Soluble Enolase 1 of Candida albicans and Aspergillus fumigatus Stimulates Human and Mouse B Cells and Monocytes.

Because of the growing numbers of immunocompromised patients, the incidence of life-threatening fungal infections caused by Candida albicans and Aspergillus fumigatus is increasing. We have recently identified enolase 1 (Eno1) from A. fumigatus as an immune evasion protein. Eno1 is a fungal moonlighting protein that mediates adhesion and invasion of human cells and also immune evasion through complement inactivation. We now show that soluble Eno1 has immunostimulatory activity. We observed that Eno1 from both C. albicans and A. fumigatus directly binds to the surface of lymphocytes, preferentially human and mouse B cells. Functionally, Eno1 upregulated CD86 expression on B cells and induced proliferation. Although the receptor for fungal Eno1 on B lymphocytes is still unknown, the comparison of B cells from wild-type and MyD88-deficient mice showed that B cell activation by Eno1 required MyD88 signaling. With respect to infection biology, we noted that mouse B cells stimulated by Eno1 secreted IgM and IgG2b. These Igs bound C. albicans hyphae in vitro, suggesting that Eno1-induced Ab secretion might contribute to protection from invasive fungal disease in vivo. Eno1 also triggered the release of proinflammatory cytokines from monocytes, particularly IL-6, which is a potent activator of B cells. Together, our data shed new light on the role of secreted Eno1 in infections with C. albicans and A. fumigatus. Eno1 secretion by these pathogenic microbes appears to be a double-edged sword by supporting fungal pathogenicity while triggering (antifungal) immunity.

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses.

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4+ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4+ T-cell recall responses. Therapeutically, CD4+ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4+ T cells with CaEno1 modulated host CD4+ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4+ T-cell responses.