{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:06:05Z","timestamp":1790701565342,"version":"4.1.0"},"reference-count":41,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI160722"],"award-info":[{"award-number":["R21AI160722"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI178010"],"award-info":[{"award-number":["R01AI178010"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005347","name":"American Association for the Study of Liver Diseases","doi-asserted-by":"publisher","award":["PNC23-216751"],"award-info":[{"award-number":["PNC23-216751"]}],"id":[{"id":"10.13039\/100005347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Histoplasma capsulatum<\/jats:italic>\n                      is a fungal pathogen that thrives in macrophages until activated by interferon-gamma (IFN-\u03b3). Tumor necrosis factor-\u03b1 (TNF-\u03b1) is required for control of infection during adaptive immunity but does not directly activate macrophages to eliminate fungal elements. Collapse of immunity associated with TNF-\u03b1 blockade is not accompanied by depression of IFN-\u03b3. To determine if TNF-\u03b1 antagonism impairs fungal clearance prior to adaptive immunity, we infected mice given anti-TNF-\u03b1 and quantified lung\n                      <jats:italic toggle=\"yes\">H. capsulatum<\/jats:italic>\n                      up to day 3 of infection. Anti-TNF-\u03b1 elevated the number of organisms in the lungs by day 3. Neutralization of IFN-\u03b3 manifested a similar effect. Since neutralization of both cytokines impaired innate immunity, we hypothesized that the action of IFN-\u03b3 required TNF-\u03b1. IFN-\u03b3-stimulated macrophages expressed fungicidal activity\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , and TNF-\u03b1 neutralization or its congenital deficiency in macrophages reversed this effect. Blockade of TNF-\u03b1 slightly dampened M1 response but did not promote M2. TNF-\u03b1 was not required for IFN-\u03b3 to shift the metabolic capacity of macrophages. We investigated the production of nitric oxide, which is a mediator of anti-\n                      <jats:italic toggle=\"yes\">H<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">capsulatum<\/jats:italic>\n                      activity by macrophages. In the absence of TNF-\u03b1, there was no difference when compared to IFN-\u03b3 stimulation alone. Lung macrophages harbored the highest infection burden in anti-TNF-\u03b1 recipients. Though IFN-\u03b3 receptor 1 was modestly downregulated by anti-TNF-\u03b1 blockade, this treatment downregulated pSTAT1 at day 2 of infection. TNF-\u03b1 is required for optimal IFN-\u03b3 signaling and effector function of cytokine-stimulated macrophages. When TNF-\u03b1 is absent, macrophages are insufficiently activated and fail to halt intracellular growth of yeast cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00302-26","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:23:32Z","timestamp":1790699012000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Tumor necrosis factor-\u03b1 coordinates the macrophage innate immune response to\n                    <i>Histoplasma capsulatum<\/i>"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1118-2554","authenticated-orcid":true,"suffix":"III","given":"Bradford L.","family":"Crowther","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01e3m7079","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, Department of Medicine, University of Cincinnati College of 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