A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis
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Acidification of the phagosome is considered to be a major mechanism used by macrophages against bacteria, including Mycobacterium tuberculosis (Mtb). Mtb blocks phagosome acidification, but interferon-gamma (IFN-gamma) restores acidification and confers antimycobacterial activity. Nonetheless, it remains unclear whether acid kills Mtb, whether the intrabacterial pH of any pathogen falls when it is in the phagosome and whether acid resistance is required for mycobacterial virulence. In vitro at pH 4.5, Mtb survived in a simple buffer and maintained intrabacterial pH. Therefore, Mtb resists phagolysosomal concentrations of acid. Mtb also maintained its intrabacterial pH and survived when phagocytosed by IFN-gamma-activated macrophages. We used transposon mutagenesis to identify genes responsible for Mtb's acid resistance. A strain disrupted in Rv3671c, a previously uncharacterized gene encoding a membrane-associated protein, was sensitive to acid and failed to maintain intrabacterial pH in acid in vitro and in activated macrophages. Growth of the mutant was also severely attenuated in mice. Thus, Mtb is able to resist acid, owing in large part to Rv3671c, and this resistance is essential for virulence. Disruption of Mtb's acid resistance and intrabacterial pH maintenance systems is an attractive target for chemotherapy.
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M. tuberculosis can survive at pH of 4.5, which has been linked to the expression of a specific resistance gene named Rv3671c.
“However, M. tuberculosis can survive at pH of 4.5, which has been linked to the expression of a specific resistance gene named Rv3671c (47, 48).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [47]
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Self-citation
- Authors
- Vandal, O. H., Pierini, L. M., Schnappinger, D., Nathan, C. F., & Ehrt, S.
- Affiliations
- Weill Cornell Medicine (US)
- Corresponding author
- Nathan, Carl F
- Ehrt, Sabine
- Venue
- Nature Medicine
- Published
- 2008-07-20
- Volume
- 14
- Issue
- 8
- Pages
- 849-854
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2538620
- OpenAlex
- W1966448483
- Cited by
- 368
- References
- 41
- Citations by year
- 2026: 22 · 2025: 19 · 2024: 14 · 2023: 25 · 2022: 25 · 2021: 20 · 2020: 18 · 2019: 28 · 2018: 22 · 2017: 23 · 2016: 18 · 2015: 22 · 2014: 20 · 2013: 23 · 2012: 20
- FWCI
- 10.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Hospital for Special Surgery
- National Institutes of Health
- Weill Cornell Medical College
- National Institute of Allergy and Infectious Diseases (P01AI056293)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- Mycobacterium tuberculosis, phagosome acidification, acid resistance, membrane proteins, interferon-gamma, macrophage phagocytosis, bacterial virulence, transposon mutagenesis, phagolysosomes
- MeSH terms
- Animals, Cell Membrane, DNA Transposable Elements, Genetic Complementation Test, Hydrogen-Ion Concentration, Interferon-gamma, Lysosomes, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Mutation, Mycobacterium tuberculosis, Mutagenesis, Drug Resistance, Bacterial, Mice
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