Chlamydia psittaci infection induces IFN-I and IL-1β through the cGAS-STING-IRF3/NLRP3 pathway via mitochondrial oxidative stress in human macrophages

Hongyu Yang; Peiyuan Sun; Shi Zhou; Yuanyuan Tang; Sijia Li; Weiwei Li; Xiang Yu; Hanying Liu; Yimou Wu

doi:10.1016/j.vetmic.2024.110292

Chlamydia psittaci infection induces IFN-I and IL-1β through the cGAS-STING-IRF3/NLRP3 pathway via mitochondrial oxidative stress in human macrophages

Vet Microbiol. 2024 Nov 16:299:110292. doi: 10.1016/j.vetmic.2024.110292. Online ahead of print.

Authors

Hongyu Yang¹, Peiyuan Sun¹, Shi Zhou¹, Yuanyuan Tang¹, Sijia Li¹, Weiwei Li², Xiang Yu¹, Hanying Liu³, Yimou Wu⁴

Affiliations

¹ Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China.
² Department of Clinical Laboratory, The Second People's Hospital of Foshan, China.
³ Health Management Medicine Center, the Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: liuduolin@csu.edu.cn.
⁴ Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China. Electronic address: yimouwu@sina.com.

PMID: 39581075
DOI: 10.1016/j.vetmic.2024.110292

Abstract

Chlamydia psittaci (C. psittaci) is a multi-host pathogen that elicits robust innate immune responses in macrophages. Chlamydiae target host mitochondria to manipulate the cellular fate and metabolic functions. However, the effect of C. psittaci on the host mitochondria remains obscure. This study investigated how C. psittaci, post-infection in human macrophages, induces mitochondrial oxidative stress and damage to activate the cGAS-STING-IRF3/NLRP3 pathway for IFN-I and IL-1β production. Results demonstrate that C. psittaci increased mitochondrial ROS (mtROS) production. This induced the release of oxidized mitochondrial DNA (mtDNA) into the cytoplasm of macrophages. It also augmented IFN-I and IL-1β production dependent on the cGAS-STING pathway. Macrophages pre-treated with mtROS inhibitor mito-TEMPO displayed reduced oxidized mtDNA. This consequently lowered IFN-I and IL-1β production via the cGAS-STING pathway induced by C. psittaci. Additionally, we found that mtROS production may inhibit C. psittaci proliferation through the synergistic action of IFN-I and IL-1β. In conclusion, our study reveals that C. psittaci induces mtROS production leading to mtDNA release. This activates the cGAS-STING-IRF3/NLRP3 pathway to increase IFN-I and IL-1β production. This study elucidates a novel mechanism of bacterial pathogen activation in the cGAS-STING pathway. This reveals the molecular mechanisms underlying the immune response to C. psittaci infection and proposes potential targets for the treatment of C. psittaci related diseases.

Keywords: CGAS-STING; Chlamydia psittaci; Type I interferon; mtDNA; mtROS.