{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:33:37Z","timestamp":1768505617733,"version":"3.49.0"},"posted":{"date-parts":[[2023,8,9]]},"group-title":"Microbiology","reference-count":64,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The magnitude and duration of vertebrate viremia are critical determinants of arbovirus transmission, geographic spread, and disease severity\u2014yet, mechanisms determining arbovirus viremia levels are poorly defined. Previous studies have drawn associations between in vitro virion-glycosaminoglycan (GAG) interactions and in vivo clearance kinetics of virions from blood circulation. From these observations, it is commonly hypothesized that GAG-binding virions are rapidly removed from circulation due to ubiquitous expression of GAGs by vascular endothelial cells, thereby limiting viremia. Using an in vivo model for viremia, we compared the vascular clearance of low and enhanced GAG-binding viral variants of chikungunya (CHIKV), eastern-(EEEV), and Venezuelan-(VEEV) equine encephalitis viruses. We find GAG-binding virions are more quickly removed from circulation than their non-GAG-binding variant; however individual clearance kinetics vary between GAG-binding viruses, from swift (VEEV) to slow removal from circulation (EEEV). Remarkably, we find phagocytes are required for efficient vascular clearance of some enhanced GAG-binding virions. Moreover, transient depletion of vascular heparan sulfate (HS) impedes vascular clearance of only some GAG-binding viral variants and in a phagocyte-dependent manner, implying phagocytes can mediate vascular GAG-virion interactions. Finally, in direct contrast to mice, we find enhanced GAG-binding EEEV is resistant to vascular clearance in avian hosts, suggesting the existence of species-specificity in virion-GAG interactions. In summary, these data support a role for GAG-mediated clearance of some viral particles from the blood circulation, illuminate the potential of blood-contacting phagocytes as a site for GAG-virion binding, and suggest a role for species-specific GAG structures in arbovirus ecology.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Previously, evidence of arbovirus-GAG interactions in vivo has been limited to associations between viral residues shown to promote enhanced GAG-binding phenotypes in vitro and in vivo phenotypes of viral dissemination and pathogenesis. By directly manipulating host GAG expression, we identified virion-GAG interactions in vivo and discovered a role for phagocyte-expressed GAGs in viral vascular clearance. Moreover, we observe species-specific differences in viral vascular clearance of enhanced GAG-binding virions between murine and avian hosts. These data suggest species-specific variation in GAG structure is a mechanism to distinguish amplifying from dead-end hosts for arbovirus transmission.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.08.09.552690","type":"posted-content","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T02:16:26Z","timestamp":1691633786000},"source":"Crossref","is-referenced-by-count":1,"title":["Phagocyte-expressed glycosaminoglycans promote capture of alphaviruses from the blood circulation in a host species-specific manner"],"prefix":"10.64898","author":[{"given":"Stephanie E.","family":"Ander","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Guston","family":"Parks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bennett J.","family":"Davenport","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances S.","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Bosco-Lauth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn S.","family":"Carpentier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengqun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cormac J.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William B.","family":"Klimstra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory D.","family":"Ebel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas E.","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023081404300455000_2023.08.09.552690v1.1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.4.608-637.2005"},{"key":"2023081404300455000_2023.08.09.552690v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.10.4901-4911.2002"},{"key":"2023081404300455000_2023.08.09.552690v1.3","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2000.0546"},{"key":"2023081404300455000_2023.08.09.552690v1.4","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00611-08"},{"key":"2023081404300455000_2023.08.09.552690v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12034"},{"key":"2023081404300455000_2023.08.09.552690v1.6","first-page":"001726","article-title":"Klimstra, Glycosaminoglycan binding by arboviruses: a cautionary tale","volume":"103","year":"2022","journal-title":"Journal of General Virology"},{"key":"2023081404300455000_2023.08.09.552690v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9084(01)01290-1"},{"key":"2023081404300455000_2023.08.09.552690v1.8","first-page":"e00432","article-title":"Genome-Wide Screening Uncovers the Significance of N-Sulfation of Heparan Sulfate as a Host Cell Factor for Chikungunya Virus Infection","volume":"91","year":"2017","journal-title":"Journal of Virology"},{"key":"2023081404300455000_2023.08.09.552690v1.9","first-page":"e01751","article-title":"A Genome-Wide CRISPR-Cas9 Screen Identifies the Dolichol-Phosphate Mannose Synthase Complex as a Host Dependency Factor for Dengue Virus Infection","volume":"94","year":"2020","journal-title":"Journal of Virology"},{"key":"2023081404300455000_2023.08.09.552690v1.10","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02055-15"},{"key":"2023081404300455000_2023.08.09.552690v1.11","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.5.3587-3594.1998"},{"key":"2023081404300455000_2023.08.09.552690v1.12","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.2.1204-1210.2003"},{"key":"2023081404300455000_2023.08.09.552690v1.13","first-page":"e01500","article-title":"Chikungunya Virus Strains from Each Genetic Clade Bind Sulfated Glycosaminoglycans as Attachment Factors","volume":"94","year":"2020","journal-title":"Journal of Virology"},{"key":"2023081404300455000_2023.08.09.552690v1.14","doi-asserted-by":"crossref","unstructured":"A. S. Andrade , et al., Dengue virus 3 genotype I shows natural changes in heparan sulphate binding sites, cell interactions, and neurovirulence in a mouse model. Journal of General Virology 102 (2021).","DOI":"10.1099\/jgv.0.001630"},{"key":"2023081404300455000_2023.08.09.552690v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2013.04.017"},{"key":"2023081404300455000_2023.08.09.552690v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01364-12"},{"key":"2023081404300455000_2023.08.09.552690v1.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1110617108"},{"key":"2023081404300455000_2023.08.09.552690v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00937-13"},{"key":"2023081404300455000_2023.08.09.552690v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910670117"},{"key":"2023081404300455000_2023.08.09.552690v1.20","doi-asserted-by":"crossref","first-page":"e49163","DOI":"10.7554\/eLife.49163","article-title":"Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses","volume":"8","year":"2019","journal-title":"eLife"},{"key":"2023081404300455000_2023.08.09.552690v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2007.07.061"},{"key":"2023081404300455000_2023.08.09.552690v1.22","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.17.9278-9286.2003"},{"key":"2023081404300455000_2023.08.09.552690v1.23","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01672-14"},{"key":"2023081404300455000_2023.08.09.552690v1.24","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03116-13"},{"key":"2023081404300455000_2023.08.09.552690v1.25","first-page":"5","article-title":"In Vitro and In Vivo Phenotypes of Venezuelan, Eastern and Western Equine Encephalitis Viruses Derived from cDNA Clones of Human Isolates","volume":"15","year":"2023","journal-title":"Viruses"},{"key":"2023081404300455000_2023.08.09.552690v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(89)90178-6"},{"key":"2023081404300455000_2023.08.09.552690v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(94)90012-4"},{"key":"2023081404300455000_2023.08.09.552690v1.28","doi-asserted-by":"crossref","first-page":"e108966","DOI":"10.15252\/embj.2021108966","article-title":"MARCO+ lymphatic endothelial cells sequester arthritogenic alphaviruses to limit viremia and viral dissemination","volume":"40","year":"2021","journal-title":"The EMBO Journal"},{"key":"2023081404300455000_2023.08.09.552690v1.29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31990"},{"key":"2023081404300455000_2023.08.09.552690v1.30","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00175.2019"},{"key":"2023081404300455000_2023.08.09.552690v1.31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611259200"},{"key":"2023081404300455000_2023.08.09.552690v1.32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.330803"},{"key":"2023081404300455000_2023.08.09.552690v1.33","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1369\/0022155420937087","article-title":"Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression","volume":"68","year":"2020","journal-title":"J Histochem Cytochem"},{"key":"2023081404300455000_2023.08.09.552690v1.34","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X1999000500005"},{"key":"2023081404300455000_2023.08.09.552690v1.35","doi-asserted-by":"crossref","first-page":"150","DOI":"10.4161\/cib.4.2.14547","article-title":"Evolution of glycosaminoglycans","volume":"4","year":"2011","journal-title":"Communicative & Integrative Biology"},{"key":"2023081404300455000_2023.08.09.552690v1.36","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/0304-4165(77)90092-7","article-title":"Tissue specific distribution of sulfated mucopolysaccharides in mammals","volume":"498","year":"1977","journal-title":"Biochimica et Biophysica Acta (BBA) - General Subjects"},{"key":"2023081404300455000_2023.08.09.552690v1.37","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/0305-0491(82)90329-7","article-title":"Distribution of heparin and other sulfated glycosaminoglycans in vertebrates","volume":"73","year":"1982","journal-title":"Comparative Biochemistry and Physiology Part B: Comparative Biochemistry"},{"key":"2023081404300455000_2023.08.09.552690v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(83)91379-7"},{"key":"2023081404300455000_2023.08.09.552690v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9150(71)90005-0"},{"key":"2023081404300455000_2023.08.09.552690v1.40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jme\/tjab077","article-title":"Ecology and Epidemiology of Eastern Equine Encephalitis Virus in the Northeastern United States: An Historical Perspective","volume":"59","year":"2022","journal-title":"Journal of Medical Entomology"},{"key":"2023081404300455000_2023.08.09.552690v1.41","doi-asserted-by":"publisher","DOI":"10.1093\/jme\/tjv195"},{"key":"2023081404300455000_2023.08.09.552690v1.42","doi-asserted-by":"crossref","first-page":"106","DOI":"10.4049\/jimmunol.73.2.106","article-title":"Use of Chicks in Eastern and Western Equine Encephalitis Studies","volume":"73","year":"1954","journal-title":"Journal of Immunology"},{"key":"2023081404300455000_2023.08.09.552690v1.43","first-page":"286","article-title":"Studies on the North American arthropod-borne encephalitides","volume":"60","year":"1954","journal-title":"VII. Estimation of amount of eastern equine encephalitis virus inoculated by infected Aedes aegypti. Am J Hyg"},{"key":"2023081404300455000_2023.08.09.552690v1.44","doi-asserted-by":"publisher","DOI":"10.1603\/0022-2585-39.3.480"},{"key":"2023081404300455000_2023.08.09.552690v1.45","doi-asserted-by":"publisher","DOI":"10.1093\/jmedent\/30.1.281"},{"key":"2023081404300455000_2023.08.09.552690v1.46","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.9.7357-7366.1998"},{"key":"2023081404300455000_2023.08.09.552690v1.47","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02494-06"},{"key":"2023081404300455000_2023.08.09.552690v1.48","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02509-07"},{"key":"2023081404300455000_2023.08.09.552690v1.49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002719"},{"key":"2023081404300455000_2023.08.09.552690v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.12.020"},{"key":"2023081404300455000_2023.08.09.552690v1.51","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06449-11"},{"key":"2023081404300455000_2023.08.09.552690v1.52","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1016\/j.celrep.2016.06.076","article-title":"Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence","volume":"16","year":"2016","journal-title":"Cell Reports"},{"key":"2023081404300455000_2023.08.09.552690v1.53","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.22.010605.093433"},{"key":"2023081404300455000_2023.08.09.552690v1.54","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.3390\/ijms23041963","article-title":"Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation","volume":"23","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"key":"2023081404300455000_2023.08.09.552690v1.55","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.71.110601.135458"},{"key":"2023081404300455000_2023.08.09.552690v1.56","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1021\/acsmedchemlett.1c00343","article-title":"On the Selectivity of Heparan Sulfate Recognition by SARS-CoV-2 Spike Glycoprotein","volume":"12","year":"2021","journal-title":"ACS Med. Chem. Lett"},{"key":"2023081404300455000_2023.08.09.552690v1.57","doi-asserted-by":"crossref","first-page":"e1009803","DOI":"10.1371\/journal.ppat.1009803","article-title":"The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus entry into host cells","volume":"17","year":"2021","journal-title":"PLoS Pathog"},{"key":"2023081404300455000_2023.08.09.552690v1.58","first-page":"32","article-title":"The inapparent infection:disease ratio","volume":"87","author":"The 1959 outbreak of Eastern encephalitis in New Jersey. 5","year":"1968","journal-title":"Am J Epidemiol"},{"key":"2023081404300455000_2023.08.09.552690v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2008.10.013"},{"key":"2023081404300455000_2023.08.09.552690v1.60","doi-asserted-by":"crossref","first-page":"100121","DOI":"10.1016\/j.mbplus.2022.100121","article-title":"Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function","volume":"16","year":"2022","journal-title":"Matrix Biology Plus"},{"key":"2023081404300455000_2023.08.09.552690v1.61","first-page":"187","article-title":"Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein","volume":"4","year":"2019","journal-title":"Nat Microbiol"},{"key":"2023081404300455000_2023.08.09.552690v1.62","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02666-13"},{"key":"2023081404300455000_2023.08.09.552690v1.63","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040731"},{"key":"2023081404300455000_2023.08.09.552690v1.64","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.67.3.1269-1277.1993"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.08.09.552690","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:03:16Z","timestamp":1768453396000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.08.09.552690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,9]]},"references-count":64,"URL":"https:\/\/doi.org\/10.1101\/2023.08.09.552690","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1093\/pnasnexus\/pgae119","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,8,9]]},"subtype":"preprint"}}