{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:06:46Z","timestamp":1777493206353,"version":"3.51.4"},"posted":{"date-parts":[[2024,9,13]]},"group-title":"Immunology","reference-count":95,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T00:00:00Z","timestamp":1726185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,13]]},"abstract":"<jats:title>\n                  <jats:bold>Abstract<\/jats:bold>\n                <\/jats:title>\n                <jats:p>\n                  COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI\/ARDS) and\/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes (\n                  <jats:italic>SFTPA1<\/jats:italic>\n                  and\n                  <jats:italic>SFTPA2<\/jats:italic>\n                  ) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A\n                  <jats:sup>2<\/jats:sup>\n                  , 6A\n                  <jats:sup>4<\/jats:sup>\n                  ) and SP-A2 (variants 1A\n                  <jats:sup>0<\/jats:sup>\n                  , 1A\n                  <jats:sup>3<\/jats:sup>\n                  ). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2\/6A\n                  <jats:sup>2<\/jats:sup>\n                  (6A\n                  <jats:sup>2<\/jats:sup>\n                  ), hACE2\/6A\n                  <jats:sup>4<\/jats:sup>\n                  (6A\n                  <jats:sup>4<\/jats:sup>\n                  ), hACE2\/1A\n                  <jats:sup>0<\/jats:sup>\n                  (1A\n                  <jats:sup>0<\/jats:sup>\n                  ), and hACE2\/1A\n                  <jats:sup>3<\/jats:sup>\n                  (1A\n                  <jats:sup>3<\/jats:sup>\n                  ), one SP-A knockout (hACE2\/SP-A KO (KO) and one hACE2\/mouse SP-A (K18) mice, were challenged intranasally with 10\n                  <jats:sup>3<\/jats:sup>\n                  PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A\n                  <jats:sup>0<\/jats:sup>\n                  mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A\n                  <jats:sup>0<\/jats:sup>\n                  , and 6A\n                  <jats:sup>2<\/jats:sup>\n                  mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as\n                  <jats:italic>MyD88<\/jats:italic>\n                  ,\n                  <jats:italic>Stat3<\/jats:italic>\n                  ,\n                  <jats:italic>IL-18<\/jats:italic>\n                  , and\n                  <jats:italic>Jak2<\/jats:italic>\n                  in the lungs of KO and 1A\n                  <jats:sup>0<\/jats:sup>\n                  mice. However,\n                  <jats:italic>Mapk1<\/jats:italic>\n                  was significantly downregulated in 6A\n                  <jats:sup>2<\/jats:sup>\n                  versus 1A\n                  <jats:sup>0<\/jats:sup>\n                  mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1\/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6 and IL-1\u03b2 were comparatively higher in the lungs and sera of KO and 1A\n                  <jats:sup>0<\/jats:sup>\n                  mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.\n                <\/jats:p>","DOI":"10.1101\/2024.09.11.612497","type":"posted-content","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T01:28:45Z","timestamp":1726450125000},"source":"Crossref","is-referenced-by-count":1,"title":["Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung Disease"],"prefix":"10.64898","author":[{"given":"Ikechukwu B.","family":"Jacob","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinkunmi O.","family":"Lawal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salma S.","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emerson M.","family":"Kopsack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin S.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghe","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongkuan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul T.","family":"Massa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4269-5993","authenticated-orcid":false,"given":"Saravanan","family":"Thangamani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongpeng","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guirong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024091717450952000_2024.09.11.612497v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"2024091717450952000_2024.09.11.612497v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04442-5"},{"key":"2024091717450952000_2024.09.11.612497v1.3","unstructured":"https:\/\/covid19.who.int\/. 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