Study of Liver Injury and Cellular Infiltration in Mice Infected by Dengue Virus
Date Issued
2004
Date
2004
Author(s)
Sung, Jui-Min
DOI
en-US
Abstract
Lymphocyte activation, hepatic infiltration and elevated liver enzyme levels are observed in patients infected with dengue virus. However, the pathogenic mechanism of liver damage has never been studied. In this study, we observed that immunocompetent mice infected with DEN-2 strain 16681 had elevated serum ALT and AST levels and the liver cells were apoptotic, indicating that dengue virus induces liver damage in the mouse. Immunohistochemical staining revealed there was hepatic cellular infiltration and NK cells constituted the majority of infiltrating cells at day 1 of infection. By day 5, infiltrating cells consisted of mostly T cells, macrophages and neutrophils. Flow cytometric analysis revealed greater percentage of CD8 T cells than CD4 T cells in the liver and the ratio was 1.9, and most infiltrating T cells expressed CD44hi phenotype. When mice were given a second inoculation of DEN-2, the CD8 T to CD4 T cell ratio increased to 2.6 at day 3 after the second inoculation. Moreover, the liver enzyme levels also increased in mice after second inoculation, suggesting liver damage is associated with lymphocyte infiltration.
TCRβ as well as perforin knockout mice were used in order to delineate the role of T cells and NK cells in mediating liver damage. The results showed that liver enzyme levels in DEN-2 infected TCRβ knockout mice were significantly greater than uninfected controls at days 1 and 3 but not day 5 of infection and the enzyme levels in infected perforin knockout mice were significantly greater in day5, but not days 1 and 3 of infection. Further examination of anti-CD8 antibody treated wild type mice and MHC class I knockout mice indicated the role of CD8+ T cells in liver damage at day 5 of infection. Moreover, treating DEN-2 infected immunocompetent wild-type mice with anti-IP-10 antibody reduced the serum enzyme levels to that as in uninfected mice. These results indicate that a perforin-dependent mechanism, perhaps through recruited NK cells mediated liver damage at early time points of infection, whereas infiltrating T cells mediated liver damage at later time points.
Subjects
細胞浸潤
肝臟損傷
登革熱病毒
liver injury
cellular infiltration
dengue virus
SDGs
Type
other