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To determine whether granuloma formation is key for containment of<jats:italic>C. neoformans<\/jats:italic>\u0394<jats:italic>gcs1<\/jats:italic>, we studied the role of<jats:italic>C. neoformans<\/jats:italic>glucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tg\u03b526) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tg\u03b526 mice infected with \u0394<jats:italic>gcs1<\/jats:italic>do not produce a lung granuloma and that the \u0394<jats:italic>gcs1<\/jats:italic>mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since \u0394<jats:italic>gcs1<\/jats:italic>can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice \u0394<jats:italic>gcs1<\/jats:italic>proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tg\u03b526 mouse survival and decreased the dissemination of \u0394<jats:italic>gcs1<\/jats:italic>cells to the central nervous system. Thus, these results suggest that the growth of \u0394<jats:italic>gcs1<\/jats:italic>in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbate<jats:italic>C. neoformans<\/jats:italic>infection in conditions in which there is severe host immunodeficiency.<\/jats:p>","DOI":"10.1128\/iai.00587-07","type":"journal-article","created":{"date-parts":[[2007,7,31]],"date-time":"2007-07-31T00:59:11Z","timestamp":1185843551000},"page":"4792-4798","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":118,"title":["Depletion of Alveolar Macrophages Decreases the Dissemination of a Glucosylceramide-Deficient Mutant of<i>Cryptococcus neoformans<\/i>in Immunodeficient Mice"],"prefix":"10.1128","volume":"75","author":[{"given":"Talar B.","family":"Kechichian","sequence":"first","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Shea","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Del Poeta","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Molecular Biology"},{"name":"Microbiology and Immunology"},{"name":"Division of Infectious Diseases, Medical University of South Carolina, Charleston, South Carolina 29425"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.09.061"},{"key":"e_1_3_2_3_2","first-page":"381","year":"1998","unstructured":"Casadevall, A., and J. 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