Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages

Xionghui Ding, Hiroto Kambara, Rongxia Guo, Apurva Kanneganti, Maikel Acosta-Zaldívar, Jiajia Li, Fei Liu, Ting Bei, Wanjun Qi, Xuemei Xie, Wenli Han, Ningning Liu, Cunling Zhang, Xiaoyu Zhang, Hongbo Yu, Li Zhao, Fengxia Ma, Julia R. Köhler and Hongbo R. Luo ()
Additional contact information
Xionghui Ding: Boston Children’s Hospital
Hiroto Kambara: Boston Children’s Hospital
Rongxia Guo: Boston Children’s Hospital
Apurva Kanneganti: Boston Children’s Hospital
Maikel Acosta-Zaldívar: Division of Infectious Diseases, Boston Children’s Hospital/Harvard Medical School
Jiajia Li: Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College
Fei Liu: Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College
Ting Bei: Boston Children’s Hospital
Wanjun Qi: Division of Infectious Diseases, Boston Children’s Hospital/Harvard Medical School
Xuemei Xie: Boston Children’s Hospital
Wenli Han: Boston Children’s Hospital
Ningning Liu: Division of Infectious Diseases, Boston Children’s Hospital/Harvard Medical School
Cunling Zhang: Boston Children’s Hospital
Xiaoyu Zhang: Boston Children’s Hospital
Hongbo Yu: VA Boston Healthcare System, Department of Pathology and Laboratory Medicine
Li Zhao: Boston Children’s Hospital
Fengxia Ma: Institute of Hematology & Blood Diseases Hospital, CAMS Key laboratory for prevention and control of hematological disease treatment related infection, Chinese Academy of Medical Sciences & Peking Union Medical College
Julia R. Köhler: Division of Infectious Diseases, Boston Children’s Hospital/Harvard Medical School
Hongbo R. Luo: Boston Children’s Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-24

Abstract: Abstract Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.

Date: 2021
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DOI: 10.1038/s41467-021-27034-9

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