Cited by 370Tuberculosis Research and EpidemiologyMycobacterium research and diagnosisInfectious Diseases and Tuberculosis

A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis

Open access
Vandal, Omar H, Pierini, Lynda M, Schnappinger, Dirk, Nathan, Carl F, Ehrt, Sabine·2008·Nature Medicine

Abstract

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.

Integrity signals

Registry

Crossref · 10.1038/nm.1795

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review