We study what properties of some RNA viruses make them cause more severe disease than others, and how this relates to detection of viral infection by the immune system.
Despite their association with severe disease, RNA virus infections are not necessarily highly pathogenic.
We use a “vertical integration” approach, working with simple systems (e.g. purified proteins and cultured cells) as well as more complex ones (e.g. tissues, complex animal models, in vivo imaging) in order to characterise what particular viral proteins, genes, and functions determine the level of pathogenicity. By working closely with the Crick’s science technology platforms (STPs), we aim to understand the molecular basis of differing virus pathogenicity and virus growth from the single-molecule to whole-organism level.
Some of this variation relates to how well adapted a virus is to its host — hantaviruses, for example, are endemic in rodents without causing major disease, but cause severe disease in humans. Avian influenza viruses typically cause severe disease in humans, but seasonal influenza and seasonal coronavirus infections (responsible for perhaps a fifth of the ‘common colds’ each year) that circulate in human populations, typically do not. In these cases, variation in disease severity is also driven by comorbidities that affect disease progression and outcome.
Inevitably, the mechanisms of host adaptation and comorbidities intersect with immunity and our response as a host to viral infection.
The activation of innate immune responses following infection is driven by the detection of pathogen-associated molecular patterns (PAMPs). For RNA viruses, the structured viral genomic RNA itself constitutes a major PAMP, and detection by host pattern recognition receptors (TLR3, RIG-I, or MDA5) leads to interferon production via MAVS signalling of NF-κB and IRF1/3, and the subsequent generation of an antiviral state and recruitment of lymphocytes to the site of infection.
While some viruses have evolved to cope with interferon activation (e.g. paramyxoviruses), diverse others have evolved to avoid detection in the first place by “hiding” their PAMPs. Influenza viruses typically fall within this second group, however highly-pathogenic influenza viruses are known to ‘over-activate’ the innate immune system, driving the production of a cytokine storm that promotes excessive inflammation and viral pneumonia.
We have previously shown that highly-pathogenic influenza infections are characterised by the presence of a large amount of short, structured RNA products, which we term mini viral RNAs (mvRNAs). These form when viral genome replication proceeds abnormally — notably when viruses that are adapted to avian species infect human hosts — and are ideal substrates for binding and activation of RIG-I.
Our work focuses on two main areas: first, characterising the precise RNA species that are responsible for innate immune activation in RNA viruses, and second, dissecting the molecular pathways by which they are generated (e.g. degradation, editing, aberrant replication) using a combination of in vitro study and viral mutants. We then use our existing complex models of infection to explore the wider impact of virus pathogenicity that arises in vivo during infection.