Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury

Author(s):Show less -

Bailey, Adam L. ^[1] ; Kang, I, Liang- ; Francisco de Assis Barros D'Elia Zanella, Luiz Gonzaga ^{[2, 3]} ; Silveira, Cassia G. T. ^[2] ; Ho, Yeh-Li ^[4] ; Foquet, Lander ^[5] ; Bial, Greg ^[5] ; McCune, Broc T. ^[6] ; Duarte-Neto, Amaro Nunes ^[7] ; Thomas, Archana ^[8] ; Raue, Hans-Peter ^[8] ; Byrnes, Kathleen ^[9] ; Kallas, Esper G. ^[4] ; Slifka, Mark K. ^[8] ; Diamond, Michael S. ^{[10, 9, 6, 11]}

Affiliation:Show less -

^[1] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 - USA

^[2] Univ Sao Paulo, Sch Med, Div Clin Immunol & Allergy, BR-01246903 Sao Paulo - Brazil

^[3] State Civil Servants Hosp, BR-04028000 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Med, Dept Infect & Parasit Dis, BR-01246903 Sao Paulo - Brazil

^[5] Yecuris Corp, Tualatin, OR 97062 - USA

^[6] Washington Univ, Dept Med, Sch Med, St Louis, MO 63110 - USA

^[7] Univ Sao Paulo, Clin Hosp, Sch Med, Dept Pathol, BR-01246903 Sao Paulo - Brazil

^[8] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 - USA

^[9] Kang, Liang-, I, Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 - USA

^[10] Washington Univ, Dept Mol Microbiol, Sch Med, St Louis, MO 63110 - USA

^[11] Washington Univ, Andrew M & Jane M Bursky Ctr Human Immunol & Immu, Sch Med, St Louis, MO 63110 - USA

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 117, n. 51, p. 32648-32656, DEC 22 2020.
• Web of Science Citations: 0

Abstract

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 Fah(-/-), Rag2(-/-), and Il2r gamma(-/-) 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. (AU)

• FAPESP's process: 16/01735-2 - Viral metagenomics to track, explain and predict the transmission and spatiotemporal spread of Dengue and Chikungunya viruses in Brazil
• Grantee: Ester Cerdeira Sabino
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/21728-2 - The use of modern autopsy techniques to investigate human diseases (MODAU)
• Grantee: Paulo Hilário Nascimento Saldiva
• Support Opportunities: Research Projects - Thematic Grants