{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:18:13Z","timestamp":1787498293726,"version":"build-2736575974"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/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                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\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 MEM medium (Sham).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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. Furthermore, we observed the complexity of COVID-19, such as the difference between lung and systemic immune response to viral infection and of viral load and mortality among SP-A variants in this model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1462278","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T01:14:17Z","timestamp":1743556457000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Differential immunoregulation by human surfactant protein A variants determines severity of SARS-CoV-2-induced lung disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Ikechukwu B.","family":"Jacob","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinkunmi O.","family":"Lawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma S.","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emerson M.","family":"Kopsack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin 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