Chlamydia trachomatis subverts neutrophil cell death pathways through RIP3 and Mcl-1 manipulation

作者：Rebecca Koch, Naveen Challagundla, Kathrin Stelzner, Thomas Rudel · 发表于：mBio · 年份：2025 · DOI：10.1128/mbio.02098-25 · 研究领域：Medicine

ABSTRACT Chlamydia trachomatis, an obligate intracellular pathogen, manipulates host cells to evade immune detection, contributing to sexually transmitted diseases with severe complications. Neutrophils, short-lived effector cells, form the first line of innate immune defense against infection. Here, we demonstrate that Chlamydia infection extends the lifespan of human neutrophils, creating a cellular niche for its own survival. Lifespan extension involves the neutrophil PI3K/Akt- and the NF-κB signaling pathways. In addition, infection activates the necroptotic effector receptor-interacting protein kinase 3 (RIP3) without inducing cell death. Instead, RIP3 stabilizes the anti-apoptotic protein Mcl-1, enhancing neutrophil survival. This extended survival of neutrophils correlates with an increased number of infectious Chlamydia particles. Mcl-1 plays a critical role in neutrophil survival, lifespan extension, and Chlamydia survival. Notably, inhibiting RIP3 reduces Mcl-1 levels in neutrophils without affecting their survival. Under these conditions, however, Chlamydia load increases, and the dependence on Mcl-1 is bypassed. Our data reveal a new role for necroptosis in neutrophil defense against intracellular Chlamydia, highlighting a complex interplay between RIP3 and Mcl-1 that extends neutrophil lifespan and enhances Chlamydia survival within these hostile cells. IMPORTANCE This study reveals how Chlamydia trachomatis, a common sexually transmitted bacterium, manipulates t...