IMMUNOLOGY2024™ Conference Recordings-Contributions of innate immune responses to tuberculosis disease outcomes

Contributions of innate immune responses to tuberculosis disease outcomes

Video Transcription

Video Summary

The speaker described research on how neutrophils influence tuberculosis (TB) severity and how the gene ATG5 helps restrain damaging inflammation. TB kills more people than any other infection, and while most exposed people control it, about 10% develop active disease driven by excessive immune responses. In mouse models, deleting ATG5 in myeloid cells caused severe TB, with lungs filled by neutrophils and high bacterial loads. Neutrophil depletion rescued survival, showing these cells were contributing to disease rather than protection.<br /><br />The work then showed that ATG5 acts specifically in neutrophils, independent of autophagy. Loss of ATG5 increased type I interferon signaling, which promoted neutrophil extracellular trap formation (NETosis) and neutrophil clustering/swarming. Blocking type I interferon signaling, PAD4-mediated NETosis, or neutrophil swarming reduced disease severity. ATG5 normally suppresses both NETosis and swarming by limiting interferon-driven CXCL2 production and PAD4 activity.<br /><br />Overall, the talk revealed a previously unrecognized ATG5-dependent brake on destructive neutrophil responses during TB, explaining how inflammation can worsen infection and suggesting new therapeutic targets.

Keywords

tuberculosis

neutrophils

ATG5

type I interferon

NETosis

PAD4

inflammation