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We evaluated the role of macrophage autophagy in the response to<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptococcus neoformans<\/jats:named-content>and<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida albicans<\/jats:named-content>, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>. In contrast, LC3 was found in only a few vacuoles containing<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>previously opsonized with antibody but never after complement-mediated phagocytosis. Disruption of host autophagy<jats:italic>in vitro<\/jats:italic>by RNA interference against ATG5 (autophagy-related 5) decreased the phagocytosis of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>and the fungistatic activity of J774.16 macrophage-like cells against both fungi, independent of the opsonin used. ATG5-knockout bone marrow-derived macrophages (BMMs) also had decreased fungistatic activity against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>when activated. In contrast, nonactivated ATG5-knockout BMMs actually restricted<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>growth more efficiently, suggesting that macrophage autophagy plays different roles against<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>, depending on the macrophage type and activation. Interference with autophagy in J774.16 cells also decreased nonlytic exocytosis of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>, increased interleukin-6 secretion, and decreased gamma interferon-induced protein 10 secretion. Mice with a conditionally knocked out ATG5 gene in myeloid cells showed increased susceptibility to intravenous<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>infection. In contrast, these mice manifested no increased susceptibility to<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. neoformans<\/jats:named-content>, as measured by survival, but had fewer alternatively activated macrophages and less inflammation in the lungs after intratracheal infection than control mice. These results demonstrate the complex roles of macrophage autophagy in restricting intracellular parasitism by fungi and reveal connections with nonlytic exocytosis, humoral immunity, and cytokine signaling.<\/jats:p>","DOI":"10.1128\/iai.00358-12","type":"journal-article","created":{"date-parts":[[2012,6,19]],"date-time":"2012-06-19T02:56:25Z","timestamp":1340074585000},"page":"3065-3076","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":108,"title":["Macrophage Autophagy in Immunity to Cryptococcus neoformans and Candida albicans"],"prefix":"10.1128","volume":"80","author":[{"given":"Andr\u00e9 Moraes","family":"Nicola","sequence":"first","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis R.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Antonio","family":"Dal-Rosso","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Saylor","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdia","family":"De Jesus","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Nosanchuk","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Casadevall","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700036104"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.09.061"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.6.1437"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1997.00238.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/49.suppl_1.37"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2009.05.016"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.08.016"},{"key":"e_1_3_3_9_2","volume-title":"Cryptococcus from human pathogen to model yeast","author":"Dromer F","year":"2011","unstructured":"DromerFCasadevallAPerfectJRSorrellT. 2011. 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