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 inf...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-derivedα-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.展开更多
基金This work was supported by the National Natural Science Foundation of China(31970889,31622023 to X.M.J.and 81902039 to Q.Z.L.)the Innovation Program of Shanghai Municipal Education Commission(201901070007E00022 to X.M.J.)+5 种基金the Outstanding Academic Leader Program of the Shanghai Health and Family Planning Commission(2017BR024 to X.M.J.)the Shuguang Program of the Shanghai Municipal Education Commission(17SG24 to X.M.J.)the Fundamental Research Funds for the Central Universities(X.M.J.)by a member of the Innovative Research Team of High-Level Local University in Shanghai(X.M.J.)the Key fund for basic research of Shanghai Science and Technology Commission(20JC1417700 to X.M.J.)Shanghai Municipal Natural Science Foundation(19ZR1461800 to D.D.L.).
文摘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-derivedα-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.
