Year: 2024
Type: article
Abstract: During infection Mycobacterium tuberculosis (Mtb) forms physiologically distinct subpopulations that are recalcitrant to treatment and undetectable using standard diagnostics. These difficult to culture or differentially culturable (DC) Mtb are revealed in liquid media, their revival is often stimulated by resuscitation-promoting factors (Rpf) and prevented by Rpf inhibitors. Here, we investigated the role of nitric oxide (NO) in promoting the DC phenotype. Rpf-dependent DC Mtb were detected following infection of interferon-γ-induced macrophages capable of producing NO, but not when inducible NO synthase was inactivated. After exposure of Mtb to a new donor for sustained NO release (named NOD), the majority of viable cells were Rpf-dependent and undetectable on solid media. Gene expression analyses revealed a broad transcriptional response to NOD, including down-regulation of all five rpf genes. The DC phenotype was partially reverted by over-expression of Rpfs which promoted peptidoglycan remodelling. Thus, NO plays a central role in the generation of Rpf-dependent Mtb, with implications for improving tuberculosis diagnostics and treatments.
Source: Communications Biology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
Funders: European Federation of Pharmaceutical Industries and Associations, National Institute for Health and Care Research, University of Leicester, European Commission, Directorate for Biological Sciences, Biotechnology and Biological Sciences Research Council, Health Services Research Programme, St. George's, University of London, NIHR Leicester Biomedical Research Centre
Awards: G1073258374, MOLECULAR BASIS OF PKNB ESSENTIALITY IN MYCOBACTERIA, G1638752504, G2473961061, Model-based preclinical development of anti-tuberculosis drug combinations, G3207356259, G3820645210, G393177772, Integrating cAMP- and nitric oxide- signalling in Mycobacterium tuberculosis: novel regulatory networks that challenge established paradigms, G5110391135, Midlands Integrative Biosciences Training Partnership 2020, G5702163051, Midlands Integrative Biosciences Training Partnership (MIBTP)
OpenAlex ID: W4402949291