversion can be confidently stated to have occurred when a previously tuberculin-negative individual becomes tuberculin test positive after receiving BCG vaccination, or following significant exposure such as during an outbreak or as a result of close contact with a highly contagious index case [17, 18]. Among subjects vaccinated in infancy, and tested after an interval of 5 years or more, prevalence of initial tuberculin reactions is the same in vaccinated and unvaccinated reference populations but prevalence of boosting was 7% higher in vaccinated than unvaccinated [19].
The other method of detecting LTBI is based on IFNγ release assays (IGRA). These tests detect a set of Mtb genes that are present in Mtb complex but not present in BCG immunized or in a setting of NTM infection. In this test, the sera of patients is incubated with Mtb specific T lymphocytes. The T cells respond to Mtb-specific gene products by secretion of pro-inflammatory cytokines that are detected. Two IGRAs are commercially available today. QuantiFERON-Gold In Tube test (QFT; Germany) uses whole blood and is ELISA based. The T-SPOT.TB test (Oxford Immunotec, Abingdon, UK) uses peripheral blood mononucleated cell (PBMC) and ELISPOT technique. Both IGRAs incorporate the region of difference 1 (RD1)-encoded 6 kDa early secretory antigenic target (ESAT-6) and 10 kDa culture filtrate protein (CFP10) antigens, whereas an additional single peptide from TB7.7, encoded in RD11, is added to the QFT [20]. The selections of antigens for these tests are critical. Natural immunity to M. tuberculosis is highly individual, multi-epitopic and multiantigenic, and more than 80 antigens are necessary to capture 80% of the MTB-specific T-cell response [21]. The currently used antigens ESAT-6, CFP10 and TB7.7 were selected for their high immunogenicity and specificity for M. tuberculosis infection, not for their predictive potential. ESAT-6 is considered among the most immunogenic proteins, but it has a drawback when used to detect LTBI. It is secreted through the entire spectrum of latency and also in active stages of the infection. Therefore, disease stage-specific diagnosis is impossible using ESAT-6 [22].
Various studies have evaluated the utility of IGRAs and TST. A study from Turkey published in 2007 seems relevant to countries like India as Turkey is also a country with high prevalence of TB and high BCG vaccination coverage [23]. The workers compared TST with QuantiFERON®-TB in three population groups: household contacts of smear-positive TB cases, community members who had been exposed to index smear-positive TB cases and healthcare workers dealing with TB cases or handling TB specimens. They did a Kappa analysis to look for agreement between the tests. They found that QuantiFERON®-TB values were higher in the first group of patients when compared to the other two groups. In case of TST, there was no difference among the three groups. Evaluation for agreement rates between the groups showed poor agreement in all three groups. The authors concluded that while Quantiferon Gold was more objective, practical and gave quantitative values, it was more expensive and required a well-equipped laboratory and thus did not have a programmatic role in detection of LTBI in a country will high TB prevalence and high BCG coverage [23].
In a Japanese study, the specificity of IGRA was studied in healthy low-risk individuals with history of BCG vaccination [24]. It was seen that TST was positive (≥ 10 mm) in 64.6% (specificity 35.4%) while QuantiFERON®-TB test was positive in 1.9% (specificity 98.1%,) [24]. Similar results were obtained in another study done in Korea [25].In this study, 273 participants were included, 220 (95.7%) had received BCG vaccine. Participants were grouped according to their risk of infection: group 1, no identifiable risk of M. tuberculosis infection (n = 99); group 2, recent casual contacts (n = 72); group 3, recent close contacts (n = 48); group 4, bacteriologically or pathologically confirmed TB patients (n = 54). They studied the levels of agreement between the TST and the IFN-gamma assay and the likelihood of infection in the various groups and found out that the overall agreement between the TST and the IFN-gamma assay in healthy volunteers was a kappa value of 0.16. The odds of a positive test result per unit increase in exposure across the four groups increased by a factor of 5.31 (95% confidence interval [CI], 3.62–7.79) for the IFN-gamma assay and by a factor of 1.52 (95% CI, 1.20–1.91) for the TST (P < .001). In another study of 590 HIV-infected patients, QuantiFERON® -TB Gold test correlated with known risk factors for LTBI or past history of TB [26].
Both TST and IGRAs are acceptable but imperfect LTBI tests, with advantages and disadvantages [27]. In some situations, neither test is appropriate (e.g., active TB diagnosis in adults) and in some situations, both the tests may be necessary to detect M. tuberculosis infection (e.g., immunocompromised populations), and there are situations where one test may be preferable to another. For example, IGRAs may be preferable to the TST in populations where BCG is given after infancy or given multiple times. In contrast, TST may be preferable to the IGRAs for serial testing of health care workers. Both TST and IGRAs have reproducibility challenges, and dichotomous cut-offs are inadequate for interpretation [27]. The ability of tuberculin skin tests and IGRAs to identify persons at highest risk of progressing to active tuberculosis is poor. Neither test reliably predicts future disease among persons with positive tests nor do strongly positive tests mean a higher risk. In one meta-analysis, the pooled positive predictive value for progression to active tuberculosis was 2.7% (95% confidence interval [CI], 2.3–3.2) for IGRAs and 1.5% (95% CI, 1.2–1.7) for the tuberculin skin test [28]. A meta-analysis of only longitudinal studies of IGRAs, with a median follow-up of 4 years, showed a moderate association between positive tests and subsequent tuberculosis (unadjusted incidence ratio, 2.10 [95% CI, 1.42–3.08]) [29]. The other limitations of these tests are inability to distinguish reactivation from reinfection, reduced accuracy in immunocompromised patients, and inability to discriminate the various stages within the spectrum of LTBI [30]. To maximize the positive predictive value of existing LTBI tests, LTBI screening should be reserved only for those who are at sufficiently high risk of progressing to disease. The recommendations for systematic testing for LTBI as per WHO 2015 guidelines are as follows [31]:
Population groups | Test | Quality of recommendation |
---|---|---|
PLHA, child contacts of TB cases, patients being initiated on anti-TNF treatment, patients receiving dialysis, patients preparing for organ/haemotologic transplant and patients of silicosis | IGRA/TST | Strong recommendation, low/very low quality evidence |
Prisoners, health-care workers, immigrants from high TB-burden countries, homeless persons and illicit drug users | IGRA/TST | Conditional recommendation, low/very low quality evidence |
In the long term, highly predictive biomarkers need to be identified. This is an active area of research, and future generations of LTBI tests should overcome the limitations of current assays. A great endeavor is on to discover reliable, low-cost biomarkers. Gene signatures can distinguish between active and latent TB [32]. A lot of works have been done to identify differential expression of cytokines and chemokines in active TB and LTBI. It has been shown that plasma levels of the CXC chemokine IP-10 and soluble TNF receptor type 2 (sTNFr2) can significantly differentiate active TB from the LTBI group, irrespective of HIV status [33]. Another study showed that serum IL-2, IL-9, IL-13, IL-17, TNF-α, sCD40L and VEGF-A levels may be adjunctive biomarkers for differential diagnosis of active TB, LTBI, and NTM disease [34]. Assessment of serum sCD40L and Mtb antigen-specific IFN-γ, TNF-α, and IL-2 levels could also help predict successful anti-TB treatment in conjunction with Mtb clearance [31]. Achkar et al. looked at biomarkers to distinguish active TB and LTBI from no TB infection in HIV positive and negative populations [35]. They did so because inflammatory response and repair are both blunted in PLHA. They identified a set of biomarkers which reliably predict active TB. The biomarkers identified are shown in Table 1 [32]:
Functional category | HIV-Positive TB | HIV-Negative TB |
---|---|---|
Immune response | CD14, SEPP1, SELL | CD14, SEPP1, PGL YR P2 |
Tissue development & repair | TNXB, LUM, PEPD, QSOX1, COMP | PFN1, VASN |
Lipid metabolism | APOC1 | |
Other | GP1BA | CPN2, TAGLN2, IGFBP6 |
Newer biomarkers for diagnosis of active TB.
SEPP, selenoprotein P; SELL, selectin L; TNXB, tenascin XB; LUM, lumican; PEPD-peptidase D; QSOX1, quiescin sulfhydryl oxidase 1; COMP, cartilage oligomeric matrix protein; APOC1, apolipoprotein C-I; GP1 BA-glycoprotein 1 BA; VASN, vasorin; PFN 1, profilin1; CPN 2, chaperon 2; TAGLN2, transgelin 2; IGFBP 6, insulin-like growth factor binding protein 6; PGLYRP2, peptidoglycan recognition protein 2.
Treatment of LTBI reduces the risk for active disease and hence various authorities have recommended treatment for this entity. Chemoprophylaxis for LTBI can prevent 60–90% of reactivation TB [36]. But chemoprophylaxis cannot be considered as a universal approach due to the inherent toxicity of all TB drugs. However, in vulnerable populations, the benefits far outweigh the risks [33].
The International Union against Tuberculosis (IUAT) trial, conducted in Eastern Europe, randomized approximately 28,000 individuals with positive tuberculin skin tests (TST) and fibronodular changes on chest X-ray [37]. Approximately 7000 participants each were randomized to placebo, 3, 6 or 12 months of INH. Compared to participants who took placebo, participants who completed 3 months INH had 31% reduction in TB; those who completed 6 months INH (6INH) 69% reduction and the subjects who completed 12 months INH (12INH) had 93% reduction in TB. The efficacy of 6INH and 12INH waned during 5 years of follow-up but remained significantly better than the placebo. It is to be noted that fewer people completed 12 INH regimens as compared to 6INH [34].
Concerns regarding the relatively low efficacy of 6INH, and equally serious concerns regarding the poor completion of 12INH resulted in recommendations for 9 months INH by the American Thoracic Society in 2000 [38]. The optimal duration of INH was recommended as 9 months, with estimated efficacy of 90% and no significant gain with extension to 12 months [35].
In another trial, in Hong Kong, people who had pulmonary silicosis with a positive TST were randomized to placebo, 6INH, 3 m INH + Rifampin, or 3 m Rifampin alone [39]. During 5 years of follow-up, 27% of those randomized to placebo arm developed active TB, compared to 16, 13, and 10% for the three regimens respectively [36]. The estimated effectiveness of 3-months rifampin was approximately 65%; this was better than the other regimens although the differences between active regimens were not significant, and all were significantly better than placebo [36].
A series of randomized trials have demonstrated that the efficacy of 3-4INH + RIF to be equivalent to that of 6INH (four studies) or 9INH (one study) although adverse events are significantly more frequent [40, 41].
For adults, the recommended duration of treatment is at least 6, and preferably 9, months. Children younger than 18 years and persons with HIV infection should be treated for 9 months [42]. In HIV TB setting, IPT has been shown to slow the progression to active disease. A Cochrane systematic review of 12 trials, published in 2010 among 8578 patients showed that IPT reduced the risk of active TB by 64% among TST positive HIV-infected participants [43]. WHO has recommended that in resource-limited countries and other middle-income countries, people living with HIV and children below 5 years of age who are household or close contacts of people with TB and who, after an appropriate clinical evaluation, are found not to have active TB but have LTBI should be treated. WHO has recommended the following regimens for the treatment of LTBI which are similar to current CDC guidelines [26, 44, 45, 46].
The 9-month regimen with isoniazid is preferred because it is more efficacious. However, treatment of LTBI for 6 months rather than 9 months may be more cost-effective and result in greater adherence by patients.
Regimen | Dose isoniazid | Dose rifapentine or rifampicin | Maximum dose |
---|---|---|---|
6 m or 9 m isoniazid daily | Adults = 5 mg/kg Children = 10 mg/kg | isoniazid - 300 mg | |
3 m rifapentine + isoniazid weekly | Adults & children isoniazid - 15 mg/kg | Rifapentine (wt band): 10.0–14.0 kg = 300 mg; 14.1–25.0 kg = 450 mg; 25.1–32.0 kg = 600 mg; 32.1–49.9 kg = 750 mg; ≥50.0 kg = 900 mg | isoniazid - 900 mg Rifapentine - 900 mg |
3 or 4 m isoniazid + rifampicin daily | Isoniazid: Adults - 5 mg/kg Children - 10 mg/kg | Rifampicin: Adults & children - 10 mg/kg | isoniazid-300 mg Rifampicin - 600 mg |
3 or 4 m rifampicin alone daily | Adults & children 10 mg/kg | Rifampicin - 600 mg |
Directly observed once-weekly regimen of isoniazid and rifapentine is recommended as an option equal to the standard INH 9-month daily regimen for treating LTBI. The regimen may be used in otherwise healthy HIV-infected persons, 12 years of age and older, who are not on antiretroviral medications. It may also be considered for children aged 2–11 years if completion of 9 months of INH is unlikely and hazard of TB disease is great.
The regimen using 4 months of rifampicin can be considered for persons who cannot tolerate INH or who have been exposed to INH-resistant TB. It should also not be used to treat HIV-infected persons taking some combinations of ART especially protease inhibitors.
The National Aids Control Organization guidelines for LTBI in PLHA published in 2016 recommends the following strategy [8]
Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered Isoniazid Preventive Therapy (IPT).
Children living with HIV (more than 12 months of age) who do not report poor weight gain, fever, current cough or history of contact with a TB case, are unlikely to have active TB and should be offered IPT.
Additional investigations will help in ruling out active TB (X-ray chest and tuberculin skin test) but are not mandatory.
The treatment recommended in adult and adolescent is Isoniazid 300 mg + Pyridoxine 50 mg (Vitamin B6) per day for 6 months and for children above 12 months is Isoniazid 10 mg/kg + Pyridoxine 25 mg (Vitamin B6) per day for 6 months.
Treatment of close contacts of drug-resistant active TB cases is difficult and yet is an increasingly common clinical problem. For contacts of INH-resistant index cases, INH will be ineffective, so 4RIF is recommended [47, 48].
In a prospective study, two of 41 children receiving tailored preventive therapy developed TB (confirmed and probable TB) compared to 13 of 64 children not receiving preventive treatment (OR 0.2, 95% CI 0.04–0.94) [49]. However, WHO has not recommended any form of preventive therapy for MDR contact cases. Based on the available evidence and the probability of increased likelihood to develop active TB disease following recent infection, strict clinical observation and close monitoring for the development of active TB disease for at least 2 years is preferred over the provision of preventive treatment for contacts of MDR-TB cases [1].
Clinical management of latent tuberculosis infection should also address such concomitant risk factors as illicit-drug use, alcohol abuse, and smoking through opioid-substitution treatment and counseling about alcohol and smoking cessation, respectively. Acceptance of and adherence to the full course of latent tuberculosis treatment must be encouraged. In a study conducted in the United States and Canada, 17% of persons who were offered treatment for latent infection refused it [1]. Treatment completion varies widely (from 19 to 96%), and the reasons for non-completion need to be fully assessed [1]. The use of various incentives to promote treatment initiation and adherence, depending on the specific need of the person being treated, should be considered. Peer education, counseling, people-friendly services, and properly trained service providers boost confidence and may improve adherence to treatment [1].
The lengthy duration of treatment reduces patient compliance, while the potential occurrence of serious adverse events such as hepatitis, further discourages patients’ and providers’ acceptance of this therapy [50, 51, 52].
INH has the major disadvantage of potential serious adverse events. Of particular concern is hepatotoxicity, as this is difficult to detect, and can be fatal. Surveillance studies have confirmed that hepatotoxicity is quite common in patients taking INH and can be severe resulting in up to 1 per cent mortality in older patients [53].The relative risk for developing hepatotoxicity associated with isoniazid compared with placebo were 3.45 (95% CI, 1.49–7.99) for 12 weeks of treatment, 4.59 (95% CI, 2.03–10.39) for 24 weeks of treatment, and 6.21 (95% CI, 2.79–13.79) for 52 weeks of treatment in the IUAT trial [34].
In another randomized trial, rates of grade 3 and 4 adverse events were significantly lower with 4RIF than 9INH [54]. Grade 3–4 hepatotoxicity occurred in 4% of patients taking 9INH compared to less than 1% in those taking 4RIF [54].
Comparison of drug toxicity of INH and Rifampicin has been studied in many trials. Rates of hepatotoxicity among patients receiving isoniazid were 5.2, 3.7, 34 and 11.4% compared to rates among patients treated with rifampicin (0.0, 0.7 and 4.4%, respectively) [55, 56].
In PREVENT TB study, rates of grade 3 and 4 hepatotoxicity were 4.9 and 1.0% in the rifapentine plus isoniazid arm and 5.5 and 1.1% in the isoniazid-only arm, respectively [57]. The RR for grade 3 or 4 hepatotoxicity was 0.90 (95% CI, 0.75–1.08). Mortality from hepatotoxicity was reported to be 1.0% among patients on isoniazid and 0.8% on those on isoniazid plus rifapentine (RR, 0.83 [95% CI, 0.51–1.35]) [57]. Therefore, unless the index TB case has INH-resistant TB or an abbreviated regimen is required in a special situation, there is no reason not to use INH for LTBI chemoprophylaxis.
Identification and early chemoprophylaxis for LTBI can prevent reactivation TB and thus reduce both TB morbidity and transmission of TB in the community. In low TB-burden countries LTBI detection and IPT are important strategies for TB eradication. Diagnosis of LTBI is based on either TST or TB IGRA. The test preferred usually depends on the financial support available for public health programmes. In high TB- burden countries, LTBI detection and treatment can contribute to decreasing TB burden and transmission and also emergence of drug resistant TB. Here the guidelines are pretty straightforward and IPT should be offered to all children less than 5 years who have contact with pulmonary TB cases or HIV-positive individuals. INH is the preferred drug for LTBI and a 9-month regimen is considered optimal. However, careful clinical monitoring is required to detect drug induced liver injury early and also to ensure adherence to therapy. Clinical trials in different parts of the world have shown that this effort is worth it.
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I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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