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

doi:10.1016/j.isci.2024.109807

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

iScience. 2024 Apr 24;27(5):109807. doi: 10.1016/j.isci.2024.109807. eCollection 2024 May 17.

Authors

Yue Ding¹, Jingfeng Tong¹, Geyang Luo¹, Rongfeng Sun¹, Cheng Bei¹, Zhihua Feng², Lu Meng³, Fei Wang⁴, Jing Zhou^{5

6}, Zihan Chen^{5

6}, Duoduo Li⁵, Yufeng Fan¹, Shu Song⁵, Decheng Wang⁶, Carl G Feng⁷, Haipeng Liu⁴, Qi Chen², Bo Yan⁵, Qian Gao¹

Affiliations

¹ 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.
² Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University Qishan Campus, Fuzhou, China.
³ 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.
⁴ Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
⁶ 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.
⁷ Immunology and Host Defence Laboratory, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.

Abstract

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.

Keywords: Immunology; Microbiology; Molecular microbiology.