{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T06:24:49Z","timestamp":1787207089708,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,14]]},"group-title":"Immunology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Institute of Health","award":["R21IAI167956-01A1"],"award-info":[{"award-number":["R21IAI167956-01A1"]}]},{"name":"University at Buffalo Vice President for Health Sciences Aging Seed Funding"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                  (pneumococcus) are asymptomatic colonizers of the nasopharynx but can progress to pulmonary and systemic pathogens upon influenza A virus (IAV) infection. Polymorphonuclear cells (PMNs) are key for controlling\n                  <jats:italic>S. pneumoniae<\/jats:italic>\n                  , but their antibacterial function is impaired by IAV. Using a mouse model that allows transition of pneumococci from colonizers to disease-causing pathogens upon IAV co-infection, we examined the signaling pathways impairing PMN responses. We found that type I interferons (IFN) produced upon IAV infection drives impairment of PMN antibacterial responses as treatment with IFN inhibited pneumococcal killing by PMNs\n                  <jats:italic>ex vivo<\/jats:italic>\n                  , and\n                  <jats:italic>in vivo<\/jats:italic>\n                  blocking of IFN receptor 1 (IFNAR1) in IAV infected mice rescued PMN function. In exploring what controls PMN responsiveness to IFN, we tested CD73, an ectonucleotidase that regulates PMN responses in primary pneumococcal pneumonia. CD73 was required for the ability of neutrophils to respond to IFN. While wildtype and CD73KO mice had comparable IFNAR expression on PMNs and IFN\u0251 and IFN\ua7b5 levels upon co-infection, CD73KO PMNs expressed significantly lower levels of the interferon stimulated protein IFIT1 and were less responsive to IFN-mediated inhibition of antimicrobial activity\n                  <jats:italic>ex vivo<\/jats:italic>\n                  . In exploring mechanisms, we found that IFN and CD73 elevated reactive oxygen species production by PMN in response to IAV, which impaired their ability to kill pneumococci. Importantly, co-infected CD73KO mice cleared bacteremia and survived significantly better than wildtype controls. These findings suggest that CD73 impairs host defense against IAV\/\n                  <jats:italic>S. pneumoniae<\/jats:italic>\n                  co-infection in part by sensitizing PMNs to type I IFN-mediated inhibition of antibacterial function.\n                <\/jats:p>","DOI":"10.64898\/2026.08.12.744509","type":"posted-content","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T02:40:14Z","timestamp":1786761614000},"source":"Crossref","is-referenced-by-count":0,"title":["CD73 controls neutrophil responsiveness to type I interferon impairing antibacterial responses during secondary pneumococcal pneumonia"],"prefix":"10.64898","author":[{"given":"Alexsandra P.","family":"Lenhard","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe E.","family":"Picciano","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miles J.","family":"Stefko","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaunna R.","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manmeet","family":"Bhalla","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa N.","family":"Bou Ghanem","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University at Buffalo School of Medicine, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081922503039000_2026.08.12.744509v2.1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.01041"},{"key":"2026081922503039000_2026.08.12.744509v2.2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00058-05"},{"key":"2026081922503039000_2026.08.12.744509v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(04)00938-7"},{"key":"2026081922503039000_2026.08.12.744509v2.4","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005982"},{"key":"2026081922503039000_2026.08.12.744509v2.5","first-page":"194","article-title":"Hakansson AP: Streptococcus pneumoniae biofilm formation and dispersion during colonization and disease","volume":"4","year":"2014","journal-title":"Front Cell Infect Microbiol"},{"key":"2026081922503039000_2026.08.12.744509v2.6","doi-asserted-by":"crossref","unstructured":"Joma BH , Siwapornchai N , Vanguri VK , Shrestha A , Roggensack SE , Davidson BA , Tai AK , Hakansson AP , Meydani SN , Leong JM , et al.: A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity Upon Viral Infection and Advanced Age. 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