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GSDMD-mediated pyroptosis restrains intracellular Chlamydia trachomatis growth in macrophages
Ping Jiang1, Hongzhi Chen2, Xiaojing Feng1
1Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Abstract:
Pyroptosis, a type of programmed necrosis associated with inflammatory, is a host defense mechanism against microbial infections. Although Chlamydia has been shown to induce pyroptosis, whether pyroptosis directly impacts the growth of Chlamydia has not been demonstrated. In this study, we found that C. trachomatis L2 infection of the mouse macrophage RAW 264.7 cells induced pyroptosis by monitoring the ultrastructural changes under transmission electron microscopy and the release of LDH and IL-1β. More importantly, this C. trachomatis-triggered pyroptosis with activation of caspase-1 and caspase-11 was also accompanied by gasdermin D (GSDMD) activation. Suppression of these two inflammatory caspases inhibited GSDMD activation. Interestingly, the C. trachomatis-triggered pyroptosis significantly inhibited the intracellular growth of C. trachomatis since inactivation of either GSDMD or caspase-1/11 significantly rescued infectious C. trachomatis yields, which suggests pyroptosis response can be utilized as an intrinsic mechanism to restrict C. trachomatis intracellular infection in addition to the well- documented extrinsic mechanisms by recruiting and enhancing inflammatory responses. This study may reveal novel targets for attenuating C. trachomatis infectivity and/or pathogenicity.
Insights
Chlamydia trachomatis infection triggers pyroptosis, a cell death process that limits bacterial growth. Inhibiting pyroptosis components like gasdermin D (GSDMD) or caspases rescues Chlamydia yields, revealing pyroptosis as a host defense.
Area of Science:
- Cellular Biology
- Immunology
- Microbiology
Background:
- Pyroptosis is programmed necrosis and an inflammatory host defense against microbial infections.
- Chlamydia trachomatis is known to induce pyroptosis, but its direct impact on bacterial growth remains unclear.
Purpose of the Study:
- To investigate the direct effect of Chlamydia trachomatis-induced pyroptosis on intracellular bacterial growth.
- To elucidate the role of inflammatory caspases and gasdermin D (GSDMD) in this process.
Main Methods:
- Infection of mouse macrophage RAW 264.7 cells with C. trachomatis L2.
- Monitoring pyroptosis via transmission electron microscopy, LDH, and IL-1β release.
- Assessing the impact of caspase-1/11 and GSDMD inhibition on bacterial yields.
Main Results:
- C. trachomatis infection induced pyroptosis, marked by caspase-1/11 and GSDMD activation.
- Inhibition of caspase-1/11 or GSDMD significantly increased intracellular C. trachomatis yields.
- Pyroptosis activation was shown to directly inhibit C. trachomatis intracellular growth.
Conclusions:
- Pyroptosis acts as an intrinsic host defense mechanism to restrict C. trachomatis intracellular infection.
- Targeting pyroptosis pathways, including GSDMD and inflammatory caspases, may offer novel strategies to control Chlamydia infectivity and pathogenicity.
