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

## TL;DR

Chlamydia trachomatis extends the life of immune cells called neutrophils by manipulating proteins RIP3 and Mcl-1, helping the bacteria survive and reproduce.

## Contribution

The study reveals a novel role for RIP3 in stabilizing Mcl-1 to prolong neutrophil survival during Chlamydia infection.

## Key findings

- Chlamydia infection prolongs human neutrophil lifespan via PI3K/Akt and NF-κB pathways.
- RIP3 stabilizes Mcl-1, enhancing neutrophil survival and Chlamydia replication.
- Inhibiting RIP3 reduces Mcl-1 but allows Chlamydia to survive independently of Mcl-1.

## 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.

This study reveals how Chlamydia trachomatis, a common sexually transmitted bacterium, manipulates the body’s first immune responders, the neutrophils, to aid its own survival. Normally short-lived, neutrophils live longer when infected by Chlamydia, creating a safe environment for the bacteria. This lifespan extension is driven by specific cell survival signals and a protein called RIP3, which surprisingly does not cause cell death here, but helps stabilize another protein, Mcl-1, that keeps neutrophils alive. Blocking RIP3 reduces Mcl-1, but Chlamydia still manages to survive, suggesting it can adapt to changes in the host environment. These findings uncover a new layer of complexity in how our immune system interacts with infections and could inform future strategies for treating Chlamydia and similar infections.