The Achromobacter type 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes

Keren Turton, Hannah J. Parks, Paulina Zarodkiewicz, Mohamad A. Hamad, Rachel Dwane, Georgiana Parau, Rebecca J. Ingram, Rebecca C. Coll, Clare E. Bryant, Miguel A. Valvano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
8 Downloads (Pure)

Abstract

How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical isolates from two species, we show that the type 3 secretion system (T3SS) is required to induce cell death in human macrophages by inflammasome-dependent pyroptosis. Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 undergo pyroptosis upon bacterial internalization, but those deficient in both NLRC4 and NLRP3 do not, suggesting either sensor mediates pyroptosis in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicates that the intracellular bacteria reside in a late phagolysosome. Using an intranasal mouse infection model, we observe that Achromobacter damages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate that Achromobacter species can survive phagocytosis by promoting macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction in a T3SS-dependent manner.

Original languageEnglish
Article number113012
Number of pages22
JournalCell Reports
Volume42
Issue number8
Early online date21 Aug 2023
DOIs
Publication statusPublished - 29 Aug 2023

Keywords

  • pyroptosis
  • cytotoxicity
  • macrophages
  • CP: Microbiology
  • CP: Immunology
  • opportunistic bacteria
  • cystic fibrosis

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