Molecular pathogenesis of arboviruses and their interaction with the mammalian immune system.

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Alphaviruses are arthropod-borne viruses that can cause serious epidemics in humans and equines. Chikungunya virus (CHIKV) is an alphavirus currently affecting millions of people worldwide. CHIKV infection produces a debilitating disease in humans that can last for days, months or years. The molecular clone of Semliki Forest virus (SFV), SFV4, provides a well characterised model to study alphavirus infections, including CHIKV. This project focuses on understanding the molecular pathogenesis of both CHIKV and SFV and their interaction with the mammalian immune system. One part of the project focuses on CHIKV and the type-I interferon (IFN) pathway. Type-I IFN is probably the most important host defence against viruses. CHIKV is pathogenic in humans, but is avirulent in mice. In contrast, SFV is generally virulent in mice, but avirulent in humans with only one death reported in an immunocompromised individual. Our hypothesis to explain the species specific disease of CHIKV and SFV is that the viruses vary in their ability to inhibit and/or to replicate in the presence of human or mouse IFN. The ability of CHIKV and SFV4 to induce IFN will be compared between mouse and human cell lines. The second part of this project focuses on understanding the molecular determinants of pathogenesis of SFV. To determine the genetic differences between two strains of SFV, L10 and SFV4, Solexa (Illumina) sequencing was carried out. The genome sequences both strains were very similar with only 12 nucleotide differences. To determine which of these differences was responsible for pathogenesis, a panel of SFV4 mutants, containing one or more of these nucleotide changes, was created and inoculated into mice. Change of a single amino acid in E2 at position 162, lysine to glutamic acid, affected virulence. E2 amino acid 162 is located in Domain A of the ectodomain, a domain associated with receptor binding. The role of E2 during SFV infection is under investigation.

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