{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T00:42:27Z","timestamp":1778892147257,"version":"3.51.4"},"posted":{"date-parts":[[2023,6,7]]},"group-title":"Microbiology","reference-count":51,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Invasive pulmonary aspergillosis (IPA) is a life-threatening infection caused by species in the ubiquitous fungal genus\n                  <jats:italic>Aspergillus<\/jats:italic>\n                  . 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 cell impermeable (live\/dead) stain, we observed that loss of\n                  <jats:italic>A. 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 in part 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%-30%. Individuals at risk of 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 remains limited, and resistance to the few existing drug classes is emerging. Recently, the World Health Organization (WHO) classified\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    as a critical priority fungal pathogen. Our 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":"10.1101\/2023.06.07.544103","type":"posted-content","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T01:30:10Z","timestamp":1686187810000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Aspergillus fumigatus<\/i>\n                  cytochrome c impacts conidial survival during sterilizing immunity"],"prefix":"10.64898","author":[{"given":"Matthew R","family":"James","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-438X","authenticated-orcid":false,"given":"Mariano A","family":"Aufiero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4745-9276","authenticated-orcid":false,"given":"Elisa M","family":"Vesely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sourabh","family":"Dhingra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ko-Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-5412","authenticated-orcid":false,"given":"Tobias M","family":"Hohl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5503-5006","authenticated-orcid":false,"given":"Robert A","family":"Cramer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023061212101822000_2023.06.07.544103v1.1","unstructured":"World Health Organization . 2022. 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