Pharmacological inhibition of USP18 improves antibacterial responses and the intracellular control of Mycobacterium tuberculosis in macrophages
Year: 2026
Type: article
Abstract: Introduction Type I interferon (IFN-I) responses correlate with the severity of Tuberculosis. ISG15, a ubiquitin-like protein, regulates immune responses intracellularly by protein posttranslational modification (ISGylation) or extracellularly, in a cytokine-like manner. The ubiquitin specific protease USP18 deconjugates ISG15 from target proteins and is a major negative regulator of IFN-I signaling. Methods Here we show that M. tuberculosis infection induces ISGylation associated transcripts in murine bone marrow-derived macrophages (BMM). The expression of these transcripts was dependent on IFN-I signaling and was further enhanced by supplementation of IFN-β, but not with IFN-γ or IL-1β. While stimulation with IFN-β impaired the intracellular control of M. tuberculosis in BMM, the bacterial growth was not altered by addition of extracellular ISG15. Treatment with two USP18 inhibitors, increased the ISGylation in uninfected and M. tuberculosis -infected BMM. Results The inhibition of USP18 enhanced both IFN-I responses and antimicrobial responses in BMM and increased NF-κB-activation and IL-1β expression. Moreover, the USP18 inhibitors improved the intracellular macrophage control of M. tuberculosis in an IFN-I independent manner. Instead, the addition of IFN-β to the BMM cultures at least partially reversed the bacterial control conferred by the USP18 inhibition. Discussion Our results suggest that the pharmacological inhibition of USP18 can be further explored as a therapeutic tool in the control of tuberculosis.
Source: Frontiers in Immunology
Institutions: Southwest University, Karolinska Institutet, Anhui Medical University, Second Affiliated Hospital of Anhui Medical University, Medical University of Vienna, Zhejiang University, Leiden University Medical Center, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Second Xiangya Hospital of Central South University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Awards: G1304725737, Scalable target identification for metabolic liver disease, G3591610437, Mapping of human immune protective responses in the lung of individuals with latent or active Tuberculosis infection, Targeting tissue crosstalk to combat non-alcoholic fatty liver disease, Functional human 3D in vitro models as a preclinical screening platform for understanding the hepatotoxicity and liver biodistribution of biologics, Regulation and topography of pulmonary cellular immune responses in clinical and experimental Tuberculosis, Targeting adipose tissue-liver cross talk to combat non-alcoholic fatty liver disease
OpenAlex ID: W7133553372