{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:03:27Z","timestamp":1768507407423,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,30]]},"group-title":"Immunology","reference-count":39,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Inhalation of airborne conidia of the ubiquitous fungus\n                  <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                  commonly occurs but invasive aspergillosis is rare except in profoundly immunocompromised persons. Severe influenza predisposes patients to invasive pulmonary aspergillosis by mechanisms that are poorly defined. Using a post-influenza aspergillosis model, we found that superinfected mice had 100% mortality when challenged with\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  conidia on days 2 and 5 (early stages) of influenza A virus infection but 100% survival when challenged on days 8 and 14 (late stages). Influenza-infected mice superinfected with\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  had increased levels of the pro-inflammatory cytokines and chemokines IL-6, TNF\u03b1, IFN\u03b2, IL-12p70, IL-1\u03b1, IL-1\u03b2, CXCL1, G-CSF, MIP-1\u03b1, MIP-1\u03b2, RANTES and MCP-1. Surprisingly, on histopathological analysis, superinfected mice did not have greater lung inflammation compared with mice infected with influenza alone. Mice infected with influenza had dampened neutrophil recruitment to the lungs following subsequent challenge with\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  , but only if the fungal challenge was executed during the early stages of influenza infection. However, influenza infection did not have a major effect on neutrophil phagocytosis and killing of\n                  <jats:italic>A. fumigatus<\/jats:italic>\n                  conidia. Moreover, minimal germination of conidia was seen on histopathology even in the superinfected mice. Taken together, our data suggest that the high mortality rate seen in mice during the early stages of influenza-associated pulmonary aspergillosis is multifactorial, with a greater contribution from dysregulated inflammation than microbial growth.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Severe influenza is a risk factor for fatal invasive pulmonary aspergillosis; however, the mechanistic basis for the lethality is unclear. Utilizing an influenza-associated pulmonary aspergillosis (IAPA) model, we found that mice infected with influenza A virus followed by\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    had 100% mortality when superinfected during the early stages of influenza but survived at later stages. While superinfected mice had dysregulated pulmonary inflammatory responses compared to controls, they had neither increased inflammation nor extensive fungal growth. Although influenza-infected mice had dampened neutrophil recruitment to the lungs following subsequent challenge with\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    , influenza did not affect the ability of neutrophils to clear the fungi. Our data suggest that the lethality seen in our model IAPA is multifactorial with dysregulated inflammation being a greater contributor than uncontrollable microbial growth. If confirmed in humans, our findings provide a rationale for clinical studies of adjuvant anti-inflammatory agents in the treatment of IAPA.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.06.27.546808","type":"posted-content","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T16:15:10Z","timestamp":1688141710000},"source":"Crossref","is-referenced-by-count":0,"title":["Dysregulated Pulmonary Inflammatory Responses Exacerbate the Outcome of Secondary Aspergillosis Following Influenza"],"prefix":"10.64898","author":[{"given":"Chrono K.","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena V. N.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Akalin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles A.","family":"Specht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Lourenco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina L.","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaida G.","family":"Ramirez-Ortiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2556-9100","authenticated-orcid":false,"given":"Jennifer P.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3799-3064","authenticated-orcid":false,"given":"Stuart M.","family":"Levitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023070504350633000_2023.06.27.546808v1.1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00140-18"},{"key":"2023070504350633000_2023.06.27.546808v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00055-08"},{"key":"2023070504350633000_2023.06.27.546808v1.3","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00014-09"},{"key":"2023070504350633000_2023.06.27.546808v1.4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3390\/jof3040057","article-title":"Global and Multi-National Prevalence of Fungal Diseases\u2014Estimate Precision","volume":"3","year":"2017","journal-title":"Journal of Fungi"},{"key":"2023070504350633000_2023.06.27.546808v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"2023070504350633000_2023.06.27.546808v1.6","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.cmi.2019.04.031","article-title":"Intensive care management of influenza-associated pulmonary aspergillosis","volume":"25","year":"2019","journal-title":"Clin Microbiol Infect"},{"key":"2023070504350633000_2023.06.27.546808v1.7","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000504"},{"key":"2023070504350633000_2023.06.27.546808v1.8","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1108710"},{"key":"2023070504350633000_2023.06.27.546808v1.9","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2013.0095"},{"key":"2023070504350633000_2023.06.27.546808v1.10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathmechdis.3.121806.154316"},{"key":"2023070504350633000_2023.06.27.546808v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.08.030"},{"key":"2023070504350633000_2023.06.27.546808v1.12","doi-asserted-by":"crossref","first-page":"ofz247","DOI":"10.1093\/ofid\/ofz247","article-title":"Outcomes in Invasive Pulmonary Aspergillosis Infections Complicated by Respiratory Viral Infections in Patients With Hematologic Malignancies: A Case-Control Study","volume":"6","year":"2019","journal-title":"Open Forum Infect Dis"},{"key":"2023070504350633000_2023.06.27.546808v1.13","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1093\/cid\/ciaa010","article-title":"Influenza-Associated Pulmonary Aspergillosis: A Local or Global Lethal Combination?","volume":"71","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2023070504350633000_2023.06.27.546808v1.14","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S2213-2600(18)30274-1","article-title":"Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study","volume":"6","year":"2018","journal-title":"Lancet Respir Med"},{"issue":"2","key":"2023070504350633000_2023.06.27.546808v1.15","doi-asserted-by":"crossref","first-page":"480","DOI":"10.4049\/jimmunol.2000067","article-title":"Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis","volume":"205","year":"2020","journal-title":"The Journal of Immunology"},{"key":"2023070504350633000_2023.06.27.546808v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02854-22:e0285422"},{"key":"2023070504350633000_2023.06.27.546808v1.17","doi-asserted-by":"crossref","first-page":"eabq6682","DOI":"10.1126\/scitranslmed.abq6682","article-title":"A B1a - 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