{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T01:25:30Z","timestamp":1771637130845,"version":"3.50.1"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Apoptosis of leukocytes is known to strongly influence the immunopathogenesis of infection. In this study, we dissected the death pathways of murine macrophages (M\u03a6s) infected with the intracellular pathogen Histoplasma capsulatum. Yeast cells caused apoptosis of M\u03a6s at a wide range of multiplicity of infection, but smaller inocula resulted in delayed detection of apoptosis. Upon infection, caspases 3 and 1 were activated, and both contributed to cell death; however, only the former was involved in apoptosis. The principal driving force for apoptosis involved the extrinsic pathway via engagement of TNFR1 by TNF-\u03b1. Infected M\u03a6s produced IL-10 that dampened apoptosis. The chronology of TNF-\u03b1 and IL-10 release differed in vitro. The former was detected by 2 h postinfection, and the latter was not detected until 8 h postinfection. In vivo, the lungs of TNFR1\u2212\/\u2212 mice infected for 1 d contained fewer apoptotic M\u03a6s than wild-type mice, whereas the lungs of IL-10\u2212\/\u2212 mice exhibited more. Blockade of apoptosis by a pan-caspase inhibitor or by simvastatin sharply reduced the release of TNF-\u03b1 but enhanced IL-10. However, these treatments did not modify the fungal burden in vitro over 72 h. Thus, suppressing cell death modulated cytokine release but did not alter the fungal burden. These findings provide a framework for the early pathogenesis of histoplasmosis in which yeast cell invasion of lung M\u03a6s engenders apoptosis, triggered in part in an autocrine TNF-\u03b1\u2013dependent manner, followed by release of IL-10 that likely prevents apoptosis of newly infected neighboring phagocytes.<\/jats:p>","DOI":"10.4049\/jimmunol.1102175","type":"journal-article","created":{"date-parts":[[2011,11,19]],"date-time":"2011-11-19T05:56:16Z","timestamp":1321682176000},"page":"334-344","source":"Crossref","is-referenced-by-count":37,"title":["Deciphering the Pathways of Death of <i>Histoplasma capsulatum<\/i>-Infected Macrophages: Implications for the Immunopathogenesis of Early Infection"],"prefix":"10.1093","volume":"188","author":[{"suffix":"Jr.","given":"George S","family":"Deepe","sequence":"first","affiliation":[{"name":"Medical Service, Veterans Affairs Hospital , Cincinnati, OH 45220"},{"name":"Division of Infectious Diseases, University of Cincinnati College of Medicine , Cincinnati, OH 45267"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William R","family":"Buesing","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Cincinnati College of Medicine , Cincinnati, OH 45267"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2025032409434788600_r1","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1128\/IAI.73.4.1907-1916.2005","article-title":"Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells","volume":"73","author":"Fink","year":"2005","journal-title":"Infect. 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