Cell Mol Immunol. 2021 Aug;18(8):2010-2023. doi: 10.1038/s41423-020-00576-6. Epub 2020 Nov 05.

Priming with FLO8-deficient Candida albicans induces Th1-biased protective immunity against lethal polymicrobial sepsis.

Cellular & molecular immunology

Quan-Zhen Lv, De-Dong Li, Hua Han, Yi-Heng Yang, Jie-Lin Duan, Hui-Hui Ma, Yao Yu, Jiang-Ye Chen, Yuan-Ying Jiang, Xin-Ming Jia

PMID: 33154574 PMCID: PMC7642578 DOI: 10.1038/s41423-020-00576-6

Abstract

The morphological switch between yeast and hyphae of Candida albicans is essential for its interaction with the host defense system. However, the lack of understanding of host-pathogen interactions during C. albicans infection greatly hampers the development of effective immunotherapies. Here, we found that priming with the C. albicans FLO8-deficient (flo8) mutant, locked in yeast form, protected mice from subsequent lethal C. albicans infection. Deficiency of Dectin-2, a fungus-derived α-mannan recognition receptor, completely blocked flo8 mutant-induced protection. Mechanistically, the flo8 mutant-induced Dectin-2/CARD9-mediated IL-10 production in DCs and macrophages to block thymus atrophy by inhibiting the C. albicans-induced apoptosis of thymic T cells, which facilitated the continuous output of naive T cells from the thymus to the spleen. Continuous recruitment of naive T cells to the spleen enhanced Th1-biased antifungal immune responses. Consequently, depletion of CD4+ T cells or blockade of IL-10 receptor function using specific antibodies in mice completely blocked the protective effects of flo8 mutant priming against C. albicans infection. Moreover, mannans exposed on the surface of the flo8 mutant were responsible for eliciting protective immunity by inhibiting the C. albicans-induced apoptosis of thymic T cells to sustain the number of naive T cells in the spleen. Importantly, priming with the flo8 mutant extensively protected mice from polymicrobial infection caused by cecal ligation and puncture (CLP) by enhancing Th1-biased immune responses. Together, our findings imply that targeting FLO8 in C. albicans elicits protective immune responses against polymicrobial infections and that mannans extracted from the flo8 mutant are potential immunotherapeutic candidate(s) for controlling infectious diseases.

© 2020. CSI and USTC.

Keywords: Apoptosis; Candida albicans; Fungi infection; Protective immunity; Thymus atrophy

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Publication Types

• Journal Article
• Research Support, Non-U.S. Gov't

Grant support

• 201901070007E00022/Shanghai Municipal Education Commission
• 17SG24/Shanghai Municipal Education Commission
• 31970889/National Natural Science Foundation of China (National Science Foundation of China)
• 31622023/National Natural Science Foundation of China (National Science Foundation of China)
• 81902039/National Natural Science Foundation of China (National Science Foundation of China)