Abstract
Cryptococcosis, caused by Cryptococcus neoformans, has been demonstrated to be controlled by T helper (Th)1 cells while Th2 cells are associated with fungal growth and dissemination. Although cryptococcal immunoreactive protein antigens were previously identified, their association with Th1 or Th2 immune responses was not provided. In mice, Th1-dependent IFN-γ induces the production of IgG2a, whereas the Th2 cytokine IL-4 stimulates the expression of IgG1 rendering each isotype an indicator of the underlying Th cell response. Therefore, we performed an immunoproteomic study that distinguishes Th1- and Th2-associated antigens by their reactivity with Th1-dependent IgG2a or Th2-dependent IgG1 antibodies in sera from C. neoformans-infected wild-type mice. We additionally analysed sera from Th2-prone IL-12-deficient and Th1-prone IL-4Rα-deficient mice extending the results found in wild-type mice. In total, ten, four, and three protein antigens associated with IgG1, IgG2a, or both isotypes, respectively, were identified. Th2-associated antigens represent promising candidates for development of immunotherapy regimens, whereas Th1-associated antigens may serve as candidates for vaccine development. In conclusion, this study points to intrinsic immunomodulatory effects of fungal antigens on the process of Th cell differentiation based on the identification of cryptococcal protein antigens specifically associated with Th1 or Th2 responses throughout mice of different genotypes.
Highlights
Cryptococcus neoformans, an encapsulated basidiomycetous yeast, is the main etiological agent of cryptococcosis, a systemic and potentially fatal fungal infection
Opposite, infected IL-4Rα-deficient mice showed a marked diminution in their Th2-associated B cell response, with no production of IgE and notably lower levels of total IgG1 compared to wild-type mice (Fig. 1a,b), consistent with previously published experiments[20]
Among all three groups of infected mice, production of total Th1-dependent IgG2a was determined to be lower in IL-12deficient mice, while IL-4Rα-deficient mice produced the highest levels of this IgG isotype, without statistical significance (Fig. 1c)
Summary
Cryptococcus neoformans, an encapsulated basidiomycetous yeast, is the main etiological agent of cryptococcosis, a systemic and potentially fatal fungal infection. Immunoreactive proteins of C. gattii, the closest related species to C. neoformans and the second most common etiological agent of cryptococcosis, have been identified using antibodies from sera of naturally infected koalas[15] Those studies lack the specific discrimination between immunoprotective and immunopathologic properties of the antigen that are associated with either a Th1 or a Th2 response. The proteomic approach allows separating the cellular proteins and the identification of immunoglobulins binding specific antigens[19] Using this technique, distinct Th2- and Th1-associated fungal proteins were identified which are likely to play a role in shaping the Th cell response to C. neoformans and may be used for development of anti-fungal immunotherapy or vaccination regimens
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