Oral Presentation 14th Lorne Infection and Immunity 2024

A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation (#30)

Mary Speir 1 2 , Hazel Tye 1 2 , Timothy A Gottschalk 1 2 , Daniel S Simpson 3 4 , Tirta M Djajawi 1 2 , Pankaj Deo 5 , Rebecca L Ambrose 1 2 , Stephanie A Conos 1 2 , Jack Emery 1 2 , Isabella Kong 3 4 , Marco J Herold 3 4 , Jaclyn S Pearson 1 2 6 , Najoua Lalaoui 3 4 , Thomas Naderer 5 , James E Vince 3 4 , Kate E Lawlor 1 2 3 4
  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
  3. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  5. Department of Biochemistry and Molecular Biology, Monash University, Clatyon, VIC, Australia
  6. Department of Microbiology, Monash University, Clayton, VIC, Australia

Programmed cell death plays an integral role in alerting the innate immune system to a microbial threat and promoting pathogen clearance. Activation of intrinsic apoptosis is widely thought to promote the non-immunogenic phagocytic clearance of infected cells. However, with the recent discovery that apoptotic signalling can crosstalk with the NLRP3 inflammasome1, it remains to be seen how intrinsic apoptosis is regulated during infection and whether it can induce inflammation. Here, we identify that the pro-survival BCL-2 family member, A1, combines with distinct family members to regulate intrinsic BAX/BAK-mediated cell death in macrophages and inflammatory monocytes upon Gram-negative bacterial lipopolysaccharide (LPS) sensing. We show that due to its tight transcriptional and post-translational regulation, A1 acts as a molecular rheostat to regulate intrinsic apoptosis and the subsequent NLRP3 inflammasome-dependent and -independent activation and release of IL-1β. Importantly, Neisseria gonorrhoeae-derived outer membrane vesicles (NOMVs), which are known to damage the mitochondria and trigger intrinsic apoptosis2,3, also induced A1 expression in inflammatory monocytes to limit cell death and IL-1β activation. In experimental models, the absence of A1 enhanced IL-1β activation to intraperitoneal NOMV injection and impaired the clearance of the lower respiratory tract intracellular pathogen, Legionella pneumophila (Δfla mutant). These results suggest that myeloid cells upregulate A1 expression in response to Gram-negative bacteria to limit early and potentially detrimental cell death and inflammatory responses. With the increasing prevalence of antibiotic resistant bacteria, these findings have implications for the development and deployment of drugs targeting cell death regulators as host-directed antimicrobial therapeutics.

  1. 1. Vince JE et al. 2018 Cell Reports 25:2239
  2. 2. Deo P et al. 2018 Plos Pathogens 14: e1006945
  3. 3. Deo P et al. 2020 Nature Microbiology 5:1418
  4. 4. Speir M* et al. 2023 EMBO Reports doi: 10.15252/embr.202356865