Specific Humoral Immunity versus Polyclonal B Cell Activation in Trypanosoma cruzi Infection of Susceptible and Resistant Mice

Abstract

BackgroundThe etiologic agent of Chagas Disease is Trypanosoma cruzi. Acute infection results in patent parasitemia and polyclonal lymphocyte activation. Polyclonal B cell activation associated with hypergammaglobulinemia and delayed specific humoral immunity has been reported during T. cruzi infection in experimental mouse models. Based on preliminary data from our laboratory we hypothesized that variances in susceptibility to T. cruzi infections in murine strains is related to differences in the ability to mount parasite-specific humoral responses rather than polyclonal B cell activation during acute infection.Methodology/Principal FindingsRelatively susceptible Balb/c and resistant C57Bl/6 mice were inoculated with doses of parasite that led to similar timing and magnitude of initial parasitemia. Longitudinal analysis of parasite-specific and total circulating antibody levels during acute infection demonstrated that C57Bl/6 mice developed parasite-specific antibody responses by 2 weeks post-infection with little evidence of polyclonal B cell activation. The humoral response in C57Bl/6 mice was associated with differential activation of B cells and expansion of splenic CD21highCD23low Marginal Zone (MZ) like B cells that coincided with parasite-specific antibody secreting cell (ASC) development in the spleen. In contrast, susceptible Balb/c mice demonstrated early activation of B cells and early expansion of MZ B cells that preceded high levels of ASC without apparent parasite-specific ASC formation. Cytokine analysis demonstrated that the specific humoral response in the resistant C57Bl/6 mice was associated with early T-cell helper type 1 (Th1) cytokine response, whereas polyclonal B cell activation in the susceptible Balb/c mice was associated with sustained Th2 responses and delayed Th1 cytokine production. The effect of Th cell bias was further demonstrated by differential total and parasite-specific antibody isotype responses in susceptible versus resistant mice. T cell activation and expansion were associated with parasite-specific humoral responses in the resistant C57Bl/6 mice.Conclusions/SignificanceThe results of this study indicate that resistant C57Bl/6 mice had improved parasite-specific humoral responses that were associated with decreased polyclonal B cell activation. In general, Th2 cytokine responses are associated with improved antibody response. But in the context of parasite infection, this study shows that Th2 cytokine responses were associated with amplified polyclonal B cell activation and diminished specific humoral immunity. These results demonstrate that polyclonal B cell activation during acute experimental Chagas disease is not a generalized response and suggest that the nature of humoral immunity during T. cruzi infection contributes to host susceptibility.

Curcumin Enhances the Anti-Trypanosoma cruzi Activity of Benznidazole-Based Chemotherapy in Acute Experimental Chagas Disease

“…In the present study, treatment with Bz, especially when combined with curcumin, caused a remarkable reduction in serum reactivity for both IgG1 and IgG2a isotypes. Although the production of IgG2a is predominant in the humoral response against T. cruzi, similar lytic activities of IgG2a and IgG1 have been previously reported; these antibodies have been shown to be the major effector molecules that control parasitemia (37,42). However, high IgG1 levels are not always beneficial to the host, since IgG1 can block the activities of different isotypes of anti-T. cruzi antibodies through cross-linking with irrelevant antigens in the defense against the parasite, thus deflecting humoral immunity toward a nonspecific and ineffective response (37,43).…”

“…Previous studies showed that although early treatment with Bz is effective at eliminating parasitemia, parasitological cure is not always achieved due to the presence of T. cruzi reservoirs resistant to chemotherapy, which are distributed throughout multiple organs and tissues (35,36). Thus, there is evidence that the efficiency of etiological treatment is directly influenced by multiple factors, especially the variable profiles of resistance to infection observed in different mouse strains (28,37), parasite virulence, and the different sensitivities of T. cruzi strains to Bz (9,38). All these factors represent major challenges to the rational development of effective drugs or therapeutic regimens for the treatment of ChD.…”

Kinetics, subcellular localization, and contribution to parasite virulence of a Trypanosoma cruzi hybrid type A heme peroxidase ( Tc APx-CcP)

“…(five mice per group) with culture-derived trypomastigotes (1.5 × 10 7 trypomastigotes) from wt (CL-Brener strain) or TcAPx-CcP overexpressers. The different susceptibility of these murine models to acute T. cruzi infection was previously characterized (67). Blood trypomastigote count (parasitemia) was assayed on blood (3 μL) drawn from the tail tips of mice, and the number of trypomastigotes per 32 fields was recorded from fresh blood in Neubauer chambers under a microscope (400× magnification).…”

AKT Network of Genes and Impaired Myocardial Contractility During Murine Acute Chagasic Myocarditis

“…9 The increased mortality in Balb/c mice was not characterized by a more pronounced weight loss. However, weight loss is not always an accurate measure of morbidity in acutely infected mice, because loss of solid tissue mass can be masked by an increase in weight caused by fluid retention related to cardiac/renal functional impairment.…”

“…8 C57BL/6J and Balb/c strains of mice have been identified as differentially susceptible to infection with T. cruzi, 9,10 with C57BL/6J mice considered to be resistant and Balb/c mice considered to be susceptible. However, susceptibility has significant variability depending on the T. cruzi strain used.…”