{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:15:39Z","timestamp":1791353739797,"version":"4.3.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014213","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AI103083"],"award-info":[{"award-number":["R01-AI103083"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AI150095"],"award-info":[{"award-number":["R01-AI150095"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AI131685"],"award-info":[{"award-number":["R01-AI131685"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R41-AI177204"],"award-info":[{"award-number":["R41-AI177204"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Hepatitis A virus (HAV) is a globally important cause of enterically-transmitted hepatitis. It is one of 9 distinct\n                    <jats:italic>Hepatovirus<\/jats:italic>\n                    species in the\n                    <jats:italic>Picornaviridae,<\/jats:italic>\n                    among which phylogenetic reconstructions suggest multiple past host species jumps. HAV readily infects mice with defective type I interferon responses, suggesting the major barrier preventing human HAV from replicating in a rodent host is an inability to overcome innate immune responses. In prior studies, only a single nonsynonymous mutation of uncertain significance (3D\n                    <jats:sup>pol<\/jats:sup>\n                    -R468K) was identified within the genome of wild-type HAV following passage in interferon-receptor knockout mice. Here, we show that R468K and other mutations in the 3D\n                    <jats:sup>pol<\/jats:sup>\n                    polymerase (E461D and D473G) are uniformly present in virus recovered from\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice following intrahepatic injection of HAV RNA. Reverse molecular genetics experiments confirmed RNAs with R468K or D473G mutations were more likely to initiate sustained infection than wild-type RNA in mice. In competition experiments using cell culture-adapted virus, a K468 mutant out-replicated wild-type R468 in murine cells, whereas R468 rapidly replaced K468 in human cells. These 3D\n                    <jats:sup>pol<\/jats:sup>\n                    mutations thus promote HAV replication in a host species-specific manner. AlphaFold 3 modeling indicates E461, R468, and D473 are closely positioned on the surface of the 3D\n                    <jats:sup>pol<\/jats:sup>\n                    thumb domain, suggesting they modulate interactions with species-specific host factor(s). Proteomics analysis of proteins co-precipitating with HA-3D\n                    <jats:sup>pol<\/jats:sup>\n                    expressed in Huh-7.5 cells identified heat shock 70 protein HSPA8 and its co-chaperone, BAG2. HSPA8 is known to be a critical hepatovirus host factor and HAV genome replication is highly dependent upon heat shock chaperone activity. The mouse-adaptive R468K mutation enhances co-immunoprecipitation of 3D\n                    <jats:sup>pol<\/jats:sup>\n                    with murine HSPA8 and BAG2, suggesting it facilitates chaperone-dependent acquisition of polymerase function in mouse cells. Our results identify a non-immune barrier to HAV replication in mice and enable future reverse molecular genetics studies in a small animal model.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014213","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T17:40:02Z","timestamp":1778521202000},"page":"e1014213","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Host species-specific mutations in the thumb domain of the 3Dpol polymerase are required for efficient replication of human hepatitis A virus in mice"],"prefix":"10.1371","volume":"22","author":[{"given":"Ichiro","family":"Misumi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Shirasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Yonish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Gonz\u00e1lez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asuka","family":"Hirai-Yuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Whitmire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1450-806X","authenticated-orcid":true,"given":"Stanley M.","family":"Lemon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"issue":"12","key":"ppat.1014213.ref001","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.3201\/eid2212.160123","article-title":"Assessing the Epidemic Potential of RNA and DNA Viruses","volume":"22","author":"MEJ Woolhouse","year":"2016","journal-title":"Emerg Infect Dis"},{"issue":"2","key":"ppat.1014213.ref002","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41579-018-0115-z","article-title":"Host and viral determinants of influenza A virus species specificity","volume":"17","author":"JS Long","year":"2019","journal-title":"Nat Rev 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