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

Autor: Bobba, Suhas, Chauhan, Kuldeep S., Akter, Sadia, Das, Shibali, Mittal, Ekansh, Mathema, Barun, Philips, Jennifer A., Khader, Shabaana A.
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Zdroj: PLoS Pathogens; 4/11/2024, Vol. 20 Issue 4, p1-22, 22p
Abstrakt: 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. Author summary: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and is responsible for 10 million active cases worldwide annually. The acquisition and dissemination of drug resistance to front-line antibiotics have stifled efforts to control and combat TB. Understanding the immune responses elicited during Mtb infection is imperative to develop novel therapeutics that bolster protective responses and limit detrimental processes. Recently, we found that mice do not require the inflammatory interleukin-1 (IL-1) signaling pathway to control Mtb infection if the infecting bacterial strains carry a specific drug resistance-conferring mutation. Instead, here we show that a different signaling pathway, type I interferon (IFN), mediates protection against drug-resistant mutant Mtb infection in the absence of IL-1 signaling. We also found that the primary producers of type I IFN during drug-resistant Mtb infection were recruited innate cells, namely monocytes and macrophages. The downstream impacts of IFN signals were varied, with macrophages restricting bacterial replication while other immune cell functions were likely impaired by IFN signaling. Our study provides new insights into the different host requirements for protection against infection by various Mtb strains and highlights the unexpected roles for type I IFN signaling during Mtb infection. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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