Mycobacterial CpsA activates type I IFN signaling in macrophages via cGAS-mediated pathway

Yue Ding; Jingfeng Tong; Geyang Luo; Rongfeng Sun; Cheng Bei; Zhihua Feng; Lu Meng; Fei Wang; Jing Zhou; Zihan Chen; Duoduo Li; Yufeng Fan; Shu Song; Decheng Wang; Carl G. Feng; Haipeng Liu; Qi Chen; Bo Yan; Qian Gao

iScience (May 2024)

Mycobacterial CpsA activates type I IFN signaling in macrophages via cGAS-mediated pathway

Yue Ding,
Jingfeng Tong,
Geyang Luo,
Rongfeng Sun,
Cheng Bei,
Zhihua Feng,
Lu Meng,
Fei Wang,
Jing Zhou,
Zihan Chen,
Duoduo Li,
Yufeng Fan,
Shu Song,
Decheng Wang,
Carl G. Feng,
Haipeng Liu,
Qi Chen,
Bo Yan,
Qian Gao

Affiliations

Yue Ding: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Jingfeng Tong: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Geyang Luo: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Rongfeng Sun: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Cheng Bei: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Zhihua Feng: Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, Fuzhou, China
Lu Meng: The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, China
Fei Wang: Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
Jing Zhou: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences; Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, P.R China
Zihan Chen: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences; Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, P.R China
Duoduo Li: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Yufeng Fan: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Shu Song: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Decheng Wang: Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences; Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, P.R China
Carl G. Feng: Immunology and Host Defence Laboratory, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
Haipeng Liu: Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; Corresponding author
Qi Chen: Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, Fuzhou, China; Corresponding author
Bo Yan: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Corresponding author
Qian Gao: Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Corresponding author

Journal volume & issue: Vol. 27, no. 5
p. 109807

Abstract

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Summary: Type I interferon (IFN) production is crucial in tuberculosis pathogenesis, yet the bacterial factors initiating this process are incompletely understood. CpsA, protein of Mycobacterium marinum and Mycobacterium tuberculosis, plays a key role in maintaining bacterial virulence and inhibiting host cell LC3-associated phagocytosis. By utilizing CpsA full deletion mutant studies, we re-verified its essential role in infection-induced pathology and revealed its new role in type I IFN expression. CpsA deficiency hindered IFN production in infected macrophages in vitro as well as zebrafish and mice in vivo. This effect was linked to the cGAS-TBK1-IRF3 pathway, as evidenced by decreased TBK1 and IRF3 phosphorylation in CpsA-deficient bacterial strain-infected macrophages. Moreover, we further show that CpsA deficiency cause decreased cytosolic DNA levels, correlating with impaired phagosomal membrane rupture. Our findings reveal a new function of mycobacterial CpsA in type I IFN production and offer insight into the molecular mechanisms underlying mycobacterial infection pathology.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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