title: Evolutionary origins of hepatitis A virus in small mammals.
abstract: Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins. We conducted a targeted search for hepatoviruses in 15,987 specimens collected from 209 small mammal species globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews, which by pairwise sequence distance comprise 13 novel Hepatovirus species. Near-complete genomes from nine of these species show conservation of unique hepatovirus features, including predicted internal ribosome entry site structure, a truncated VP4 capsid protein lacking N-terminal myristoylation, a carboxyl-terminal pX extension of VP1, VP2 late domains involved in membrane envelopment, and a cis-acting replication element within the 3D(pol) sequence. Antibodies in some bat sera immunoprecipitated and neutralized human HAV, suggesting conservation of critical antigenic determinants. Limited phylogenetic cosegregation among hepatoviruses and their hosts and recombination patterns are indicative of major hepatovirus host shifts in the past. Ancestral state reconstructions suggest a Hepatovirus origin in small insectivorous mammals and a rodent origin of human HAV. Patterns of infection in small mammals mimicked those of human HAV in hepatotropism, fecal shedding, acute nature, and extinction of the virus in a closed host population. The evolutionary conservation of hepatovirus structure and pathogenesis provide novel insight into the origins of HAV and highlight the utility of analyzing animal reservoirs for risk assessment of emerging viruses.
authors.affiliation: Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany; German Centre for Infection Research, Bonn-Cologne, Germany; drexler@virology-bonn.de.
authors.forename: Jan Felix
authors.initials: JF
authors.lastname: Drexler
authors.affiliation: Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany; German Centre for Infection Research, Bonn-Cologne, Germany;
authors.forename: Victor M
authors.initials: VM
authors.lastname: Corman
authors.affiliation: Chumakov Institute of Poliomyelitis and Viral Encephalitides, Moscow 142782, Russia;
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Lukashev
authors.affiliation: Department of Viroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands;
authors.forename: Judith M A
authors.initials: JM
authors.lastname: van den Brand
authors.affiliation: Chumakov Institute of Poliomyelitis and Viral Encephalitides, Moscow 142782, Russia; Lomonosov Moscow State University, Moscow 119991, Russia;
authors.forename: Anatoly P
authors.initials: AP
authors.lastname: Gmyl
authors.affiliation: Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brünink
authors.affiliation: Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasche
authors.affiliation: Laboratory of Virus Research, University of Bremen, 28359 Bremen, Germany;
authors.forename: Nicole
authors.initials: N
authors.lastname: Seggewiβ
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292;
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Viroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands;
authors.forename: Lonneke M
authors.initials: LM
authors.lastname: Leijten
authors.affiliation: Institute of Evolutionary Ecology and Conservation Genomics, University of Ulm, 89069 Ulm, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Vallo
authors.affiliation: Department of Viroscience, Erasmus MC, 3000 CA, Rotterdam, The Netherlands;
authors.forename: Thijs
authors.initials: T
authors.lastname: Kuiken
authors.affiliation: Laboratory of Virus Research, University of Bremen, 28359 Bremen, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Dotzauer
authors.affiliation: Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, 17493 Greifswald-Insel Riems, Germany.
authors.forename: Rainer G
authors.initials: RG
authors.lastname: Ulrich
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292;
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
authors.affiliation: Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany; German Centre for Infection Research, Bonn-Cologne, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
mesh_terms: D000818:Animals; D005075:Biological Evolution; D030041:Hepatitis A virus / Q000235:genetics*; D006801:Humans; D008322:Mammals / Q000821:virology*; D008969:Molecular Sequence Data; D010802:Phylogeny
keywords: hepatitis A virus; pathogenesis; small mammals; viral evolution; zoonosis