Chlamydia evasion of neutrophil host defense results in NLRP3 dependent myeloid-mediated sterile inflammation through the purinergic P2X7 receptor

Chunfu Yang,Ian N Moore,Christine Bonner,David W Dorward ,Craig Martens ,John W.marshall Collins ,Stacy Ricklefs ,Anuj Kashyap ,Kiyoshi Takeda,Lei Lei,Grant Mcclarty,Yoichiro Iwakura,Gail L Sturdevant,Kevin W Bock,Chih-Yu Chen,Masahiro Yamamoto,Hua Su,Michael Briones,Li Ma,Harlan D Caldwell

doi:10.1038/s41467-021-25749-3

Abstract

Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. Here we show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertility by using a female mouse genital tract chlamydial infection model. We find the chlamydial parasitophorous vacuole protein CT135 triggers NLRP3 inflammasome activation via TLR2/MyD88 signaling as a pathogenic strategy to evade neutrophil host defense. Paradoxically, a consequence of CT135 mediated neutrophil killing results in a submucosal macrophage-associated endometritis driven by ATP/P2X7R induced NLRP3 inflammasome activation. Importantly, macrophage-associated immunopathology occurs independent of macrophage infection. We show chlamydial infection of neutrophils and epithelial cells produce elevated levels of extracellular ATP. We propose this source of ATP serves as a DAMP to activate submucosal macrophage NLRP3 inflammasome that drive damaging immunopathology. These findings offer a paradigm of sterile inflammation in infectious disease pathogenesis.

Highlights

Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility
The only significant difference in infection kinetics between strains was at day 3 pi, we thought CT135 might function in colonization or early infection interactions with genital tract (GT) epithelial cells
We found CT135 activates the NLRP3 inflammasome through TLR2/ MyD88 signaling pathway as a pathogenic strategy to evade neutrophil host defense, this strategy conjointly caused NLRP3 dependent macrophage-associated endometritis

Summary

Introduction

Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. We show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertility by using a female mouse genital tract chlamydial infection model. We show chlamydial infection of neutrophils and epithelial cells produce elevated levels of extracellular ATP We propose this source of ATP serves as a DAMP to activate submucosal macrophage NLRP3 inflammasome that drive damaging immunopathology. These findings offer a paradigm of sterile inflammation in infectious disease pathogenesis. Chlamydial inflammatory diseases commonly exist with an absence or paucity of detectable infectious chlamydiae[5] with accompanying severe inflammation; this enigma is not understood

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