By Emilie Walker - Biological Natural Sciences Student @ St John's College, Cambridge
Smallpox was a contagious and deadly disease caused by the variola virus (VARV). It had a mortality rate of up to 30% and it is estimated that 300 million people died globally in the 20th century alone. However, smallpox is also the only human infectious disease to be eradicated with the last naturally occurring case recorded in 1977 in Somalia. This success was due to a vaccine developed using live vaccinia virus (VACV), a poxvirus similar to VARV. Its viral genome was only sequenced after smallpox eradication and it was shown that the capsid and envelope proteins of VACV and VARV are highly conserved. Not only that, VACV has a large and complex dsDNA genome, around 190kbp encoding over 200 genes. Considering that most viruses only code for a few genes and most of those are necessary for its replication, VACV’s large number of genes can encode for proteins that are non-essential for replication, those that affect virulence, host range and immunomodulation.
Located in the variable terminal regions of the linear genome, between one third and one half of VACV proteins function to interfere with the host innate immune response to infection. These proteins are diverse and target many components of our immune system such as interferons, complement, cytokines, chemokines, apoptosis and natural killer cells and are often expressed early during infection to enable its survival within the host.
Interferons (IFNs) are secreted glycoproteins in response to viral infections. They bind to its IFN receptors on cells and induce an antiviral state. VACV has multiple mechanisms that target and interfere with the IFN pathway. For example, VACV protein E3 is a dsRNA-binding protein which prevents virus dsRNA from activating pattern recognition receptors on cells. This minimises the production of IFNs. VACV can also express and secrete proteins that bind and neutralise IFNs preventing it from reaching its receptors. Upon binding of IFNs to its receptor, the JAK-STAT signalling pathway will be activated and will lead to the production of antiviral proteins such as protein kinase R (PKR). PKR phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) and inactivates it. This prevents viral protein synthesis and hence its replication. VACV expresses many proteins that target and inhibit the JAK-STAT signalling pathway and block the antiviral activity of IFN-induced proteins. For example, VACV protein K3 is structurally similar to eIF2α and therefore competitively inhibits the phosphorylation of eIF2α by PKR preventing its antiviral action.
The importance of understanding how VACV and other viruses evade the immune system goes beyond developing vaccines and treatments for virus infections. It can increase our understanding of our own immune system, discovering new proteins within pathways that were not known before. It can also help design and develop novel therapeutics such as using engineered viruses as an oncolytic agent to treat certain tumours, some of which are currently undergoing clinical trials. VACV proteins which target cytokines and chemokines can also be harnessed to treat inflammatory conditions such as rheumatoid arthritis. This is why VACV and its strategies to evade the immune system have been so intensely studied in recent years and will continue to have an impact in our lives.
Further reading list:
Stefan Riedel (2005) Edward Jenner and the History of Smallpox and Vaccination, Baylor University Medical Center Proceedings, 18:1, 21-25.
Fenner, F., Anderson, D. A., Arita, I., Jezek, Z. & Ladnyi, I. D. (1988). Smallpox and its Eradication. Geneva: World Health Organisation.
Smith, G.L., Benfield, C.T.O., Maluquer de Motes, C., Mazzon, M., Ember, S.W.J., Ferguson, B.J., Sumner, R.P. (2013). Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. Journal of General Virology 94, 2367–2392.