title: Hepatic damage associated with dengue-2 virus replication in liver cells of BALB/c mice.
abstract: One difficulty in studying dengue virus (DENV) is the lack of an experimental model that reproduces the human disease. In a previous work, we have shown that BALB/c mice intraperitoneally inoculated with a DENV-2 isolate presented viremia and mild focal areas of liver injuries. In this study, mice were inoculated by the intravenous route and presented extensive damage areas in the liver tissue, which were evaluated by histopathological and ultrastructural analysis. Hepatic injury was noted mainly around the central vein and portal tracts. Damages consist of hepatocyte injury, including steatosis, swelling and necrosis. Further, erythrophagocytosis, intercellular edema and vascular damages were evident, including hemorrhage, which is characteristic of the dengue-induced hepatitis in human liver. Hepatic lesions were already noted 2 days post infection (p.i.), although effects were more extensive after the seventh day p.i. An increase in alanine aminotransferase and aspartate aminotransferase serum levels was detected 7 and 14 days p.i., respectively, and had correlation to hepatic lesions. Alterations caused by the DENV infection were self-limiting, with a remarkable reduction of all liver damages 49 days p.i. Virus antigens were detected in hepatocytes, Kupffer cells and vascular endothelium, suggesting virus replication in these cells. In situ hybridization, using a probe that anneals in the virus negative RNA strand, showed positive reaction in hepatocytes and vascular endothelium cells of infected mice, thus confirming virus replication in such cells. In general, results revealed that this mouse model reproduces some histopathological effects observed in humans and supports previous findings indicating virus replication in the hepatic tissue.
authors.affiliation: Laboratório de Biotecnologia e Fisiologia de Infecções Virais, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Marciano Viana
authors.initials: MV
authors.lastname: Paes
authors.forename: Henrique Leonel
authors.initials: HL
authors.lastname: Lenzi
authors.forename: Ana Cristina Martins
authors.initials: AC
authors.lastname: Nogueira
authors.forename: Gerard James
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Angela Teixeira
authors.initials: AT
authors.lastname: Pinhão
authors.forename: Ester Maria
authors.initials: EM
authors.lastname: Mota
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Basílio-de-Oliveira
authors.forename: Hermann
authors.initials: H
authors.lastname: Schatzmayr
authors.forename: Ortrud Monika
authors.initials: OM
authors.lastname: Barth
authors.forename: Ada Maria de Barcelos
authors.initials: AM
authors.lastname: Alves
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000956:Antigens, Viral / Q000032:analysis; D001219:Aspartate Aminotransferases / Q000097:blood; D003715:Dengue / Q000097:blood / Q000473:pathology* / Q000821:virology; D003716:Dengue Virus / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012367:RNA, Viral / Q000032:analysis*; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D012367:RNA, Viral; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase