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PMA1-containing extracellular vesicles of Candida albicans triggers immune responses and colitis progression
Zhen Xu1,2,3, Shuping Qiao1,2,3, Zelin Wang1,2,3
1Department of Oncology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Abstract:
Candida albicans (C. albicans) exhibits aberrant changes in patients with colitis, and it has been reported to dominate the colonic mucosal immune response. Here, we found that PMA1 expression was significantly increased in C. albicans from patients with IBD compared to that in healthy controls. A Crispr-Cas9-based fungal strain editing system was then used to knock out PMA1 expression in C. albicans. Compared to WT-C.a, ΔPMA1-C.a could not aggravate colitis. Proteomic analysis showed that PMA1 was transported by extracellular vesicles (EVs) of C. albicans. PMA1-containing EVs aggravated colitis, modulated the migration of cDC2 from the lamina propria to mesenteric lymph nodes, and induced TH17 cell differentiation. Moreover, the adaptor protein CARD9 was critical in PMA1-containing EV-induced colitis, and CARD9-deficient DCs did not induce TH17 cell differentiation or IL-17A production. Mechanically, CARD9 combines with the glycolytic protein GAPDH (aa2-146 domain) through its CARD region. CARD9 deficiency led to decreased enzyme activity of GAPDH and decreased glycolysis of DCs. These findings indicate that PMA1 is a potential virulence factor responsible for the pathogenesis of C. albicans colitis.
Insights
Candida albicans PMA1 protein, when transported by extracellular vesicles, aggravates colitis. Deleting PMA1 in C. albicans prevents colitis aggravation, identifying PMA1 as a key virulence factor in fungal colitis.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Candida albicans (C. albicans) dysbiosis is linked to colitis.
- C. albicans dominates the colonic immune response in inflammatory bowel disease (IBD).
Purpose of the Study:
- Investigate the role of PMA1 in C. albicans-induced colitis.
- Identify the mechanism by which C. albicans contributes to colitis pathogenesis.
Main Methods:
- Utilized a Crispr-Cas9 system to generate a PMA1 knockout C. albicans strain (ΔPMA1-C.a).
- Performed proteomic analysis to identify PMA1 localization.
- Assessed colitis severity in mouse models.
- Analyzed immune cell migration and differentiation (cDC2, TH17).
- Investigated the interaction between CARD9 and GAPDH.
Main Results:
- PMA1 expression was elevated in C. albicans from IBD patients.
- ΔPMA1-C.a did not aggravate colitis compared to wild-type (WT-C.a).
- PMA1 is secreted via extracellular vesicles (EVs).
- PMA1-containing EVs exacerbated colitis, promoting cDC2 migration and TH17 differentiation.
- CARD9 is essential for PMA1-EV-induced colitis, linking CARD9 to GAPDH and DC glycolysis.
Conclusions:
- PMA1 is a novel virulence factor in C. albicans colitis.
- PMA1-containing EVs mediate colitis pathogenesis through CARD9-dependent pathways.
- Targeting PMA1 may offer therapeutic strategies for C. albicans-associated colitis.
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