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

Chunfu Yang, Lei Lei, John W. Marshall Collins, Michael Briones, Li Ma, Gail L. Sturdevant, Hua Su, Anuj K. Kashyap, David Dorward, Kevin W. Bock, Ian N. Moore, Christine Bonner, Chih-Yu Chen, Craig A. Martens, Stacy Ricklefs, Masahiro Yamamoto, Kiyoshi Takeda, Yoichiro Iwakura, Grant McClarty and Harlan D. Caldwell ()
Additional contact information
Chunfu Yang: National Institutes of Health
Lei Lei: National Institutes of Health
John W. Marshall Collins: National Institutes of Health
Michael Briones: National Institutes of Health
Li Ma: National Institutes of Health
Gail L. Sturdevant: National Institutes of Health
Hua Su: National Institutes of Health
Anuj K. Kashyap: National Institutes of Health
David Dorward: National Institutes of Health
Kevin W. Bock: National Institutes of Health
Ian N. Moore: National Institutes of Health
Christine Bonner: Public Health Agency of Canada
Chih-Yu Chen: Public Health Agency of Canada
Craig A. Martens: National Institutes of Health
Stacy Ricklefs: National Institutes of Health
Masahiro Yamamoto: Osaka University
Kiyoshi Takeda: Osaka University
Yoichiro Iwakura: Tokyo University of Science
Grant McClarty: University of Manitoba
Harlan D. Caldwell: National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25749-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25749-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25749-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().