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Department of Pathology


Jonas Dutra Albarnaz and Geoffrey L Smith

Researchers from the Department of Pathology and the Gurdon Institute have uncovered a new mechanism by which pathogenic viruses antagonise our immune defences. Using molecular mimicry, the protein F14 from vaccinia virus (VACV) disables the immune response to inflammatory signals selectively and thereby impairs the control of virus infection.

The new findings have just been published in Nature Microbiology

VACV is best known as the smallpox vaccine and was used in a WHO global vaccination campaign that led to smallpox eradication in 1980. Thereafter, virologists and immunologists studied what made VACV such an effective vaccine and how to harness this knowledge to improve other vaccines and develop VACV as a vaccine vector against other diseases, including COVID-19.

The immune system defends us against invading viruses. In response, viruses have evolved means to overcome these immune defences, and so replicate and spread to new hosts. NF-κB is a cellular transcription factor (a protein that drives the expression of specific genes at the right time) that is activated when our cells sense virus infection. Once activated, NF-κB translocates from the cytoplasm to the nucleus of the cell where it stimulates the expression of antiviral proteins and proteins that promote inflammation. Inflammation is a process by which the host responds to the infection and turns on the immune system. The research led by Dr Jonas Dutra Albarnaz in Geoffrey Smith’s lab found that VACV protein F14 inhibits NF-κB after its translocation into the nucleus, and in that respect differs from other NF-κB inhibitors made by VACV.

When dissecting F14’s mechanism of action, Jonas found that F14 mimics a region of NF-κB and thereby disrupts the interaction of NF-κB with another cellular protein called CBP. Surprisingly, he also discovered that F14 did not inhibit the expression of all NF-κB-responsive genes and so was a selective inhibitor of NF-κB, a feature unique among viral NF-κB inhibitors. CBP is an enzyme that adds an acetyl group to NF-κB and, once acetylated, NF-κB interacts with the regulatory protein BRD4 to drive gene expression (see top panel of the Figure). Together with researchers from the Gurdon Institute, the team found that the recruitment of BRD4 to genes that are inhibited by F14 was blocked, whereas BRD4 was still recruited to genes that are not inhibited by F14 and in a manner independent of the recognition of acetylated proteins (see middle and bottom panels of the Figure). So, although BRD4 can be recruited to some genes in an acetylation-dependent way, somehow BRD4 can also be recruited to other genes in a manner that is independent of acetylation.

Searches in genomic databases showed that other viruses in the same genus as VACV, including variola virus the cause of smallpox, also have a gene encoding F14. Even ancient variola virus genomes from the Viking era (10th century) contained a gene encoding F14. This conservation suggested that F14 must exert an important function that matters to the virus and the observation that a VACV engineered to lack F14 was less virulent confirmed this hypothesis. VACV has been developed as vaccine vector against other diseases, and as oncolytic agents for the treatment of cancer. Therefore, the attenuation of the VACV lacking F14 can inform the development of safer vaccines or biotherapeutics.

Figure legend:  

Schematic representation of how NF-κB drives gene expression (top panel) and how vaccinia virus protein F14 selectively interferes with this process (middle and bottom panels). NF-κB is composed of two proteins, p65 and p50. TAD means transactivation domain. 


Albarnaz, J.D., Ren, H., Torres, A.A. et al. Molecular mimicry of NF-κB by vaccinia virus protein enables selective inhibition of antiviral responses. Nat Microbiol 7, 154–168 (2022).