We study how viral RNA polymerases work and contribute to RNA virus pathogenicity.
Emerging RNA viruses diseases have a severe impact on our economy (approximately $90 billion in the USA per year), but they also pose an unpredictable threat to our health. For instance, influenza A virus outbreaks in 1918, 1957, 1968 and 2009 have caused millions of deaths. Unfortunately, we know still relatively little about how pathogens like the influenza A virus cause lethal disease and how they amplify themselves. However, we do know that both are strongly linked to the activity of the viral enzyme that copies the viral genome. Clearly, we need to make an effort to study this enzyme in more detail.
RNA viruses use RNA as the genetic material of their genome. This RNA can be single-stranded (ssRNA) or double-stranded (dsRNA). In addition, the single-stranded RNA can be of positive sense (+RNA), which means that it is infectious in a cell, or negative sense -RNA), which means that it needs to be associated with viral proteins in order to be infectious. Important human viruses belong to ssRNA viruses, such as the influenza A virus and Ebolavirus (both -RNA) or the SARS-coronavirus and Denguevirus (both +RNA).
The influenza A virus
Influenza A virus strains are identified by the glycoproteins that reside on the outside of the virus: the haemagglutinin (HA) protein and the neuraminidase (NA). For simplicity, these different HA and NA proteins are numbered (e.g. H1N1). For humans, the H1N1, H2N2, and H3N2 subtypes have historically been the most important. In addition to subtyping, human influenza A viruses can be classified into seasonal, pandemic or zoonotic influenza A viruses. The outcome of infections with these three viruses is strikingly different.
Seasonal | Infections with seasonal influenza viruses usually lead to mild upper respiratory tract disease. This affects 5-10% of the adult population and 20-30% of children every year. However, in up to 5 million cases seasonal influenza infections require hospitalisation and in up to half a million of these cases may be fatal.
Zoonotic | By contrast, infections with zoonotic influenza A strains, such as the avian H5N1 or H7N9 viruses, is much more severe. Typically, these infections lead to severe pneumonia and are currently estimated to have a 38% (for H7N9) to 50% (for H5N1) or mortality rate.
Pandemic | Infections with pandemic influenza A viruses vary from relatively mild (the 2009 pandemic) to devastating (the 1918 Spanish Flu). The latter pandemic has been estimated to have killed 50 million people worldwide.
An RNA viruses genome can only be replicated and transcribed by a viral RNA polymerase. This is a specialised enzyme that is able to RNA as template and make more RNA using nucleotides as substrate.
Domains | The heart of the RNA polymerase is the RNA polymerase domain, a protein fold that is conserved among many RNA viruses. This domain can be flanked by additional domains that contribute other enzymatic functions, such as cap-snatching in the influenza A virus polymerase. The domains may also allow the RNA polymerase to interact with key cellular proteins.
Error rate | Any mistakes made by the RNA polymerase lead to mutations in the viral genome. Although these mutations frequently have deleterious effects, they can sometimes also help the virus escape antiviral or immune response pressures. It is thus beneficial for RNA viruses to have an RNA polymerase than introduces errors with a relatively high frequency (approx. one mutation per genome copy made), so they can evolve quickly. Manipulation of the RNA virus mutation is essential for medicine: life attenuated viruses often have a lower mutation frequency and a large number of antiviral drugs works by increasing the error rate of the polymerase, thereby forcing the virus to mutate essential enzymatic functions and effectively killing itself.