2. Academic Validation
  3. ATG5 suppresses type I IFN-dependent neutrophil effector functions during Mycobacterium tuberculosis infection in mice

ATG5 suppresses type I IFN-dependent neutrophil effector functions during Mycobacterium tuberculosis infection in mice

  • Nat Microbiol. 2025 Jun;10(6):1323-1339. doi: 10.1038/s41564-025-01988-8.
Rachel L Kinsella 1 2,  Chanchal Sur Chowdhury 3,  Asya Smirnov 3,  Yassin Mreyoud 3,  Jacqueline M Kimmey 3 4,  Ekaterina Esaulova 5,  Samuel R McKee 3,  Aaron Pride 3,  Darren Kreamalmeyer 3,  Maxim N Artyomov 5,  Christina L Stallings 6
Affiliations

Affiliations

  • 1 Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, MO, USA. [email protected].
  • 2 Department of Medicine, Division of Infectious Diseases and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. [email protected].
  • 3 Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, MO, USA.
  • 4 Department of Microbiology and Environmental Toxicology, UC Santa Cruz, Santa Cruz, CA, USA.
  • 5 Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
  • 6 Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St Louis, MO, USA. [email protected].
PMID: 40374743 DOI: 10.1038/s41564-025-01988-8
Abstract

Inflammation is critical for controlling infections but can cause disease when unchecked. During Mycobacterium tuberculosis (Mtb) Infection, neutrophil-dominated inflammation is associated with exacerbated disease. ATG5 expression by neutrophils mediates autophagy-independent control of Infection but mechanistic understanding of how this regulates protective neutrophil function is lacking. Using genetic mouse models along with in vivo and in vitro Infection systems, we report herein that ATG5 is required in neutrophils to suppress type I interferon-induced PAD4-mediated histone citrullination and neutrophil extracellular trap (NET) release. In addition, ATG5 suppresses type I interferon-induced CXCL2 secretion and neutrophil swarming during Mtb Infection. Elevated type I IFN signalling and NET release contribute to the early susceptibility of Atg5fl/fl-LysM-Cre mice during Infection. These findings identify ATG5 as a master regulator of how type I interferon influences neutrophil responses during Infection, revealing a potential target for host-directed therapies.

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