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Hepatoviruses in Small Mammals Provide Hints to Hepatitis A Evolution

NEW YORK (GenomeWeb) – The hepatitis A virus (HAV) appears to have evolved in small mammals before making the jump to humans, according to a new study appearing online this week in the Proceedings of the National Academy of Sciences.

Members of the Hepatovirus Ecology Consortium tested nearly 16,000 tissue, blood, or fecal samples from 209 small mammal species, using nested RT-PCR to find new and known Hepatovirus and host species. The search uncovered 117 hepatovirus-positive samples obtained from 28 bat, rodent, shrew, and hedgehog host species, containing 13 hepatoviruses not described in the past.

Along with a phylogenetic analysis that grouped the viruses into seven clades that appear susceptible to host swapping, the researchers generated 14 almost-complete genome sequences for nine of the new viruses, demonstrating the small mammal hepatoviruses closely resemble the hepatitis A virus that infects humans.

"We demonstrate that these viruses share unique biological features with HAV, including structural, genomic, antigenic, and pathogenic properties," first author Jan Felix Drexler, a virology researcher affiliated with the University of Bonn Medical Center and the German Center for Infection Research (DZIF), and co-authors wrote.

"We found evidence of major shifts of HAV-related viruses between mammalian hosts in the past," they added, "suggesting both an origin of this viral genus in small mammals and a zoonotic origin of human HAV."

In an effort to flesh out the hepatovirus phylogenetic tree and find clues to human hepatitis A evolution, the team used broadly reactive, nested PCR to search for highly conserved VP2 hepatovirus sequences in 15,987 blood, tissue, and fecal samples from 209 rodent, treeshrew, bat, hedgehog, shrews, and tenrec species from around the world.

Indeed, the researchers detected hepatovirus sequences in 117 samples, collected on five continents. They found that bat and rodent hosts were particularly common, with 13 species from each order testing positive. Hepatoviruses were also detected in one shrew species and one species of hedgehog.

A phylogenetic look at the small mammal hepatovirus set highlighted seven main clades, including clades infecting bats, bats and hedgehogs, bats and shrews, or rodents in various parts of the world.

Of those, the clade VII hepatoviruses infecting rodents in Asia and Central Europe grouped most closely to the hepatoviruses that infect humans and other primates, including HAV. From the phylogenetic groupings, the team saw signs of host switching in hepatoviruses, which appear to have started out infecting small insect-eating placental mammals.

When they focused on the 14 nearly complete genome sequences generated for nine of the new hepatoviruses, the researchers found that the genomes resemble human HAV in many respects — from their size, codon usage, and low guanine and cytosine nucleotide content to their organization, structural element repertoires, and pathogenicity effects in their hosts.

Even so, the team detected antibodies reacting to human HAV in blood samples from just eight bats. Hundreds more bats, rodents, shrews, and hedgehogs tested negative for antibodies that could interact with hepatitis A virus-infected human cells in immunofluorescence-based assays.

"The unique ecologic traits of bats, including their longevity and spatial mobility compared with other small mammals may facilitate repeated encounters with human HAV in edemic areas," the study's authors noted. "However, it seems unlikely that such an exposure would be of sufficient magnitude to evoke antibody response without replication of the virus."