Despite extensive study, the role of different components of the immune response in resolving influenza virus infection remains quantitatively unclear.
In collaboration with colleagues at the WHO Collaborating Centre for Reference and Research on Influezna at the Peter Doherty Institute, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. Experiments with influenza A(H1N1)pdm09, A(H3N2) and influenza B display a broad range of phenomena, including blocking of infection, delayed infection and a shortened infectious period. Collectively, these experiments implicate both innate and cross-reactive adaptive responses in generating the observation of viral interference.
Under this project, we are developing and analysing a family of within-host models of multi-strain viral kinetics which allow for different viruses to stimulate the immune response to different degrees. The models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their ability to reproduce the re-exposure data and explain the observed viral hierarchies. Our initial results have shown that induction of a virus-resistant state in target cells, in and of its own, is insufficient to explain the data. However, enhanced free-virus clearance and/or an increased rate of killing of infectious cells are able to generate the observed viral hierarchies. We are now extending the models to consider the role of cellular-mediated cross-reactivity, necessary to explain the observation of viral interference at longer inter-exposure intervals.
Our approach to studying influenza viral dynamics has provided the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza, its role in viral control and the subsequent implications for next-generation vaccine and antiviral drug design.