Nitric oxide induces the distinct invisibility phenotype of Mycobacterium tuberculosis
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.
Authors
- Vadim Makarov (ORCID: https://orcid.org/0000-0001-8746-2694)
- Obolbek Turapov (ORCID: https://orcid.org/0000-0002-5406-3213)
- Galina V. Mukamolova (ORCID: https://orcid.org/0000-0001-5697-2018)
- Marialuisa Crosatti
- Brindha Gap-Gaupool
- Jeffrey Green (ORCID: https://orcid.org/0000-0002-9070-3361)
- Sharon L. Kendall (ORCID: https://orcid.org/0000-0003-3277-3035)
- Joanna Bacon (ORCID: https://orcid.org/0000-0002-2217-228X)
- Olga Riabova (ORCID: https://orcid.org/0000-0002-3794-6495)
- Natalia Monakhova (ORCID: https://orcid.org/0000-0001-5448-9567)
- Simon J. Waddell (ORCID: https://orcid.org/0000-0002-3684-9116)
- Jennifer Hincks
- Martin I. Voskuil (ORCID: https://orcid.org/0000-0002-9565-7923)
- Emily Milburn
- Bradley Stewart
- Sarah Glenn
Institutions
- Brighton and Sussex Medical School (GB)
- Russian Academy of Sciences (RU)
- Royal Veterinary College (GB)
- University of Leicester (GB)
- Environment Agency (GB)
- Russian Engineering Academy (RU)
- NIHR Leicester Biomedical Research Centre (GB)
- University of Colorado Anschutz Medical Campus (US)
- University of Sheffield (GB)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-09-28
- DOI
- https://doi.org/10.1038/s42003-024-06912-0
- Citations
- 5
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.95
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
- St. George's, University of London
- NIHR Leicester Biomedical Research Centre