Strategies of the African swine fever virus to manipulate innate immunity

Dissertation presented to obtain the Ph.D degree in BiologyThe objective of this thesis was to determine the mechanisms and consequences of two non-homologous host evasion genes of the economically important, frequently fatal African Swine Fever Virus (ASFV). In order to survive, large DNA viruses, such as ASFV, typically have multiple genes/strategies for positive and negative modulation of host cell biology and immune responses. The two genes presented here inhibit a major component of innate immunity, the Interferon (IFN) response, and so function to the benefit of the virus. The conserved I329L gene was recently reported to impair the cellular responses controlled by TLR3 that lead to both IFN-β secretion and NF-κB activation. Here, this observation is extended by demonstrating that I329L not only inhibits both induction and secretion of IFN-β, but also inhibits TLR4 stimulated activation. The I329L protein was also biochemically demonstrated to target the adaptor protein TRIF, consistent with the observed inhibition of both TLR3 and TLR4 pathways. To further characterize the modulation of the type I IFN response by I329L, as well as to assess the role of each domain, truncation mutants expressing either the ectodomain or the intracellular domain were designed and tested by luciferase reporter assays.(...)FCT SFRH/BD/16349/200