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

Autor: Ding X; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA.; Department of Burn and Plastic Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China., Kambara H; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Guo R; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA.; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, 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, 288 Nanjing Road, Tianjin, 300020, China., Kanneganti A; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Acosta-Zaldívar M; Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA., Li J; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, 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, 288 Nanjing Road, Tianjin, 300020, China., Liu F; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, 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, 288 Nanjing Road, Tianjin, 300020, China., Bei T; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Qi W; Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA., Xie X; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Han W; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Liu N; Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA., Zhang C; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Zhang X; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Yu H; VA Boston Healthcare System, Department of Pathology and Laboratory Medicine, 1400 VFW Parkway West Roxbury, Boston, MA, 02132, USA.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Zhao L; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA., Ma F; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, 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, 288 Nanjing Road, Tianjin, 300020, China., Köhler JR; Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, 02115, USA., Luo HR; Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA, 02115, USA. hongbo.luo@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Nov 18; Vol. 12 (1), pp. 6699. Date of Electronic Publication: 2021 Nov 18.
DOI: 10.1038/s41467-021-27034-9
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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