{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:49:18Z","timestamp":1789181358372,"version":"build-2803163510"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01 AI139615"],"award-info":[{"award-number":["R01 AI139615"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01 AI172154"],"award-info":[{"award-number":["R01 AI172154"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01 AI125045"],"award-info":[{"award-number":["R01 AI125045"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2023,10,31]]},"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 interleukin (IL)-6, tumor necrosis factor (TNF)\u03b1, interferon (IFN)\u03b2, IL-12p70, IL-1\u03b1, IL-1\u03b2, CXC motif chemokine ligand 1 (CXCL1), granulocyte-colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1\u03b1, MIP-1\u03b2, regulated upon activation, normal T cell expressed and presumably secreted (RANTES), and monocyte chemoattractant protein (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>Aspergillus 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 of 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":"10.1128\/mbio.01633-23","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T09:02:31Z","timestamp":1694163751000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Dysregulated pulmonary inflammatory responses exacerbate the outcome of secondary aspergillosis following influenza"],"prefix":"10.1128","volume":"14","author":[{"given":"Chrono K.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Medicine, The University of Massachusetts Chan Medical School , Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena V. N.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Massachusetts Chan Medical School , Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Akalin","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Massachusetts Chan Medical School , Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Specht","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Massachusetts Chan Medical School , Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Lourenco","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Massachusetts Chan Medical School , Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina 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