Abstract
BackgroundBam32, a 32 kDa adaptor molecule, plays important role in B cell receptor signalling, T cell receptor signalling and antibody affinity maturation in germinal centres. Since antibodies against trypanosome variant surface glycoproteins (VSG) are critically important for control of parasitemia, we hypothesized that Bam32 deficient (Bam32-/-) mice would be susceptible to T. congolense infection.Methodology/Principal FindingsWe found that T. congolense-infected Bam32-/- mice successfully control the first wave of parasitemia but then fail to control subsequent waves and ultimately succumb to their infection unlike wild type (WT) C57BL6 mice which are relatively resistant. Although infected Bam32-/- mice had significantly higher hepatomegaly and splenomegaly, their serum AST and ALT levels were not different, suggesting that increased liver pathology may not be responsible for the increased susceptibility of Bam32-/- mice to T. congolense. Using direct ex vivo flow cytometry and ELISA, we show that CD4+ T cells from infected Bam32-/- mice produced significantly increased amounts of disease-exacerbating proinflammatory cytokines (including IFN-γ, TNF-α and IL-6). However, the percentages of regulatory T cells and IL-10-producing CD4+ cells were similar in infected WT and Bam32-/- mice. While serum levels of parasite-specific IgM antibodies were normal, the levels of parasite-specific IgG, (particularly IgG1 and IgG2a) were significantly lower in Bam32-/- mice throughout infection. This was associated with impaired germinal centre response in Bam32-/- mice despite increased numbers of T follicular helper (Tfh) cells. Adoptive transfer studies indicate that intrinsic B cell defect was responsible for the enhanced susceptibility of Bam32-/- mice to T. congolense infection.Conclusions/SignificanceCollectively, our data show that Bam32 is important for optimal anti-trypanosome IgG antibody response and suppression of disease-promoting proinflammatory cytokines and its deficiency leads to inability to control T. congolense infection in mice.
Highlights
African trypanosomiasis, called sleeping sickness in man, is a deadly disease of humans and livestock caused by blood parasites belonging to the genus Trypanosoma
We found that T. congolense-infected Bam32-/- mice successfully control the first wave of parasitemia but fail to control subsequent waves and succumb to their infection unlike wild type (WT) C57BL6 mice which are relatively resistant
We demonstrate that the B cell adaptor molecule, Bam32, contributes to optimum resistance to experimental T. congolense infection in mice because its deficiency negatively impacts optimal B cell responses including germinal centre formation and parasite-specific IgG responses in vivo
Summary
Called sleeping sickness in man, is a deadly disease of humans and livestock caused by blood parasites belonging to the genus Trypanosoma. The disease is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense; whereas the animal form of the disease is primarily caused by Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei brucei with T. congolense being the most important [1]. According to the World Health Organization (WHO) report, an estimated 60 million people are at risk of getting the infection with 300,000 cases of the disease occurring annually [2]. This is a gross under estimation because only about 10% of the cases are appropriately diagnosed and treated [2]. Since antibodies against trypanosome variant surface glycoproteins (VSG) are critically important for control of parasitemia, we hypothesized that Bam deficient (Bam32-/-) mice would be susceptible to T. congolense infection.
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