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

• Published in: Cell reports (Cambridge) 2023-08, Vol.42 (8), p.113012-113012, Article 113012
• Main Authors: Turton, Keren, Parks, Hannah J., Zarodkiewicz, Paulina, Hamad, Mohamad A., Dwane, Rachel, Parau, Georgiana, Ingram, Rebecca J., Coll, Rebecca C., Bryant, Clare E., Valvano, Miguel A.
• Format: Article
• Language: English
• Subjects: Achromobacter; Animals; Calcium-Binding Proteins; CARD Signaling Adaptor Proteins; CP: Immunology; CP: Microbiology; cystic fibrosis; cytotoxicity; Disease Models, Animal; Humans; Inflammasomes; macrophages; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; opportunistic bacteria; Pyroptosis; Type III Secretion Systems
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113012

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. [Display omitted] •The Achromobacter T3SS induces pyroptosis in human macrophages•The inflammasome sensors NLRC4 or NLRP3 mediate Achromobacter-induced pyroptosis•Achromobacter bacteria traffic intracellularly to a late phagolysosome compartment•Achromobacter T3SS is required to damage lung structure in a mouse infection model Turton et al. show that, upon phagocytosis, the Achromobacter T3SS activates either NLRC4 or NLRP3 sensors, causing pro-inflammatory cell death in human macrophages, and mediates lung damage in infected mice, together demonstrating that Achromobacter bacteria overcome phagocytosis via pro-inflammatory cell death induction by redundant T3SS-dependent mechanisms.