Secreted fungal proteins in immune evasion and pathogenicity

The fungal pathogens C. albicans and A. fumigatus secret immune evasion proteins to control the immune response of the human host. In project C6, we characterize the role of secreted fungal proteins in immune evasion. Both fungal pathogens use related proteins like Pra1 (C. albicans) and Aspf2 (the Pra1 homolog of A. fumigatus) to bind host regulators and plasminogen. Plasminogen attached to either the purified proteins or to the fungal pathogens is accessible for activators and can be converted to the active protease plasmin. Active plasmin then damages host endothelial and epithelial cells and induces cell retraction. Thus, the subcellular matrix is exposed and further degradation of matrix components is induced. Such local tissue damage ultimately helps the pathogenic microbe to cross host tissue barriers and to disseminate into deeper tissue layers.

Several of the secreted fungal proteins are fungal moonlighting proteins. Examples for such multifunctional fungal immune evasion proteins are Tef-1 (Translations elongation factor 1), and Pra1 (the pH regulated antigen1) that both contribute to fungal pathogenicity. Both C. albicans moonlighting proteins mediate fungal immune escape by inhibiting both innate and adaptive immune reaction of the human host. We have generated monoclonal antibodies (mAbs) against these immune evasion proteins. In the next funding period, we will continue the in vitro studies and extend the analyses to fungal immune escape in mice. Moreover, we will evaluate our anti-fungal mAbs in mouse models of C. albicans infections.