Abstract
The host’s ability to eradicate or control infection caused by intracellular pathogens depends on early interactions between these microorganisms and host cells. These events are related to the organism’s nature and stage of development and host immune status. Pathogens are recognized by host cells, which respond to infection by either mounting an efficient response or becoming a replication niche. Early interactions between the protozoan Leishmania parasite and host cell receptors activate different signaling pathways that can result in microbe elimination or, alternatively, infection establishment and the migration of Leishmania infected cells to other host tissues. This chapter focuses on Leishmania-macrophage interaction via phagocytosis, which involves a range of parasite ligands characteristic of Leishmania species and parasite stage of development and diverse host cell receptors. We also discuss alternative Leishmania entry by cell invasion and review how Leishmania spp. survive and replicate within the phagocytic compartment they induce.
Keywords
- Leishmania spp.
- early interactions
- parasite survival
- macrophage
- phagocytosis
1. Introduction
Leishmaniasis is a wide-ranging group of diseases caused by different species of
Clinical manifestations of Leishmaniasis are dependent on the infecting parasite species and host immune response [3]. The host’s ability to eradicate or control infection caused by intracellular pathogens depends on early interactions between these microorganisms and host cells. Firstly, pathogens are recognized by host cells, which either respond to infection by mounting an efficient response or becoming a replication niche. Early interactions between the protozoan
Macrophages are crucial in the host response to
2. General aspects of phagocytosis
Phagocytosis is a metabolism-dependent process involving the internalization of particulate material (>0.5 mm) by professional and non-professional phagocytes that can differentiate self from non-self, modified or damaged self-particles. It occurs in a series of distinct and complementary steps [6, 7]. Initially, when the phagocyte recognizes ligands of the particulate material by receptors on cellular membranes, occurs an increase in phosphatidyl bisphosphate (PIP2) levels, followed by a reduction in PIP2 mediated by the conversion of PIP2 to phosphatidyl triphosphate (PIP3) [8]. Next, PLCγ hydrolyzes PIP3 into diacylglycerol and inositol triphosphate (IP3) [9]. After the phagosome formation, maturation of this compartment by the acquisition of different proteins begins [10]. The parasite can promote changes in the kinetics of recruitment to the membrane and activation of these molecules, interfering with phagosome maturation and the microbicidal activity of macrophages [11].
The best-known receptors that induce the attachment and ingestion of different particles, opsonized or not, are those for the complement fractions (CR1 and CR3), those for the Fc region of antibodies (Fc RI, RII, and RIII), as well as the mannose and beta-glycan receptors involved in the recognition and phagocytosis of particles derived from yeast [12] or by circulating collectins and pentraxins [13]. In addition, microbial products defined by Medzhitov and Janeway in 1997 [14] as “pathogen-associated molecular patterns” (PAMPs) are recognized by pattern recognition receptors (PRRs), mainly the toll-like receptors (TLRs) [15] nod-like receptors [16] and dendritic cell receptors such as C-type lectins [17, 18]. The PRRs interplay between innate and adaptive immune responses by directly activating effector mechanisms and alerting the host organism to the presence of infectious agents, including the expression of a group of endogenous signals, such as inflammatory cytokines and chemokines [14, 19].
Like professional phagocytes, nonprofessional phagocytic cells have the machinery, cytoskeleton, and components for signal transduction necessary for phagocytosis [20]. Although intestinal epithelial cells and many nonprofessional cell lines phagocytose bacteria such as
The molecular processes involved in the uptake of particulate material have been well studied using particles opsonized by immunoglobulins (Ig) class G (IgG) and cells expressing a receptor for the Fc region of IgGs. This interaction results in the clustering of ligand-associated receptors on the phagocytic cell surface. The signaling steps leading to IgG engulfment of opsonized particles are also well studied. These steps comprise the recruitment and activation of kinases, phosphorylation of the cytosolic portion of the receptor, and stimulation of GTPases of the Rac and Cdc42 families, which cooperate with phosphatidyl bisphosphate promoting the stabilization of WASP family proteins. In turn, the WASP protein activates the Arp2/3 complex, promoting actin filaments polymerization, followed by the emission of pseudopodia around the particle [26]. The phagocytosed agent will be internalized in a vesicle called a phagosome. The phagosome will then fuse with lysosomes, forming the phagolysosome. Phagocytosis depends on a complex network of vesicle trafficking pathways that interconnect most intracellular compartments linked to the membrane and actin cytoskeleton and requires the use of a large amount of plasma membrane for pseudopod extension around the target particle [27].
3. Phagosome biogenesis
By analogy with the flow of substances through the endocytic pathway, it is most likely that the ligands present on the surface of particles or microorganisms contribute to the determination of particle destiny within the cell [28, 29]. In addition, the particles and microorganisms’ composition present in vacuoles determines both the nature of the vacuolar contents [30, 31] and the ability of the organelles to fuse with other vesicles of the endocytic pathway [32, 33].
Newly formed phagosomes undergo a maturation process from the plasma membrane, which comprises a series of modifications, usually leading to the internalized particle’s degradation [6]. In the past, biochemical analyses have been performed on phagosomes isolated and purified at different time points after uptake by antibody-fixed and antibody-coated staphylococcus aureus present in J774 macrophages. These studies revealed that changes in the protein composition of phagosomes are similar to those already identified during endosome maturation or for compartments successively formed during the internalization of soluble components. Identical to the maturation process of endosome compartments, the protein content within phagosomes is partly recycled and sorted. These organelles, probably by fusion with pre-lysosomes, produce a final compartment that presents at the membrane lysosomal glycoproteins, mannose-6 phosphate receptors, and the ATP-dependent proton pump [29]. The maturation of phagosomes containing IgG-opsonized particles has already been well described for the recognition process. This process involves the remodeling of membranes, gaining and losing proteins, and lipid markers during their biogenesis. These steps comprise acquisition of Rab5 with the participation of Rab20 [34]; acquisition of proton pump V-ATPases, with the release of protons in the phagosomes and acidification of the intracellular medium [35]; conversion of the membrane of the initial phagosome into a late one, due to the recruitment of some proteins such as Mon1-Ccz1 by Rab5, which by the action of guanine exchange factor (GEF) recruit and activate Rab7. The formation of phagolysosomes culminates in the fusion between late phagosomes with lysosomes [36, 37].
4. Host cell and Leishmania interactions during phagocytosis - binding molecules and internalization process
The contact of promastigote forms of
The first studies showing the interaction of infective promastigotes with macrophages were carried out in the 70s [41] and focused on the observation of the interaction of the parasite with its host cell from the very first moments of interaction until its complete internalization, passing by all intermediate stages of parasite uptake. These studies carried out using scanning electron microscopy also showed, in a pioneering way, that the phagocytosis seems to start preferentially by the tip of the parasite’s flagellum. Although parasites could be found being phagocytosed by the cell body, the flagellum appears to be the preferred portion to trigger the internalization process. The promastigote flagellum is an anterior structure, extremely active and motile, towards which the parasite moves its body. Interestingly, and due to these morphological characteristics, there is an increasing debate proposing that the promastigote flagellum is, in fact, a sensory structure and that it is probably the first portion of the parasite to interact with host cells. When macrophages were treated with cytochalasin-D, a potent phagocytosis inhibitor, about 75% of the infection was blocked [42].
Given that 25% of the cells continued to be infected even with the drug treatment, these data showed the importance of phagocytosis as a way of invasion. Furthermore, they pointed to alternative routes of infection yet to be explored. As discussed below, we now know that these parasites can penetrate cells also through non-phagocytic pathways.
The internalization process of the
In addition to classical phagocytosis receptors, PRRs also participate in the interaction of
5. A non-phagocytic route of invasion for Leishmania spp.
The fact that
6. Establishment of Leishmania within host cell intracellular compartments
Phagolysosome biogenesis, also known as phagosome maturation, is a highly regulated membrane traffic process essential for pathogen intracellular fate, survival or intracellular death and degradation, and antigen processing presentation by professional phagocytes [78, 79]. This maturation process results from sequential fusion events between phagosomes and compartments of the endocytic pathway. Classical cell biology studies have revealed several aspects of the biogenesis of
For pathogens that live in intracellular compartments, the process of phagosome maturation does not necessarily follow the steps described for other particles. Once internalized, several microorganisms, including protozoa and bacteria, are adapted to live at least one phase of their life cycle inside host cells. It has been described at least three strategies adopted by different pathogens to evade the defense mechanisms developed by the host following infection. Some microorganisms induce the formation of vacuoles that do not acidify [84]. Other pathogens are phagocytosed and settle in acidified compartments from which they then escape to live in the cytoplasm of the host cell. The last group is formed by organisms adapted to survive in the phagolysosomes of the host cell, which is the case of
After being recognized by receptors in the host cell surface,
Despite similar characteristics among
7. Macrophage effector mechanisms, parasite replication and infection amplification
Once internalized within the parasitophorous vacuoles, the amastigotes multiply by binary fission, facilitating infection amplification, and persistence in the mammalian host (Figure 4). It is commonly assumed that amastigotes are released after host cell burst, which could be occasioned by the burden imposed by the unrestrained replication of the parasite. However, this is still an unproven hypothesis. Thus, the process of infection amplification during leishmaniasis is still a black box. Therefore, our knowledge about the mechanisms that lead to infection amplification during
As mentioned earlier, cell disruption with the release of amastigotes into the extracellular environment has never been demonstrated despite being often assumed to be a mechanism of amastigote spread. On the other hand, it is entirely plausible to hypothesize that the amplification of infection in leishmaniasis occurs by the ingestion of apoptotic bodies of dead infected macrophages by new macrophages. This is even more logical if we consider that the clearance of dead cells is one of the leading roles these phagocytes play in tissue remodeling. This lack of knowledge about whether amastigotes are released extracellularly is also reflected in the few studies approaching cell invasion by free amastigotes [107, 108, 109].
Still, it is necessary to emphasize that other mechanisms have also been proposed regarding the infection amplification process.
The dissemination of infected cells containing
In leishmaniasis, macrophages function as a replicative niche for
8. Conclusions
Undoubtedly,
Acknowledgments
This work was supported by grants from the Bahia State Research Support Foundation (FAPESB) and FAPEMIG; PSTV holds a grant (305235/2019-2) from National Council for Scientific and Technological Development (CNPq). PSTV and JPBMF are professors from PGPAT and PGBSMI financed by Higher Education Personnel Council–Brazil (CAPES)—Finance Code 001.
We thank Prof. Jane Lima-Santos for kindly providing the infected macrophage image.
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