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Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses
Muhammad Daud1, Prasad Dasari2, Marion Adelfinger3
1Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Abstract:
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.
Insights
Candida albicans enolase 1 (CaEno1) binds to human CD4+ T cells, promoting fungal immune evasion. This interaction impairs T-cell responses crucial for controlling fungal infections.
Area of Science:
- Immunology
- Mycology
- Molecular Biology
Background:
- Life-threatening fungal infections caused by Candida albicans pose significant health risks.
- Understanding host-pathogen interactions is crucial for developing effective antifungal therapies.
- The moonlighting protein enolase 1 (Eno1) in C. albicans is implicated in virulence.
Purpose of the Study:
- To investigate the interaction between Candida albicans enolase 1 (CaEno1) and human CD4+ T cells.
- To elucidate the functional consequences of this interaction on T-cell responses.
- To explore the role of CaEno1 in fungal immune evasion.
Main Methods:
- In silico screening for fungal and host protein interaction partners.
- Binding assays using anti-CD4 monoclonal antibodies to identify binding sites.
- Analysis of T-cell activation and cytokine secretion profiles (Th2 skewing).
- Assessment of T-cell recall responses in memory CD4+ T cells.
- In vitro evaluation of T-cell receptor-engineered T cells against CaEno1.
Main Results:
- Bioinformatic prediction confirmed binding of human CD4 extracellular domain to C. albicans Eno1 (CaEno1).
- CaEno1 binds to extracellular domain 3 of CD4, activating lymphocyte-specific protein tyrosine kinase (LCK).
- CaEno1 binding skewed naive CD4+ T cells towards a Th2 cytokine profile, indicating poor fungal control.
- CaEno1 inhibited human memory CD4+ T-cell recall responses.
- Adoptive T-cell therapy using T-cell receptor-engineered T cells showed resistance to CaEno1 inhibition.
Conclusions:
- CaEno1 directly modulates CD4+ T-cell responses, favoring fungal survival.
- CaEno1 contributes to immune evasion by interfering with complement regulators and directly modulating T-cell immunity.
- Targeting the CaEno1-CD4 interaction may offer a therapeutic strategy against Candida albicans infections.
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