Type I IFN-mediated NET release promotes Mycobacterium tuberculosis replication and is associated with granuloma caseation

Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that duri...

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Veröffentlicht in:Cell host & microbe 2024-12, Vol.32 (12), p.2092-2111.e7
Hauptverfasser: Chowdhury, Chanchal Sur, Kinsella, Rachel L., McNehlan, Michael E., Naik, Sumanta K., Lane, Daniel S., Talukdar, Priyanka, Smirnov, Asya, Dubey, Neha, Rankin, Ananda N., McKee, Samuel R., Woodson, Reilly, Hii, Abigail, Chavez, Sthefany M., Kreamalmeyer, Darren, Beatty, Wandy, Mattila, Joshua T., Stallings, Christina L.
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Sprache:eng
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Zusammenfassung:Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication. Type I interferon promotes the formation of chromatin-containing vesicles that allow NET release without compromising plasma membrane integrity. Analysis of nonhuman primate granulomas supports a model where neutrophils are exposed to type I interferon from macrophages as they migrate into the granuloma, thereby enabling the release of NETs associated with necrosis and caseation. Our data reveal NET release as a promising target to inhibit Mtb pathogenesis. [Display omitted] •Mtb-induced NET release is PAD4 and type I IFN dependent•Type I IFN promotes NET release without compromising plasma membrane integrity•NET release by neutrophils promotes Mtb replication•NET release in granulomas is associated with necrosis and caseation in NHPs Sur Chowdhury et al. report that Mycobacterium tuberculosis (Mtb) infection results in the release of neutrophil extracellular traps (NETs) that promote Mtb replication and associate with tissue damage. Blocking NET release results in better control of Mtb replication, revealing a strategy for treating these deadly infections.
ISSN:1931-3128
1934-6069
1934-6069
DOI:10.1016/j.chom.2024.11.008