A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis

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The authors identify a previously undescribed gene that confers acid resistance to the bacterium and is essential for virulence (\n pages 809–810\n \n ). Acidification of the phagosome is considered to be a major mechanism used by macrophages against bacteria, including Mycobacterium tuberculosis (Mtb). Mtb blocks phagosome acidification1, but interferon-γ (IFN-γ) restores acidification and confers antimycobacterial activity2,3. 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-γ–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. 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c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Omar_H-Vandal-Aff1" data-author-popup="auth-Omar_H-Vandal-Aff1" data-author-search="Vandal, Omar H">Omar H Vandal</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Lynda_M-Pierini-Aff1-Aff2" data-author-popup="auth-Lynda_M-Pierini-Aff1-Aff2" data-author-search="Pierini, Lynda M">Lynda M Pierini</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Dirk-Schnappinger-Aff1" data-author-popup="auth-Dirk-Schnappinger-Aff1" data-author-search="Schnappinger, Dirk">Dirk Schnappinger</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Carl_F-Nathan-Aff1" data-author-popup="auth-Carl_F-Nathan-Aff1" data-author-search="Nathan, Carl F" data-corresp-id="c1">Carl F Nathan<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 5 authors for this article" title="Show all 5 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Sabine-Ehrt-Aff1" data-author-popup="auth-Sabine-Ehrt-Aff1" data-author-search="Ehrt, Sabine" data-corresp-id="c2">Sabine Ehrt<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/nm" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Medicine</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 14</b>, <span class="u-visually-hidden">pages </span>849–854 (<span data-test="article-publication-year">2008</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">4476 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">262 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">13 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nm.1795/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs2" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs2">Abstract</h2><div class="c-article-section__content" id="Abs2-content"><p>Acidification of the phagosome is considered to be a major mechanism used by macrophages against bacteria, including <i>Mycobacterium tuberculosis</i> (Mtb). Mtb blocks phagosome acidification<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="MacMicking, J.D., Taylor, G.A. & McKinney, J.D. Immune control of tuberculosis by IFN-γ–inducible LRG-47. Science 302, 654–659 (2003)." href="/articles/nm.1795#ref-CR1" id="ref-link-section-d273813357e358">1</a></sup>, but interferon-γ (IFN-γ) restores acidification and confers antimycobacterial activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Schaible, U.E., Sturgill-Koszycki, S., Schlesinger, P.H. & Russell, D.G. Cytokine activation leads to acidification and increases maturation of Mycobacterium avium–containing phagosomes in murine macrophages. J. Immunol. 160, 1290–1296 (1998)." href="/articles/nm.1795#ref-CR2" id="ref-link-section-d273813357e362">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Via, L.E. et al. Effects of cytokines on mycobacterial phagosome maturation. J. Cell Sci. 111, 897–905 (1998)." href="/articles/nm.1795#ref-CR3" id="ref-link-section-d273813357e365">3</a></sup>. 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. <i>In vitro</i> 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-γ–activated macrophages. We used transposon mutagenesis to identify genes responsible for Mtb's acid resistance. A strain disrupted in <i>Rv3671c</i>, a previously uncharacterized gene encoding a membrane-associated protein, was sensitive to acid and failed to maintain intrabacterial pH in acid <i>in vitro</i> 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.</p></div></div></section> <noscript> <div class="c-nature-box c-nature-box--side " data-component="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fnm.1795" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or subscribe</span> </a> </div> </div> </noscript> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> </div> <div class="c-article-access-provider u-mb-32 u-mt-0"> <p 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id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3: The Rv3671c mutant fails to maintain pH<sub>IB</sub> and is killed within activated macrophages.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.1795/MediaObjects/41591_2008_Article_BFnm1795_Fig3_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.1795/MediaObjects/41591_2008_Article_BFnm1795_Fig3_HTML.jpg" alt="" loading="lazy" width="312" height="266"></picture></div></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4: Rv3671c is required for Mtb growth and persistence <i>in vivo</i>.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.1795/MediaObjects/41591_2008_Article_BFnm1795_Fig4_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.1795/MediaObjects/41591_2008_Article_BFnm1795_Fig4_HTML.jpg" alt="" loading="lazy" width="312" height="195"></picture></div></div></figure></div> </div> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" 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Miesenböck (Oxford University) for providing ratiometric pH-GFP; F. Maxfield, J. Roberts and T. Odaira for guidance and support; and L. Cohen-Gould and T. Labissiere at the Electron Microscopy and Histology Core Facilities at Weill Cornell Medical College and Hospital for Special Surgery for assistance with electron microscopy. This work is supported by the US National Institutes of Health (grant PO1 AI056293 to C.F.N.) and the I.T. Hirschl Trust (S.E.). The Department of Microbiology and Immunology acknowledges the support of the William Randolph Hearst Foundation.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Departments of Microbiology and Immunology. Weill Cornell Medical College, 1300 York Avenue, New York, 10065, New York, USA</p><p class="c-article-author-affiliation__authors-list">Omar H Vandal, Lynda M Pierini, Dirk Schnappinger, Carl F Nathan & Sabine Ehrt</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, 10065, New York, USA</p><p class="c-article-author-affiliation__authors-list">Lynda M Pierini</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Omar_H-Vandal-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Omar H Vandal</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Omar%20H%20Vandal" class="c-article-button" data-track="click" data-track-action="author link - 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L.M.P. guided fluorescent microscopy experiments, including their analysis. D.S. guided experimental design and provided constructs. C.F.N. and S.E. guided the study. O.H.V., C.F.N. and S.E. wrote the paper. All authors discussed the results and commented on the manuscript.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding authors</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:cnathan@med.cornell.edu">Carl F Nathan</a> or <a id="corresp-c2" href="mailto:sae2004@med.cornell.edu">Sabine Ehrt</a>.</p></div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec12-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec12">Supplementary information</h2><div class="c-article-section__content" id="Sec12-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM8"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" 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Schnappinger, D. <i>et al.</i> A membrane protein preserves intrabacterial pH in intraphagosomal <i>Mycobacterium tuberculosis</i>. <i>Nat Med</i> <b>14</b>, 849–854 (2008). https://doi.org/10.1038/nm.1795</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/nm.1795?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time 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A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis | Nature Medicine