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

Nat Commun. 2021 Sep 15;12(1):5454. 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphate / immunology
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cells, Cultured
  • Chlamydia / immunology*
  • Chlamydia / physiology
  • Chlamydia Infections / immunology*
  • Chlamydia Infections / metabolism
  • Chlamydia Infections / microbiology
  • Disease Models, Animal
  • Female
  • HeLa Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immune Evasion / immunology
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / microbiology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Myeloid Cells / microbiology
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Neutrophils / microbiology
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / immunology*
  • Receptors, Purinergic P2X7 / metabolism

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate