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Role of hepatocytes and Kupffer cells in age-dependent murine hepatitis caused by a phlebovirus, Punta Toro
P S Latham1, S B Sepelak, D Y Pifat
1Department of Medicine, University of Maryland Hospital, Baltimore.
Abstract:
Punta Toro virus (PTV) infection of C57BL/6 mice results in fulminant hepatic necrosis and death in 3-week-old susceptible mice, but survival with minimal hepatocellular necrosis in 8-week-old resistant mice. Susceptibility in 3-week-old mice is associated with an earlier rise of viral titers in liver and serum than that occurring in 8-week-old resistant mice. There is also an earlier and more rapid accumulation of infectious progeny in serum vs. liver after PTV infection in both age groups, suggesting that the virus may replicate in extrahepatic sites as well as the liver. PTV infection of isolated hepatocytes and Kupffer cells from 3- and 8-week-old mice demonstrates a significant age-related difference in the ability of these cells to support replication of PTV in vitro (P less than 0.05). The age-related difference in liver cell-PTV interaction appears to be an inherent difference in the liver cells themselves, since there are no age-related differences in viral adsorption, morphogenesis, cytopathic effect, or interferon action within these cells. Thus, age-related differences in PTV replication or dissemination at extrahepatic sites, and the ability of the virus to replicate in intrahepatic sites, may be additive factors in the expression of age-related susceptibility to PTV in C57BL/6 mice.
Insights
Punta Toro virus (PTV) infection causes severe liver damage and death in young mice, but not older ones. This age-related susceptibility is due to how liver cells support PTV replication.
Area of Science:
- Virology
- Immunology
- Hepatology
Background:
- Punta Toro virus (PTV) infection exhibits age-dependent outcomes in C57BL/6 mice.
- Younger mice experience severe hepatic necrosis and mortality, while older mice survive with minimal liver damage.
Purpose of the Study:
- To investigate the age-related differences in C57BL/6 mice's susceptibility to PTV infection.
- To elucidate the mechanisms underlying differential PTV replication and dissemination in young versus aged mice.
Main Methods:
- Comparative analysis of PTV titers in liver and serum of 3-week-old (susceptible) and 8-week-old (resistant) C57BL/6 mice post-infection.
- In vitro studies using isolated hepatocytes and Kupffer cells from mice of different ages to assess PTV replication capacity.
- Evaluation of viral adsorption, replication, cytopathic effects, and interferon responses within isolated liver cells.
Main Results:
- Susceptible young mice showed earlier and higher viral loads in liver and serum compared to resistant older mice.
- PTV replicated more efficiently in isolated liver cells from younger mice than from older mice in vitro.
- No age-related differences were observed in viral adsorption, morphogenesis, cytopathic effect, or interferon action within the liver cells themselves.
Conclusions:
- Age-related differences in the intrinsic ability of liver cells to support PTV replication contribute to differential susceptibility.
- Both intrahepatic and extrahepatic PTV replication/dissemination factors likely interact additively to determine age-dependent disease severity in C57BL/6 mice.