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 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.
Authors
- Asya Smirnov (ORCID: https://orcid.org/0000-0003-4767-1680)
- Joshua T. Mattila (ORCID: https://orcid.org/0000-0002-6384-1291)
- Darren Kreamalmeyer
- Rachel L. Kinsella (ORCID: https://orcid.org/0009-0003-4191-5047)
- Wandy L. Beatty (ORCID: https://orcid.org/0000-0003-0715-7361)
- Samuel R. McKee (ORCID: https://orcid.org/0009-0005-7166-2153)
- Chanchal Sur Chowdhury (ORCID: https://orcid.org/0000-0001-5896-1224)
- Reilly Woodson
- Priyanka Talukdar
- Sthefany M. Chavez (ORCID: https://orcid.org/0000-0001-5887-8826)
- Neha Dubey (ORCID: https://orcid.org/0009-0005-1581-9099)
- Sumanta Kumar Naik (ORCID: https://orcid.org/0000-0003-4499-0811)
- Ananda N. Rankin
- Daniel S. Lane
- Christina L. Stallings (ORCID: https://orcid.org/0000-0002-2747-5618)
- Michael E. McNehlan (ORCID: https://orcid.org/0000-0003-2038-1288)
- Abigail Hii
Institutions
- University College Dublin (IE)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.chom.2024.11.008
- Citations
- 37
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 14.39
Funders
- National Science Foundation
- University of Pittsburgh
- Children's Discovery Institute
- University College Dublin
- Association Neurofibromatoses et Recklinghause
- National Institutes of Health
- Center for Cellular Imaging, Washington University