{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:40:43Z","timestamp":1785415243688,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,18]]},"group-title":"Cell Biology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["NIH\/NIAID 5R01AI159290"],"award-info":[{"award-number":["NIH\/NIAID 5R01AI159290"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NIH\/HL 2T32HL007829"],"award-info":[{"award-number":["NIH\/HL 2T32HL007829"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  New World arenaviruses (NWAs) that cause viral hemorrhagic fever, such as Jun\u00edn virus, have few therapeutic options. Entry of these viruses into cells is mediated by binding to cell surface receptors, followed by endocytosis and trafficking to a low pH compartment. We showed previously that Signal Regulatory Protein Alpha (SIRPA), a critical cell surface receptor that inhibits macrophage phagocytic activity, decreases internalization by NWAs as well as other pathogenic RNA viruses that traffic to low pH compartments. Here we demonstrate that proteins involved in the SIRPA\/integrin signaling axis, including Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), src family kinases (SFKs), particularly FYN, focal adhesion kinase (FAK), and alpha-integrin play a role in viral endocytosis and that SIRPA inhibits virus entry through blocking this pathway. In addition to defining a role for integrins in viral entry, these studies also provide additional insight into SIRPA\u2019s interference in processes dependent on integrin signaling, including phagocytosis. Moreover, using drugs that block the integrin signaling pathway\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  , we show that there are additional steps that may be targeted therapeutically for inhibiting infection by RNA viruses that traffic to acidic compartments.\n                <\/jats:p>","DOI":"10.64898\/2026.04.17.719277","type":"posted-content","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T05:35:18Z","timestamp":1776576918000},"source":"Crossref","is-referenced-by-count":0,"title":["SIRPA suppresses integrin-dependent virus endocytosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9754-0748","authenticated-orcid":false,"given":"Zhonghao","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1247-7418","authenticated-orcid":false,"given":"Kruthika","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Animal, Dairy and Veterinary Sciences and Institute for Antiviral Research, Utah State University, Logan, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0562-8479","authenticated-orcid":false,"given":"Kie Hoon","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Animal, Dairy and Veterinary Sciences and Institute for Antiviral Research, Utah State University, Logan, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0160-1708","authenticated-orcid":false,"given":"Ciara Tipping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6298-0994","authenticated-orcid":false,"given":"Natalia","family":"Ansin","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6432-1880","authenticated-orcid":false,"given":"Nicol\u00e1s","family":"Sarute","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9113-2575","authenticated-orcid":false,"given":"Brian B.","family":"Gowen","sequence":"additional","affiliation":[{"name":"Department of Animal, Dairy and Veterinary Sciences and Institute for Antiviral Research, Utah State University, Logan, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-3769","authenticated-orcid":false,"given":"Susan R.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042111151367000_2026.04.17.719277v1.1","doi-asserted-by":"publisher","DOI":"10.3201\/eid1509.090017"},{"key":"2026042111151367000_2026.04.17.719277v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2016.02.001"},{"key":"2026042111151367000_2026.04.17.719277v1.3","doi-asserted-by":"crossref","first-page":"e0024125","DOI":"10.1128\/jvi.00241-25","article-title":"Phospho-activated non-muscle myosin IIA heavy chain supports different mechanisms of virus uptake","volume":"99","year":"2025","journal-title":"J Virol"},{"key":"2026042111151367000_2026.04.17.719277v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nri1859"},{"key":"2026042111151367000_2026.04.17.719277v1.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120142"},{"key":"2026042111151367000_2026.04.17.719277v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-27279-4"},{"key":"2026042111151367000_2026.04.17.719277v1.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009899"},{"key":"2026042111151367000_2026.04.17.719277v1.8","doi-asserted-by":"crossref","first-page":"e943","DOI":"10.1002\/ctm2.943","article-title":"CD47-SIRPalpha blocking-based immunotherapy: Current and prospective therapeutic strategies","volume":"12","year":"2022","journal-title":"Clin Transl Med"},{"key":"2026042111151367000_2026.04.17.719277v1.9","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1996.0248"},{"key":"2026042111151367000_2026.04.17.719277v1.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411765200"},{"key":"2026042111151367000_2026.04.17.719277v1.11","doi-asserted-by":"crossref","first-page":"28961","DOI":"10.1038\/s41598-024-79397-w","article-title":"Lymphocytic choriomeningitis arenavirus utilises intercellular connections for cell to cell spread","volume":"14","year":"2024","journal-title":"Sci Rep"},{"key":"2026042111151367000_2026.04.17.719277v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2009.08.027"},{"key":"2026042111151367000_2026.04.17.719277v1.13","doi-asserted-by":"crossref","first-page":"9964","DOI":"10.18632\/oncotarget.7128","article-title":"FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia","volume":"7","year":"2016","journal-title":"Oncotarget"},{"key":"2026042111151367000_2026.04.17.719277v1.14","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.142.2.573"},{"key":"2026042111151367000_2026.04.17.719277v1.15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00201-12"},{"key":"2026042111151367000_2026.04.17.719277v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00050-14"},{"key":"2026042111151367000_2026.04.17.719277v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0169(200011)47:3<174::AID-CM2>3.0.CO;2-N"},{"key":"2026042111151367000_2026.04.17.719277v1.18","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.virol.2016.10.002","article-title":"Focal adhesion kinase (FAK) regulates polymerase activity of multiple influenza A virus subtypes","volume":"499","year":"2016","journal-title":"Virology"},{"key":"2026042111151367000_2026.04.17.719277v1.19","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00530-14"},{"key":"2026042111151367000_2026.04.17.719277v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2009.03.005"},{"key":"2026042111151367000_2026.04.17.719277v1.21","doi-asserted-by":"crossref","unstructured":"Emonet, S.F. , A.V. Seregin , N.E. Yun , A.L. Poussard , A.G. Walker , J.C. de la Torre , and S. Paessler . 2010. Rescue From Cloned cDNAs And In Vivo Characterization of Recombinant Pathogenic Romero And Life-Attenuated Candid #1 Strains Of Junin Virus, The Causative Agent Of Argentine Hemorrhagic Fever Disease. J Virol.","DOI":"10.1128\/JVI.02102-10"},{"key":"2026042111151367000_2026.04.17.719277v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2007.10.010"},{"key":"2026042111151367000_2026.04.17.719277v1.23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.4.669"},{"key":"2026042111151367000_2026.04.17.719277v1.24","doi-asserted-by":"publisher","DOI":"10.1021\/jm800483v"},{"key":"2026042111151367000_2026.04.17.719277v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2010.12.006"},{"key":"2026042111151367000_2026.04.17.719277v1.26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002614"},{"key":"2026042111151367000_2026.04.17.719277v1.27","doi-asserted-by":"crossref","first-page":"115921","DOI":"10.1016\/j.celrep.2025.115921","article-title":"Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity","volume":"44","year":"2025","journal-title":"Cell reports"},{"key":"2026042111151367000_2026.04.17.719277v1.28","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s13402-019-00469-5","article-title":"CD47: role in the immune system and application to cancer therapy","volume":"43","year":"2020","journal-title":"Cell Oncol (Dordr"},{"key":"2026042111151367000_2026.04.17.719277v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.03.034"},{"key":"2026042111151367000_2026.04.17.719277v1.30","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41467-021-27949-3","article-title":"Host receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections","volume":"13","year":"2022","journal-title":"Nat Commun"},{"key":"2026042111151367000_2026.04.17.719277v1.31","doi-asserted-by":"crossref","unstructured":"Hickerson, B.T. , E.J. Sefing , K.W. Bailey , A.J. Van Wettere , M.L. Penichet , and B.B. Gowen . 2020. Type I interferon underlies severe disease associated with Junin virus infection in mice. Elife. 9.","DOI":"10.7554\/eLife.55352"},{"key":"2026042111151367000_2026.04.17.719277v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104782"},{"key":"2026042111151367000_2026.04.17.719277v1.33","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-015-2579-8"},{"key":"2026042111151367000_2026.04.17.719277v1.34","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.24.6721"},{"key":"2026042111151367000_2026.04.17.719277v1.35","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1382953"},{"key":"2026042111151367000_2026.04.17.719277v1.36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003232"},{"key":"2026042111151367000_2026.04.17.719277v1.37","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202152564"},{"key":"2026042111151367000_2026.04.17.719277v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1199"},{"issue":"204r","key":"2026042111151367000_2026.04.17.719277v1.39","first-page":"a131","article-title":"siRNA screen for genes that affect Junin virus entry uncovers voltage-gated calcium channels as a therapeutic target","volume":"5","year":"2013","journal-title":"Sci Transl Med"},{"key":"2026042111151367000_2026.04.17.719277v1.40","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s12866-024-03257-w","article-title":"A review of emerging health threats from zoonotic New World mammarenaviruses","volume":"24","year":"2024","journal-title":"BMC Microbiol"},{"key":"2026042111151367000_2026.04.17.719277v1.41","doi-asserted-by":"crossref","unstructured":"Li, Y. , H. Zhou , P. Liu , D. Lv , Y. Shi , B. Tang , J. Xu , T. Zhong , W. Xu , J. Zhang , J. Zhou , K. Ying , Y. Zhao , Y. Sun , Z. Jiang , H. Cheng , X. Zhang , and Y. Ke . 2023. SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47\/SIRPalpha axis. J Clin Invest. 133.","DOI":"10.1172\/JCI162870"},{"key":"2026042111151367000_2026.04.17.719277v1.42","doi-asserted-by":"crossref","first-page":"101710","DOI":"10.1016\/j.jbc.2022.101710","article-title":"Integrin mediates cell entry of the SARS-CoV-2 virus independent of cellular receptor ACE2","volume":"298","year":"2022","journal-title":"J Biol Chem"},{"key":"2026042111151367000_2026.04.17.719277v1.43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00760.x"},{"key":"2026042111151367000_2026.04.17.719277v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5402.655"},{"key":"2026042111151367000_2026.04.17.719277v1.45","doi-asserted-by":"crossref","first-page":"e1007439","DOI":"10.1371\/journal.ppat.1007439","article-title":"A potent Lassa virus antiviral targets an arenavirus virulence determinant","volume":"14","year":"2018","journal-title":"PLoS Pathog"},{"key":"2026042111151367000_2026.04.17.719277v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2012.01.011"},{"key":"2026042111151367000_2026.04.17.719277v1.47","doi-asserted-by":"crossref","unstructured":"Miller, W.D. , A. Manion , A.K. Mishra , C.J. Sheedy , A. Bond , B.M. Gardner , D.J. Montell , and M.A. Morrissey . 2025. CD47 inhibits phagocytosis through Vav dephosphorylation. J Cell Biol. 224.","DOI":"10.1083\/jcb.202502206"},{"key":"2026042111151367000_2026.04.17.719277v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.07.008"},{"key":"2026042111151367000_2026.04.17.719277v1.49","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvu017"},{"key":"2026042111151367000_2026.04.17.719277v1.50","doi-asserted-by":"publisher","DOI":"10.1385\/IR:31:3:267"},{"key":"2026042111151367000_2026.04.17.719277v1.51","first-page":"1","article-title":"Targeting integrin pathways: mechanisms and advances in therapy","volume":"8","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"2026042111151367000_2026.04.17.719277v1.52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1159\/000149021","article-title":"Presence of viral particles in the salivary gland of Calomys musculinus infected with Junin virus by a natural route","volume":"11","year":"1979","journal-title":"Intervirology"},{"key":"2026042111151367000_2026.04.17.719277v1.53","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.9.e45"},{"key":"2026042111151367000_2026.04.17.719277v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/nature05539"},{"key":"2026042111151367000_2026.04.17.719277v1.55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009662"},{"key":"2026042111151367000_2026.04.17.719277v1.56","doi-asserted-by":"crossref","first-page":"e3000137","DOI":"10.1371\/journal.pbio.3000137","article-title":"TRIM2, a novel member of the antiviral family, limits New World arenavirus entry","volume":"17","year":"2019","journal-title":"PLoS Biol"},{"key":"2026042111151367000_2026.04.17.719277v1.57","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-virology-101416-042001","article-title":"New World Arenavirus Biology","volume":"4","year":"2017","journal-title":"Annu Rev Virol"},{"key":"2026042111151367000_2026.04.17.719277v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2747"},{"key":"2026042111151367000_2026.04.17.719277v1.59","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807578106"},{"key":"2026042111151367000_2026.04.17.719277v1.60","doi-asserted-by":"crossref","first-page":"e0060524","DOI":"10.1128\/msphere.00605-24","article-title":"Unraveling the mystery of Tacaribe virus","volume":"9","year":"2024","journal-title":"mSphere"},{"key":"2026042111151367000_2026.04.17.719277v1.61","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06451-11"},{"key":"2026042111151367000_2026.04.17.719277v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-99893-7"},{"key":"2026042111151367000_2026.04.17.719277v1.63","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00329.2010"},{"key":"2026042111151367000_2026.04.17.719277v1.64","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.11.5718"},{"key":"2026042111151367000_2026.04.17.719277v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80401-1"},{"key":"2026042111151367000_2026.04.17.719277v1.66","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-8-14"},{"key":"2026042111151367000_2026.04.17.719277v1.67","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200708043"},{"key":"2026042111151367000_2026.04.17.719277v1.68","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.21.13223"},{"key":"2026042111151367000_2026.04.17.719277v1.69","doi-asserted-by":"publisher","DOI":"10.1042\/BST20211254"},{"key":"2026042111151367000_2026.04.17.719277v1.70","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.celrep.2019.11.020","article-title":"Integrin alphavbeta5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy","volume":"30","year":"2020","journal-title":"Cell reports"},{"key":"2026042111151367000_2026.04.17.719277v1.71","doi-asserted-by":"crossref","first-page":"105952","DOI":"10.1016\/j.antiviral.2024.105952","article-title":"Coadministration of LHF-535 and favipiravir protects against experimental Junin virus infection and disease","volume":"229","year":"2024","journal-title":"Antiviral Res"},{"key":"2026042111151367000_2026.04.17.719277v1.72","doi-asserted-by":"publisher","DOI":"10.1038\/nature10632"},{"key":"2026042111151367000_2026.04.17.719277v1.73","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009835"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.17.719277","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:15:25Z","timestamp":1776795325000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.17.719277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,18]]},"references-count":73,"URL":"https:\/\/doi.org\/10.64898\/2026.04.17.719277","relation":{},"subject":[],"published":{"date-parts":[[2026,4,18]]},"subtype":"preprint"}}