ASC acts in a caspase-1-independent manner to worsen acute pneumonia caused by Pseudomonas aeruginosa

A. J. Hughes, C. A. Knoten, A. R. Morris, A. R. Hauser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose. Pseudomonas aeruginosa expresses a type III secretion system (T3SS) that activates the host inflammasomemediated immune response. We examined the role of inflammasome activation in severe infection outcomes. Methods. We infected C57BL/6 (B6) mice lacking inflammasome components ASC or caspase-1/11 with a highly virulent strain of P. aeruginosa, PSE9, using a mouse model of pneumonia. We evaluated inflammasome activation in vitro by infecting bone marrow-derived macrophages (BMDMs) with PSE9 and measuring cell death and release of inflammasomedependent cytokines IL-18 and IL-1b. A bioluminescent reporter assay was used to detect activity of caspase-1 and caspase- 3/7 in BMDMs from B6 and ASC-deficient mice. Results/Key Findings. ASC-/- mice exhibited significantly improved survival relative to caspase-1/11-/- mice and B6 mice, demonstrating that ASC and caspase-1/11 play differential roles in P. aeruginosa infection. We found that ASC-/- BMDMs exhibited significantly reduced cell death relative to B6 BMDMs, while caspase-1/11-/- BMDMs were resistant to cell death. IL-18 and IL-1b were both detected from supernatants of infected B6 BMDMs, but cytokine release was abrogated in both ASC-/- and caspase-1/11-/- BMDMs. We detected a 2.5-fold increase in the activation of caspase-3/7 in PSE9-infected B6 BMDMs, but no increase in infected ASC-/- BMDMs. Cell death, cytokine release and caspase-3/7 activity were dependent on a functional T3SS. Conclusions. Collectively, these results are consistent with a model whereby the T3SS apparatus of P. aeruginosa activates the caspase-1-dependent inflammasome and caspase-3/7 through an ASC-dependent mechanism. This activation may have implications for the outcomes of P. aeruginosa infections.

Original languageEnglish (US)
Article number000782
Pages (from-to)1168-1180
Number of pages13
JournalJournal of medical microbiology
Volume67
Issue number8
DOIs
StatePublished - Aug 2018

Keywords

  • Apoptosis
  • Caspase-1
  • Caspase-3
  • Inflammasome
  • Pseudomonas aeruginosa
  • Pyroptosis
  • T3SS
  • Type III secretion

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

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