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While leukocyte-generated reactive oxygen species (ROS) are critical for the clearance of fungal conidia from the lung and resistance to IPA, the processes that govern ROS-dependent fungal cell death remain poorly defined. Using a flow cytometric approach that monitors two independent cell death markers, an endogenous histone H2A:mRFP nuclear integrity reporter and SYTOX Blue (live\/dead) stain, we observed that loss of\n            <jats:italic>Aspergillus fumigatus<\/jats:italic>\n            cytochrome c (\n            <jats:italic>cycA<\/jats:italic>\n            ) results in reduced susceptibility to cell death from hydrogen peroxide (H\n            <jats:sub>2<\/jats:sub>\n            O\n            <jats:sub>2<\/jats:sub>\n            ) treatment. Consistent with these observations\n            <jats:italic>in vitro<\/jats:italic>\n            , loss of\n            <jats:italic>cycA<\/jats:italic>\n            confers resistance to both NADPH oxidase-dependent and -independent killing by host leukocytes. Fungal ROS resistance is partly mediated by Bir1, a homolog to survivin in humans, as Bir1 overexpression results in decreased ROS-induced conidial cell death and reduced killing by innate immune cells\n            <jats:italic>in vivo<\/jats:italic>\n            . We further report that overexpression of the Bir1 N-terminal BIR domain in\n            <jats:italic>A. fumigatus<\/jats:italic>\n            conidia results in altered expression of metabolic genes that functionally converge on mitochondrial function and cytochrome c (\n            <jats:italic>cycA<\/jats:italic>\n            ) activity. Together, these studies demonstrate that\n            <jats:italic>cycA<\/jats:italic>\n            in\n            <jats:italic>A. fumigatus<\/jats:italic>\n            contributes to cell death responses that are induced by exogenous H\n            <jats:sub>2<\/jats:sub>\n            O\n            <jats:sub>2<\/jats:sub>\n            and by host leukocytes.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              <jats:italic>Aspergillus fumigatus<\/jats:italic>\n              can cause a life-threatening infection known as invasive pulmonary aspergillosis (IPA), which is marked by fungus-attributable mortality rates of 20%\u201330%. Individuals at risk for IPA harbor genetic mutations or incur pharmacologic defects that impair myeloid cell numbers and\/or function, exemplified by bone marrow transplant recipients, patients that receive corticosteroid therapy, or patients with chronic granulomatous disease (CGD). However, treatments for\n              <jats:italic>Aspergillus<\/jats:italic>\n              infections remain limited, and resistance to the few existing drug classes is emerging. Recently, the World Health Organization classified\n              <jats:italic>A. fumigatus<\/jats:italic>\n              as a critical priority fungal pathogen. Our cell death research identifies an important aspect of fungal biology that impacts susceptibility to leukocyte killing. Furthering our understanding of mechanisms that mediate the outcome of fungal-leukocyte interactions will increase our understanding of both the underlying fungal biology governing cell death and innate immune evasion strategies utilized during mammalian infection pathogenesis. Consequently, our studies are a critical step toward leveraging these mechanisms for novel therapeutic advances.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00305-23","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T13:01:03Z","timestamp":1697115663000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["<i>Aspergillus fumigatus<\/i>\n            cytochrome c impacts conidial survival during sterilizing immunity"],"prefix":"10.1128","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8548-5080","authenticated-orcid":false,"given":"Matthew R.","family":"James","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-438X","authenticated-orcid":true,"given":"Mariano A.","family":"Aufiero","sequence":"additional","affiliation":[{"name":"Louis V Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4745-9276","authenticated-orcid":true,"given":"Elisa M.","family":"Vesely","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourabh","family":"Dhingra","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko-Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-5412","authenticated-orcid":true,"given":"Tobias M.","family":"Hohl","sequence":"additional","affiliation":[{"name":"Louis V Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA"},{"name":"Infectious Disease Service, Department of Medicine, Memorial Hospital, New York, New York, USA"},{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5503-5006","authenticated-orcid":true,"given":"Robert A.","family":"Cramer","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","volume-title":"WHO fungal priority pathogens list to guide research, development and public health action","author":"World Health Organization","year":"2022","unstructured":"World Health Organization. 2022. 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