Virus and host genes involved in re-programming of macrophage transcription in response to high and low virulence African swine fever virus isolates

We will study African swine fever virus (ASFV), which causes major losses to farmers in Africa and is a threat to pig farming worldwide. The virus codes for proteins, called evasion proteins, which help it to evade the host's defence systems and avoid being eliminated from the host. In our previous work we showed that ASFV evasion proteins prevent the host from switching on its defence genes. We compared two virus strains, one (high virulence) which kills 100 per cent of infected pigs and one (low virulence) which does not kill pigs but can infect pigs for long periods without causing disease. The high virulence isolate was more effective at switching-off host defence genes than the low virulence isolate as we predicted. In this project we will identify which of the proteins from the high virulence isolate switch-off host defence genes. We will also study other host proteins that are switched-on following virus infection to understand their role in pathogenesis and evasion.

We showed previously that transcription of macrophage immunomodulatory genes initially increases following infection with a high virulence African swine fever virus (ASFV)isolate, but returns to equivalent levels as in uninfected cells at later times during infection. In contrast transcription levels of some host defence genes remains elevated at late times following infection with a low virulence isolate. We will investigate if virus genes that are known not to be expressed by the low virulence isolate but are expressed by the high virulence isolate, are involved in suppressing host immunomodulatory gene transcription. To do this we will use virus deletion mutants and express these virus genes individually in macrophages infected with a low virulence isolate. We will study expression of cell surface and secreted proteins encoded by genes that are differentially expressed in ASFV infected macrophages to gain an understanding of their potential role in pathogenesis and activation of host responses.