In visceral leishmaniasis, the draining LN (DLN) is the initial site for colonization and establishment of infection after intradermal transmission by the sand fly vector; however, little is known about the developing immune response within this site. Using an intradermal infection model, which allows for parasite visceralization, we have examined the ongoing immune responses in the DLN of BALB/c mice infected with Leishmania infantum. Although not unexpected, at early times post-infection there is a marked B-cell expansion in the DLN, which persists throughout infection. However, the characteristics of this response were of interest; as early as day 7 post-infection, polyclonal antibodies (TNP, OVA, chromatin) were observed and the levels appeared comparable to the specific anti-leishmania response. Although B-cell-deficient J h D BALB/c mice are relatively resistant to infection, neither B-cell-derived IL-10 nor B-cell antigen presentation appear to be primarily responsible for the elevated parasitemia. However, passive transfer and reconstitution of J h D BALB/c with secretory immunoglobulins, (IgM or IgG; specific or non-specific immune complexes) results in increased susceptibility to L. infantum infection. Further, J h D BALB/c mice transgenetically reconstituted to secrete IgM demonstrated exacerbated disease in comparison to WT BALB/c mice as early as 2 days post-infection. Evidence suggests that complement activation (generation of C5a) and signaling via the C5a receptor (CD88) is related to the disease exacerbation caused by IgM rather than cytokine levels (IL-10 or IFN-c). Overall these studies indicate that polyclonal B-cell activation, which is known to be associated with human visceral leishmaniasis, is an early and intrinsic characteristic of disease and may represent a target for therapeutic intervention.Key words: Antibody . C5a . Parasitic protozoan IntroductionVisceral leishmaniasis (VL) is a potentially fatal human disease caused by the intracellular protozoan parasites Leishmania donovani and L. infantum/L. chagasi. The immune response to VL is complex and has been shown to be organ-specific, differing significantly dependent upon the site of infection examined (liver versus spleen) [1,2]. Although the lymph node is thought to be analogous to the spleen, there are considerable developmental as well as structural and functional differences [3,4]. Reflective of this is the fact that although both spleens and lymph nodes from fatal human cases of VL exhibit destruction of normal architecture, follicular DC (FDC) and GC are lost in spleens, while continuing to be present in lymph nodes [5]. However, few Eur. J. Immunol. 2010. 40: 1355-1368 DOI 10.1002 Immunity to infection 1355 experimental studies to date have examined the lymph node responses that occur as a result of infection and have instead focused on the spleen where, akin to observations in humans, the destruction of FDC and GC is evident [6]. Although these observations in the spleen might appear to preclude a role for B cells in disea...
Hookworm infection is a major cause of anemia and malnutrition in resource-poor countries. Human and animal studies suggest that infection with these intestinal nematodes is associated with impaired cellular immunity, characterized by reduced lymphocyte proliferation in response to both parasite and heterologous antigens. We report here data from studies aimed at defining mechanisms through which hookworms modulate the host cellular immune response. Splenocytes and mesenteric lymph node (MLN) cells from hamsters infected with Ancylostoma ceylanicum showed minimal proliferation in response to mitogen at days 20 and 30 postinfection (p.i.), with partial recovery noted at day 70 p.i. The proliferative capacity of enriched splenocyte T-cell preparations from infected animals following stimulation with hookworm antigens was partially restored in the presence of antigen-presenting cells from uninfected hamsters. Analysis by fluorescence-activated cell sorting revealed that hookworm infection is associated with reduced percentages of both CD4؉ and surface immunoglobulin G-positive lymphocytes in the spleen and MLN cells. Splenocytes from infected hamsters also secreted more nitric oxide (NO) in culture than did those from naïve animals. Inhibition of NO secretion was associated with partial restoration of the proliferative capacity of splenocytes from infected animals in response to concanavalin A, suggesting a role for NO in mediating this effect. Together, these data demonstrate that hookworm infection is associated with impaired function of antigen-presenting cells and depletion of important lymphocyte subpopulations and also suggests a role for NO in parasite-induced immunosuppression.It is estimated that more than 700 million people in resourcepoor countries are infected with hookworms, bloodfeeding intestinal nematodes that cause anemia and malnutrition (8,14). Together with Ascaris lumbricoides and Trichuris trichiura, the hookworms Ancylostoma duodenale and Necator americanus comprise the group of soil-transmitted nematodes that are now recognized as a major cause of global morbidity (2, 56). Significant clinical features of hookworm infection in humans include irondeficiency anemia, hypoproteinemia, and growth delay (13, 53). Although control strategies relying on targeted delivery of benzimidazole antihelminthics are generally effective at eliminating adult worms, reinfection occurs quickly and frequent treatments may be necessary for sustained improvement in the health of at-risk populations (50,52).Although sterile immunity does not appear to develop following natural infection, data from human and animal studies confirm that hookworms elicit humoral and cellular immune responses in mammalian hosts (18). Although the nature of this response has yet to be elucidated fully, infection appears to be associated with a mixed Th1/Th2 host cytokine profile (22,49). It has also been reported that hookworm infection is associated with suppression of host cellular responses to hookworm-specific and heterologous antige...
SUMMARY Hookworm infection is associated with anaemia and malnutrition in many resource-limited countries. Ancylostoma hookworms have previously been shown to modulate host cellular immune responses through multiple mechanisms, including reduced mitogen-mediated lymphocyte proliferation, impaired antigen presentation/processing, and relative reductions in CD4+ T cells in the spleen and mesenteric lymph nodes. Syrian hamsters were depleted of CD4+ for up to 9 days following intraperitoneal injection (200 μg) of a murine anti-mouse CD4 monoclonal IgG (clone GK1·5). CD4+ T-cell-depleted hamsters infected with the hookworm Ancylostoma ceylanicum exhibited a threefold higher mean intestinal worm burden and more severe anaemia than animals that received isotype control IgG. In addition, depletion of CD4+ T cells was associated with impaired cellular and humoral (serum and mucosal) immune responses to hookworm antigens. These data demonstrate an effector role for CD4+ T cells in hookworm immunity and disease pathogenesis. Ultimately, these studies may yield important insights into the relationship between intestinal nematode infections and diseases that are associated with CD4+ T-cell depletion, including HIV.
Heterologous prime-boost vaccination employing DNA-vaccinia virus (VACV) modality using the Leishmania homologue of receptors for activated C kinase (LACK) (p36) antigen has been shown to elicit protective immunity against both murine cutaneous and visceral leishmaniasis. However, DNA priming is known to have limited efficacy; therefore in the current study the effect of NKT cell activation using a-galactosylceramide (aGalCer) during intradermal DNAp36 priming was examined. Vaccinated mice receiving aGalCer + DNAp36 followed by a boost with VVp36 appeared to be resolving their lesions and had at ten-to 20-fold higher reductions in parasite burdens. NKT cell activation during aGalCer + DNAp36 priming resulted in higher numbers of antigen-reactive effector CD4 + and CD8 + T cells producing granzyme and IFN-c, with lower levels of IL-10. Although immunodepletion studies indicate that both CD4 and CD8 T cells provide protection in the vaccinated mice, the contribution of CD4 + T cells was significantly increased in mice primed with DNAp36 together with aGalCer. Notably 5 months after boosting, mice vaccinated with DNAp36 + aGalCer continued to show sustained and heightened T cell immune responses. Thus, heterologous primeboost vaccination using aGalCer during priming is highly protective against murine cutaneous leishmaniasis, resulting in the heightened activation and development of CD4 and CD8 T cells (effector and memory T cells).
Most parasitic skin infections are averted by very efficient strategies of preventing pathogen invasion. Innate immune cells such as mast cells, macrophages and dendritic cells are responsible for detecting parasites and for recruiting proinflammatory cells that help to contain and control the pathogen at sites of infection. This induces efficient adaptive immunity, which is crucially important for parasite control. Using the example of cutaneous leishmaniasis, we highlight how the skin utilizes different strategies to prevent skin infection and how containment of the infection to the skin site may reduce the harm that otherwise may result for the entire organism.
Cutaneous leishmaniasis (CL) is endemic in Central Africa, including Cameroon. However, data on its prevalence and co-infection with HIV are scarce. Here we present the results of a large cross-sectional study reporting the prevalence, clinical features and species identification of CL and HIV co-infection in northern Cameroon. A total of 32 466 subjects were clinically screened for CL during a door-to-door survey, followed by parasitological diagnosis in the field laboratory. Amongst the subjects surveyed, 146 (0.4%) were diagnosed with active CL. Seven (4.8%) of these 146 CL patients tested positive for HIV-1 and/or HIV-2. The number of lesions per CL patient ranged from 1 to 20. Three of the five subjects with >10 active lesions were co-infected with HIV. In both CL and HIV co-infected subjects, three successful parasite isolates were identified as Leishmania major by PCR. This first report of L. major/HIV co-infection in Cameroon and Central Africa confirms the endemicity of CL in the region and highlights a worsened CL pathology in HIV co-infected individuals. These findings provide important data necessary for the development and implementation of successful control programmes against CL and HIV in this geographical area.
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