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.
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Coloured electron micrograph of vaccinia virus particles.
Vaccinia virus inhibitors of NF-κB activation. A simplified version of the NF-κB pathway is shown together with individual vaccinia virus proteins (shown in red) that inhibit this pathway.
Smith Group
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.
2023
TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6.
Zhao, Y., Lu, Y., Richardson, S., Sreekumar, M., Albarnaz, J.D. & Smith, G.L
Nature – 620(7975):873-880.
2022
Smallpox vaccination induces a substantial increase in commensal skin bacteria that promote pathology and influence the host response.
Shmeleva, E.V., Gomez de Agüero, M., Wagner, J., Enright, A.J., Macpherson, A.J., Ferguson, B.J., & Smith, G.L.
PLoS Pathogens – 18, e1009854.
2022
Poxviruses and paramyxoviruses use a conserved mechanism of STAT1 antagonism to inhibit interferon signaling.
Talbot-Cooper, C., Pantelejevs, T., Shannon, J.P., Cherry, C.R., Au, M.T., Hyvönen, M., Hickman, H.D. and Smith, G.L.
Cell Host Microbe – 30(3): 357-372.e11.
2022
Molecular mimicry of NF-κB by vaccinia virus protein enables selective inhibition of antiviral responses.
Albarnaz, J.D., Ren, H., Torres, A.A., Shmeleva, E.V., de Melo, C.M.A.G., Bannister, A.J. and Smith, G.L.
Nature Microbiology – 7(1): 154-168.
2019
Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6.
Lu, Y., Stuart, J.H., Talbot-Cooper, C., Agrawal-Singh, SA., Huntly, B., Smid, A.I., Snowden, J.S., Dupont, L.. and Smith, G.L.
Proc. Natl. Acad. Sci. USA – 116(24): 11997-12006.
Study of Poxviruses Leads to New Treatment Avenues
August 2023
Published in Nature, a new study led by Prof Geoffrey L. Smith sheds light on how poxviruses evade host defences, and suggests a new way of treating these infections with existing drugs.
Prof Geoffrey L Smith (re)joins the Dunn School
January 2023
We are delighted to welcome an expert on poxviruses to the department!