A protective role for type I interferon signaling following infection with Mycobacterium tuberculosis carrying the rifampicin drug resistance-conferring RpoB mutation H445Y.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Mycobacterium tuberculosis* ; Interferon Type I*/metabolism ; Rifampin*/pharmacology ; Signal Transduction* ; DNA-Directed RNA Polymerases*/metabolism ; DNA-Directed RNA Polymerases*/genetics ; Bacterial Proteins*/genetics ; Bacterial Proteins*/metabolism; Animals ; Mice ; Mutation ; Mice, Inbred C57BL ; Drug Resistance, Bacterial/genetics ; Tuberculosis/microbiology ; Tuberculosis/immunology ; Tuberculosis/genetics ; Mice, Knockout

Interleukin-1 (IL-1) signaling is essential for controlling virulent Mycobacterium tuberculosis (Mtb) infection since antagonism of this pathway leads to exacerbated pathology and increased susceptibility. In contrast, the triggering of type I interferon (IFN) signaling is associated with the progression of tuberculosis (TB) disease and linked with negative regulation of IL-1 signaling. However, mice lacking IL-1 signaling can control Mtb infection if infected with an Mtb strain carrying the rifampin-resistance conferring mutation H445Y in its RNA polymerase β subunit (rpoB-H445Y Mtb). The mechanisms that govern protection in the absence of IL-1 signaling during rpoB-H445Y Mtb infection are unknown. In this study, we show that in the absence of IL-1 signaling, type I IFN signaling controls rpoB-H445Y Mtb replication, lung pathology, and excessive myeloid cell infiltration. Additionally, type I IFN is produced predominantly by monocytes and recruited macrophages and acts on LysM-expressing cells to drive protection through nitric oxide (NO) production to restrict intracellular rpoB-H445Y Mtb. These findings reveal an unexpected protective role for type I IFN signaling in compensating for deficiencies in IL-1 pathways during rpoB-H445Y Mtb infection.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Bobba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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R01 AI123780 United States AI NIAID NIH HHS; R01 AI134236 United States AI NIAID NIH HHS; R01 AI130454 United States AI NIAID NIH HHS; R01 AI111914 United States AI NIAID NIH HHS; T32 HL007317 United States HL NHLBI NIH HHS; R01 HL105427 United States HL NHLBI NIH HHS; P30 CA091842 United States CA NCI NIH HHS

0 (Interferon Type I)
VJT6J7R4TR (Rifampin)
EC 2.7.7.6 (DNA-Directed RNA Polymerases)
0 (Bacterial Proteins)
0 (rpoB protein, Mycobacterium tuberculosis)

Date Created: 20240411 Date Completed: 20240423 Latest Revision: 20240520

20240520

PMC11037539

10.1371/journal.ppat.1012137

38603763