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This review has addressed some of the mechanisms by which Leishmania escapes …
Biology Articles » Parasitology » Subversion Mechanisms by Which Leishmania Parasites Can Escape the Host Immune Response: a Signaling Point of View » Inhibition of macrophage functions
Sequestering itself insides the cells of the host allows Leishmania to escape many of the immune responses that would otherwise be directed against it. However, it is also necessary to inhibit numerous macrophage functions, particularly those involved in immune surveillance and macrophage activation, at either the protein or gene expression level. One study of 245 macrophage genes showed that 37% were repressed at least twofold following in vitro infection with amastigotes (18), although larger-scale microarray studies have suggested that promastigotes induce and repress to similar extents (26, 136). However, these studies, and our unpublished observations following infection in vivo, all show reduced expression of numerous genes with important roles in various immune, cell physiological, and signaling functions. We describe some of these functions, and how they are affected by Leishmania, in detail in the following paragraphs.
In contrast to mice deficient for NO production, mice deficient for the generation of ROI can ultimately control the infection, after an initial period of increased susceptibility (111), indicating that ROI play a less important role in parasite clearance. However, ROI generation is also inhibited by L. donovani infection (19, 117, 118). Inhibition appears to be dependent on the surface molecules LPG and gp63 (38, 148) and has been shown to involve abnormal PKC activity (118).
Some studies have shown that L. donovani inhibits antigen presentation by repressing major histocompatibility complex (MHC) class II gene expression, both basal and particularly following stimulation with IFN- (35, 133, 134). In contrast, macrophages infected with L. amazonensis have been shown to express normal levels of MHC class II (84, 124). Antigen presentation may be inhibited in this case by interfering with the loading of antigens onto MHC class II molecules (50, 124) or by sequestration of the MHC class II molecule and/or antigens within the phagolysosome (79, 85). De Souza Leao and colleagues demonstrated a third level of inhibition, at least for the case of L. amazonensis, when they observed direct endocytosis of MHC class II molecules by amastigotes themselves, followed by cysteine peptidase-dependent degradation (40). Consistent with the phagosomal location of the Leishmania, MHC class II appears to be more important than class I for resistance, although class I does have a role to play, at least in some situations (158). Mice defective in MHC class I presentation are resistant to infection with L. major, but MHC class II–/– mice are susceptible (68, 88).
Antigen presentation depends upon cellular communication through costimulatory molecules such as B7/CD28 and CD40/CD40L. It has been demonstrated that B7-1 of L. donovani-infected macrophages could not be further expressed in response to LPS stimulation (75) and that this inactivation process was prostaglandin dependent (137). It seems that inhibition of CD40/CD40L ligation is responsible for the absence of iNOS and macrophage microbicidal activities (72, 147) and that cure of L. major infection depends upon an active CD40/CD40L ligation (23, 62). Recent findings suggest that p38-dependent signaling triggered by CD40 interaction is altered in infected macrophages, and this may lead to diminished iNOS expression (2). In contrast, repression of MHC class II gene expression appears to involve a cyclic AMP-independent mechanism (83).
The capacity of Leishmania to infect macrophages without inducing proinflammatory cytokines, and then to inhibit their induction in response to various agonists, probably represents a survival mechanism whereby the parasites can inhibit a harmful inflammatory reaction. Nevertheless, these studies have been mainly performed in an in vitro context. Recent studies performed in vivo have clearly demonstrated that proinflammatory cytokines (IL-1, IL-6, and TNF-) as well as various chemokines, a family of cytokines responsible for recruitment of inflammatory cells to the site of infection, were induced in the early stages of L. donovani and L. major infection (98). Of interest is that L. major promastigotes were shown to be better activators of proinflammatory events than L. donovani, as shown by a greater, transient recruitment of inflammatory cells. This may reflect the different pathologies caused by the two strains. In addition, both species recruit a heterogeneous population of host inflammatory cells, including neutrophils and monocytes/macrophages (98). This is of particular interest from a host defense point of view, since neutrophils have been recently shown to be important for controlling L. major infection (46, 87).
The cytokine IL-12 plays a critical role in the regulation of cellular immune responses. It is essential for T-lymphocyte activation and subsequent IFN- secretion leading to macrophage activation and production of microbicidal molecules. It is therefore not surprising that Leishmania has developed the ability to inhibit IL-12 production. This has been shown for promastigotes of L. donovani and L. major (24), L. mexicana amastigotes (163), and the phosphoglycan portion of LPG (122) in vitro. IL-12 inhibition has been also reported to occur in L. major-infected mice (5). The intracellular mechanism is still unclear. Macrophage complement receptors and Fc receptor, which are known to interact with Leishmania during phagocytosis, have been shown to repress IL-12 (93, 152). Furthermore, Piedrafita et al. showed that L. major LPG-mediated IL-12 repression was independent of the NF-B transcription factor family, despite IL-12 being NF-B responsive (122). Instead, repression may result from increased ERK1/2 phosphorylation (44); however, that report is problematic, because it contrasts with the well-documented dephosphorylation of ERK during infection (discussed below). A very recent report has shown that the abilities of L. mexicana amastigotes to degrade NF-B and to repress IL-12 are both dependent on cysteine peptidase B activity (22). While this is purely correlative, there is no reason to assume that promastigotes of Old World species and New World amastigotes employ the same mechanisms, especially given that both species and developmental stages differ markedly in both cysteine protease and LPG type and expression.
TGF-ß production is induced by several Leishmania species in vitro and in vivo (reviewed in reference 13). Augmentation of TGF-ß secretion correlated with retarded iNOS expression and reduced NK cell activity in lymph nodes (140, 151). This is consistent with the idea that TGF-ß inhibits macrophage microbicidal action and the production of IFN- by NK cells, although the exact role of NK cells during leishmaniasis is somewhat controversial (74, 80, 90, 138, 139, 161). A recent study demonstrated that L. chagasi induces TGF-ß production in the immediate environment of the infected human macrophage, and this may permit the local inhibition of immune responses (51). Interestingly, at least for the case of L. chagasi, the increased production appears to be a result not of increased gene expression but of cleavage of pro-TGF-ß by amastigote cysteine proteases to produce active TGF-ß (51, 145). Interaction between the macrophage and phosphatidylserine motifs on the amastigote surface has also been proposed to trigger this induction (49).
IL-10 is another anti-inflammatory cytokine produced by Leishmania-infected macrophages in vitro, apparently via interaction with the Fc receptor (153). Its production may be responsible for the suppression of macrophage microbicidal activity involving NO, production of several cytokines (IL-1, IL-12, and TNF), and expression of costimulatory molecules such as B7-1/2 (reviewed in reference 32). Its importance in vivo is illustrated by the observation that transgenic mice constitutively expressing IL-10 are unable to control Leishmania infection (73). As for TGF-ß, IL-10 is apparently induced following recognition of amastigote surface phosphatidylserine residues by the macrophage (49).
Prostaglandin E2 (PGE2) seems to be generated by Leishmania-infected macrophages and to favor parasite survival and progression (43, 98, 131, 132). This arachidonic acid metabolite has been reported to cause inhibition of macrophage proliferation and to suppress production of TNF-, IL-1, and reactive oxygen intermediates (6). A recent study reports that PGE2 induction in L. donovani-infected macrophages depends upon PKC activation and cyclooxygenase-2 expression (98). Interestingly, one study has correlated increased visceralization of L. donovani in malnourished mice with increased PGE2 production in the lymph nodes (1).
It is therefore clear that Leishmania parasites are capable of modulating numerous macrophage functions in order to promote survival within the host. While we have seen that the parasite surface coat is responsible for triggering many of these effects, we have not directly addressed the intracellular mechanisms by which the signals are communicated. Some of the intracellular signaling pathways that are modulated by Leishmania are discussed in the next section.
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