<br><div> <head profile="http://www.w3.org/1999/xhtml/vocab"> <!--[if IE]><![endif]--> <meta http-equiv="Content-Type" content="text/html; charset=utf-8"/> <link rel="dns-prefetch" href="//scholar.google.com"/> <link rel="dns-prefetch" href="//pnas-movie.glencoesoftware.com"/> <link rel="dns-prefetch" href="//www.google.com"/> <link rel="dns-prefetch" href="//www.google-analytics.com"/> <link rel="dns-prefetch" href="//stats.g.doubleclick.net"/> <meta name="viewport" content="initial-scale=1, maximum-scale=1, width=device-width, user-scalable=yes"/> <meta name="citation_funding_source" content="citation_funder_id=100000060;citation_grant_number=R01 AI073755;"/> <meta name="citation_funding_source" content="citation_funder_id=100000060;citation_grant_number=R44 AI079898;"/> <meta name="issue_cover_image" content="https://www.pnas.org/sites/default/files/highwire/pnas/117/51.cover-source.jpg"/> <meta name="type" content="article"/> <meta name="category" content="research-article"/> <meta name="HW.identifier" content="/pnas/117/51/32648.atom"/> <meta name="HW.pisa" content="pnas;117/51/32648"/> <meta name="DC.Format" content="text/html"/> <meta name="DC.Language" content="en"/> <meta name="DC.Title" content="Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury"/> <meta name="DC.Identifier" content="10.1073/pnas.2014096117"/> <meta name="DC.Date" content="2020-12-22"/> <meta name="DC.Publisher" content="National Academy of Sciences"/> <meta name="DC.Rights" content="Copyright © 2020 the Author(s). Published by PNAS.. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)."/> <meta name="DC.AccessRights" content="open-access"/> <meta name="DC.Description" content="Fatal cases of yellow fever are preceded by the development of hemorrhagic complications. While yellow fever virus is known to infect hepatocytes, the relationship between hepatocyte infection and the development of hemorrhage is currently undefined. Here, we identified high concentrations of D-dimer in the blood of yellow fever patients, indicative of a process that involves the activation and consumption of clotting factors. We then developed a mouse model in which only transplanted human hepatocytes could be infected at high levels. By examining clotting parameters in this model, we determined that hepatocyte infection alone is insufficient to cause the activation and consumption of coagulation factors observed in severe cases of yellow fever in humans and nonhuman primates. All study data are included in the article and supporting information."/> <meta name="DC.Contributor" content="Adam L. Bailey"/> <meta name="DC.Contributor" content="Liang-I Kang"/> <meta name="DC.Contributor" content="Luiz Gonzaga Francisco de Assis Barros D’Elia Zanella"/> <meta name="DC.Contributor" content="Cássia G. T. Silveira"/> <meta name="DC.Contributor" content="Yeh-Li Ho"/> <meta name="DC.Contributor" content="Lander Foquet"/> <meta name="DC.Contributor" content="Greg Bial"/> <meta name="DC.Contributor" content="Broc T. McCune"/> <meta name="DC.Contributor" content="Amaro Nunes Duarte-Neto"/> <meta name="DC.Contributor" content="Archana Thomas"/> <meta name="DC.Contributor" content="Hans-Peter Raué"/> <meta name="DC.Contributor" content="Kathleen Byrnes"/> <meta name="DC.Contributor" content="Esper G. Kallas"/> <meta name="DC.Contributor" content="Mark K. Slifka"/> <meta name="DC.Contributor" content="Michael S. Diamond"/> <meta name="article:published_time" content="2020-12-22"/> <meta name="article:section" content="Biological Sciences"/> <meta name="citation_title" content="Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury"/> <meta name="citation_abstract" lang="en" content="<p>Yellow fever (YF) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the long-standing deployment of an effective vaccine. In its most severe form, YF manifests as a hemorrhagic fever that causes severe damage to visceral organs. Although coagulopathy is a defining feature of severe YF in humans, the mechanism by which it develops remains uncertain. Hepatocytes are a major target of yellow fever virus (YFV) infection, and the coagulopathy in severe YF has long been attributed to massive hepatocyte infection and destruction that results in a defect in clotting factor synthesis. However, when we analyzed blood from Brazilian patients with severe YF, we found high concentrations of plasma D-dimer, a fibrin split product, suggestive of a concurrent consumptive process. To define the relationship between coagulopathy and hepatocellular tropism, we compared infection and disease in <i>Fah</i><sup>−/−</sup>, <i>Rag2</i><sup>−/−</sup>, and <i>Il2rɣ</i><sup>−/−</sup> mice engrafted with human hepatocytes (hFRG mice) and rhesus macaques using a highly pathogenic African YFV strain. YFV infection of macaques and hFRG mice caused substantial hepatocyte infection, liver damage, and coagulopathy as defined by virological, clinical, and pathological criteria. However, only macaques developed a consumptive coagulopathy whereas YFV-infected hFRG mice did not. Thus, infection of cell types other than hepatocytes likely contributes to the consumptive coagulopathy associated with severe YF in primates and humans. These findings expand our understanding of viral hemorrhagic disease and associated coagulopathy and suggest directions for clinical management of severe YF cases.</p>"/> <meta name="citation_abstract" lang="en" scheme="executive-summary" content="<h3>Significance</h3> <p>Fatal cases of yellow fever are preceded by the development of hemorrhagic complications. While yellow fever virus is known to infect hepatocytes, the relationship between hepatocyte infection and the development of hemorrhage is currently undefined. Here, we identified high concentrations of D-dimer in the blood of yellow fever patients, indicative of a process that involves the activation and consumption of clotting factors. We then developed a mouse model in which only transplanted human hepatocytes could be infected at high levels. By examining clotting parameters in this model, we determined that hepatocyte infection alone is insufficient to cause the activation and consumption of coagulation factors observed in severe cases of yellow fever in humans and nonhuman primates.</p>"/> <meta name="citation_journal_title" content="Proceedings of the National Academy of Sciences"/> <meta name="citation_publisher" content="National Academy of Sciences"/> <meta name="citation_publication_date" content="2020/12/22"/> <meta name="citation_mjid" content="pnas;117/51/32648"/> <meta name="citation_id" content="117/51/32648"/> <meta name="citation_public_url" content="https://www.pnas.org/content/117/51/32648"/> <meta name="citation_abstract_html_url" content="https://www.pnas.org/content/117/51/32648.abstract"/> <meta name="citation_full_html_url" content="https://www.pnas.org/content/117/51/32648.full"/> <meta name="citation_pdf_url" content="https://www.pnas.org/content/pnas/117/51/32648.full.pdf"/> <meta name="citation_issn" content="0027-8424"/> <meta name="citation_issn" content="1091-6490"/> <meta name="citation_journal_abbrev" content="PNAS"/> <meta name="citation_doi" content="10.1073/pnas.2014096117"/> <meta name="citation_pmid" content="33268494"/> <meta name="citation_volume" content="117"/> <meta name="citation_issue" content="51"/> <meta name="citation_num_pages" content="9"/> <meta name="citation_article_type" content="Research Article"/> <meta name="citation_section" content="Biological Sciences"/> <meta name="citation_firstpage" content="32648"/> <meta name="citation_lastpage" content="32656"/> <meta name="citation_access" content="all"/> <meta name="citation_author" content="Adam L. Bailey"/> <meta name="citation_author_institution" content="Washington University School of Medicine"/> <meta name="citation_author_email" content="adam.bailey@wustl.edu"/> <meta name="citation_author_email" content="diamond@wusm.wustl.edu"/> <meta name="citation_author_orcid" content="https://orcid.org/0000-0002-6560-9680"/> <meta name="citation_author" content="Liang-I Kang"/> <meta name="citation_author_institution" content="Washington University School of Medicine"/> <meta name="citation_author" content="Luiz Gonzaga Francisco de Assis Barros D’Elia Zanella"/> <meta name="citation_author_institution" content="University of São Paulo"/> <meta name="citation_author_institution" content="State Civil Servant’s Hospital"/> <meta name="citation_author_orcid" content="https://orcid.org/0000-0002-3166-5633"/> <meta name="citation_author" content="Cássia G. T. 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Rojas;citation_title=Internally controlled, multiplex real-time reverse transcription PCR for dengue virus and yellow fever virus detection;citation_pages=1833-1836;citation_volume=98;citation_year=2018;citation_doi=10.4269/ajtmh.18-0024"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="twitter:title" content="Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image" content="https://www.pnas.org/content/117/51/32648/F1.large.jpg"/> <meta name="twitter:description" content="Fatal cases of yellow fever are preceded by the development of hemorrhagic complications. While yellow fever virus is known to infect hepatocytes, the relationship between hepatocyte infection and the development of hemorrhage is currently undefined. Here, we identified high concentrations of D-dimer in the blood of yellow fever patients, indicative of a process that involves the activation and consumption of clotting factors. We then developed a mouse model in which only transplanted human hepatocytes could be infected at high levels. By examining clotting parameters in this model, we determined that hepatocyte infection alone is insufficient to cause the activation and consumption of coagulation factors observed in severe cases of yellow fever in humans and nonhuman primates. All study data are included in the article and supporting information."/> <meta name="og-title" property="og:title" content="Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury"/> <meta name="og-url" property="og:url" content="https://www.pnas.org/content/117/51/32648"/> <meta name="og-site-name" property="og:site_name" content="PNAS"/> <meta name="og-description" property="og:description" content="Fatal cases of yellow fever are preceded by the development of hemorrhagic complications. While yellow fever virus is known to infect hepatocytes, the relationship between hepatocyte infection and the development of hemorrhage is currently undefined. Here, we identified high concentrations of D-dimer in the blood of yellow fever patients, indicative of a process that involves the activation and consumption of clotting factors. We then developed a mouse model in which only transplanted human hepatocytes could be infected at high levels. By examining clotting parameters in this model, we determined that hepatocyte infection alone is insufficient to cause the activation and consumption of coagulation factors observed in severe cases of yellow fever in humans and nonhuman primates. All study data are included in the article and supporting information."/> <meta name="og-type" property="og:type" content="article"/> <meta name="og-image" property="og:image" content="https://www.pnas.org/content/117/51/32648/F1.large.jpg"/> <meta name="format-detection" content="telephone=no"/> <link rel="canonical" href="https://www.pnas.org/content/117/51/32648"/> <meta name="Generator" content="Drupal 7 (http://drupal.org)"/> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="http://www.pnas.org/content/117/51/32648.full.pdf"/> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="http://www.pnas.org/content/117/51/32648.full.txt"/> <link rel="alternate" type="image/jpeg" title="Featured Figure" href="http://www.pnas.org/content/117/51/32648.featured-figure.jpg"/> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="http://www.pnas.org/content/117/51/32648.ppt"/> <link rel="shortcut icon" 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