Geoffrey L Smith

Poxvirus Evasion of Innate Immunity

Poxviruses are large DNA viruses that replicate in the cytoplasm and encode many proteins that aid evasion of host innate immunity. The most infamous poxvirus is variola virus that caused smallpox, a disease declared eradicated in 1980 by the WHO following widespread vaccination with the related orthopoxvirus, vaccinia virus (VACV). Thereafter, poxviruses have not caused major outbreaks in humans until a global monkeypox virus epidemic in 2022, but have continued to cause serious infections in animals, such as the global spread of lumpy skin disease in cattle.

To improve the safety and immunogenicity of poxvirus-based vaccines and to better understand how viruses cause disease and escape the host response to infection, our group is studying the mechanisms by which orthopoxviruses suppress innate immunity. Two parallel approaches are used.

First, the function of individual virus proteins is investigated by deleting the encoding gene from the virus and studying the consequence for virus replication and spread, and by identifying cellular binding partners of each protein, and the function of these.

Second, analysis of the cellular proteome by mass spectrometry revealed that VACV infection induced the downregulation of 265 cellular proteins, mostly by proteasome-mediated proteolysis. It was hypothesized that these degraded proteins have anti-viral activity and that is why the virus has evolved a mechanism to remove them. In several cases, such as for HDAC4, HDAC5 and TRIM5α, this hypothesis have been proved correct and has led to the discovery of new host proteins that restrict the replication or spread of poxviruses, and virus countermeasures to antagonise these factors.

During the 2022 monkeypox virus epidemic, our group has contributed to the UKRI-funded consortium that responded to this epidemic. Many of the immune evasion strategies deployed by VACV are also conserved in monkeypox virus. Recently, we reported in Nature that TRIM5α has antiviral activity against orthopoxviruses, including monkeypox virus, and that existing drugs might be re-purposed to combat these infections.

Group members

  • Geoffrey L Smith (Group leader)
  • Yiqi Zhou
  • Shulan Yang
  • Ana Gali Macedo
  • Yongxu Lu
  • Juliette Imbert

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