| Yellow fever (YF) is a significant human disease that is endemic in large parts of South America and sub-Saharan Africa. YF is caused by yellow fever virus (YFV), a mosquito-borne flavivirus (Family Flaviviridae, genus Flavivirus). An estimated 200,000 people are infected annually with a 20-50% case fatality rate. Wild-type yellow fever virus (YFV) infections result in a hepatotropic disease which is often fatal while vaccination with the live-attenuated 17-D strain results in productive infection yet is well-tolerated with few adverse events. The objective of this dissertation was to examine host responses of two human liver cell types, Kupffer cells and hepatocytes, to wild-type and vaccine strain YFV infection. Kupffer cells, which are resident liver macrophages, and hepatocytes are principal components of the liver, accounting for 82% (combined) of the liver cytoplasmic volume. These cell types are involved in host metabolism, detoxification, digestion, protein synthesis, coagulation and immune surveillance. Their dysfunction as a result of YFV infection could be associated with the development of severe disease. Kupffer cells and hepatocytes have been observed to contain large amounts of viral antigen at post-mortem examination of wild-type virus infections. Here, my study found that Kupffer cells and hepatocytes support infection and replication of both wild-type and vaccine strains. Wild-type (Asibi) virus grew to significantly higher titers in both cell types when compared to vaccine virus growth. The differences in replication efficiencies may be important for effective virus dissemination as well as immune detection. Significant differential host cytokine responses to infection by wild-type and vaccine viruses were observed in both Kupffer cells and in hepatocytes. The data reported here suggest that wild-type YFV may be able to regulate specific components of the host response, such as activation/regulation of anti-inflammatory cytokines IL-10 and IL-4, while the vaccine strain cannot. These results suggest that vaccine strain YFV stimulates an appropriate and regulated antiviral inflammatory response in hepatocytes and Kupffer cells while wild-type virus can attenuate the host response. |
