{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T01:29:55Z","timestamp":1779154195333,"version":"3.51.4"},"reference-count":28,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2013,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p><jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Histoplasma capsulatum<\/jats:named-content>is a fungal respiratory pathogen that survives and replicates within the phagolysosome of macrophages. The molecular factors it utilizes to subvert macrophage antimicrobial defenses are largely unknown. Although the ability of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. capsulatum<\/jats:named-content>to prevent acidification of the macrophage phagolysosome is thought to be critical for intracellular survival, this hypothesis has not been tested since<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. capsulatum<\/jats:named-content>mutants that experience decreased phagosomal pH have not been identified. In a screen to identify<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. capsulatum<\/jats:named-content>genes required for lysis of bone marrow-derived macrophages (BMDMs), we identified an insertion mutation disrupting the<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. capsulatum<\/jats:named-content>homolog of 3-hydroxy-methylglutaryl coenzyme A (HMG CoA) lyase (<jats:italic>HCL1<\/jats:italic>). In addition to its inability to lyse macrophages, the<jats:italic>hcl1<\/jats:italic>mutant had a severe growth defect in BMDMs, indicating that HMG CoA lyase gene function is critical for macrophage colonization. In other organisms, HMG CoA lyase catalyzes the last step in the leucine catabolism pathway. In addition, both fungi and humans deficient in HMG CoA lyase accumulate acidic intermediates as a consequence of their inability to catabolize leucine. Consistent with observations in other organisms, the<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. capsulatum<\/jats:named-content><jats:italic>hcl1<\/jats:italic>mutant was unable to grow on leucine as the major carbon source, caused acidification of its growth medium<jats:italic>in vitro<\/jats:italic>, and resided in an acidified vacuole within macrophages. Mice infected with the<jats:italic>hcl1<\/jats:italic>mutant took significantly longer to succumb to infection than mice infected with the wild-type strain. Taken together, these data indicate the importance of Hcl1 function in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. capsulatum<\/jats:named-content>replication in the harsh growth environment of the macrophage phagosome.<\/jats:p>","DOI":"10.1128\/iai.00833-12","type":"journal-article","created":{"date-parts":[[2012,11,27]],"date-time":"2012-11-27T05:57:04Z","timestamp":1353995824000},"page":"411-420","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["The 3-Hydroxy-Methylglutaryl Coenzyme A Lyase<i>HCL1<\/i>Is Required for Macrophage Colonization by Human Fungal Pathogen Histoplasma capsulatum"],"prefix":"10.1128","volume":"81","author":[{"given":"Dervla T.","family":"Isaac","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Coady","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Van Prooyen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Sil","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA"},{"name":"Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2010.00984.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1053\/srin.2001.24241"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"582","DOI":"10.4049\/jimmunol.138.2.582","article-title":"Modulation of the macrophage oxidative burst by Histoplasma capsulatum","volume":"138","author":"Wolf JE","year":"1987","unstructured":"WolfJEKerchbergerVKobayashiGSLittleJR. 1987. 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