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 gobal monkeypox virus epidemic in 2022.

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

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, studying the cellular proteome during infection by mass spectrometry revealed that after infection with VACV, about 250 cellular proteins are down-regulated, and mostly by proteasome-mediated proteolysis. It was hypothesized that these degraded proteins represent anti-viral proteins and that is why the virus has evolved a mechanism to remove them. In several cases, 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 block the function of these restriction factors.

During the 2022 monkeypox virus epidemic, our group has contributed to the UKRI funded consortium that is responding to this epidemic. Many of the immune evasion strategies deployed by VACV are also conserved in monkeypox virus.

Relevant Publications

Talbot-Cooper, C., Pantelejevs, T., Shannon, J.P., Cherry, C.R., Au, M.T., Hyvönen, M., Hickman, H.D. & Smith, G.L.

Cell Host Microbe 30, 1-16 

Albarnaz, J.D., Ren, H., Torres, A.A., Shmeleva, E.V., de Melo, C.M.A.G., Bannister, A.J. & Smith, G.L.

Nature Microbiol. 7, 154-68.  

Lu, Y., Stuart, J.H., Talbot-Cooper, C., Agrawal-Singh, SA., Huntly, B., Smid, A.I., Snowden, J.S., Dupont, L., & Smith, G.L.

Proc. Natl. Acad. Sci. USA 116, 11997-12006.

Soday, L., Lu, Y., Albarnaz, J.D., Davies, C., Antrobus, R., Smith, G.L., & Weekes, M.P.

Cell Reports 27, 1920-33 e7.

Scutts, S.R., Ember, S.W.J., Ren, H., Veyer, D.L., Sumner, R.P., Ye, C. & Smith, G.L.

Cell Reports 25, 1953-1965 e4.

Geoff Smith

Research Areas