Alteration of Clinical Outcome and Histopathology of Yellow Fever Virus Infection in a Hamster Model by Previous Infection With Heterologous Flaviviruses

Abstract

Abstract. Using a recently described hamster model of severe yellow fever (YF), we examined the hypothesis that prior infection with heterologous flaviviruses protects against severe or fatal YF. Hamsters were singly or sequentially infected with Japanese encephalitis, St. Louis encephalitis, West Nile, and/or dengue-1 viruses, and then challenged with a virulent strain of yellow fever virus (YFV). In contrast to control (naive) hamsters, many of which appeared clinically ill or died after YFV infection, the flavivirus-immune animals remained asymptomatic. The flavivirus-immune hamsters also had a reduced viremia and lower serum levels of alanine aminotransferase and total bilirubin, compared with naive hamsters, following YFV infection. Histologically, livers of animals in the flavivirus-immune and control groups showed comparable levels of multifocal necrapoptosis. However, steatosis was not observed in the flavivirus-immune animals, whereas naive hamsters developed extensive microvesicular steatosis in the liver following YFV infection. These findings suggest that hepatocytic steatosis is an adverse microscopic feature associated with severe disease in YFV infection. Our experimental results support earlier anecdotal reports that prior exposure of humans to heterologous flaviviruses reduces subsequent risk of fatal YFV infection.

Efficacy of Post-Exposure Treatment of Yellow Fever With Ribavirin in a Hamster Model of the Disease

“…A similar histologic pattern has been observed in non-fatal YF virus infections from previous studies. 19,20 As confirmation of the reduced liver pathology in the treated animals, their ALT levels also remained at normal values, and the intensity of YF viral antigen staining in their hepatocytes was markedly diminished. Interestingly, the level and duration of viremia in the YF virus-infected animals was unaffected by treatment with ribavirin.…”

Frequency of histopathological changes in Howler monkeys ( Alouatta sp.) naturally infected with yellow fever virus in Brazil

“…This is a common fi nding reported in both necrotic and preserved cells in YF infection (3) (5) (6) . The presence of hepatocyte lipid vacuoles is almost constantly found in human YF cases, and this fi nding is also common in experimental models with other species infected with YFV (10) (16) . Hepatic steatosis was observed in fewer than half of YF-infected Howler monkeys in contrast with human cases.…”

“…The distribution of Brazilian NHP epizootics, despite the great diversity of primate species in the different Brazilian biomes, strengthens the importance of Howler monkeys in YF epidemiology and their sensitivity to YFV. The most frequent liver changes observed among YFVinfected primates in Brazil were observed in natural and experimental YFV infections (2) (10) (16) . Midzonal hepatocyte necrosis, steatosis and hemorrhage showed a positive correlation with apoptosis of hepatocytes, suggesting its association with a strong YFV pathogenic effect.…”

What Does the Future Hold for Yellow Fever Virus? (I)

“…Analyses based on surveillance data could provide additional insights on the significance of coinfection between YFV and other flaviviruses. Investigations on the effect of cross-immunity to other flaviviruses have brought experimental evidence that prior immunisation with DENV and/or other flaviviruses allows to reduce viremia upon YFV infection in rhesus macaques and significantly alleviated the symptoms associated to YFV infection in hamsters [179,185]. However, the effect on subsequent mosquito-borne transmission remains to be explored.…”