Our laboratory is focused on studying arenaviruses, which not only have a unique genome arrangement and molecular biology, but are also medically highly relevant as causative agents of severe zoonotic human disease (i.e. hemorrhagic fever and neurological manifestations) in both South America and West Africa. Further, they are increasingly recognized as a risk in the form of imported infections as well as in transplant medicine.
The major goal of our research is to better understand the interaction between these viruses and the infected host cell. In particular, we are interested in the dual role of host factors in both supporting virus infection (as cofactors for essential viral processes) and suppressing virus infection (through antiviral defense pathways), and the role that differences in these interactions play in determining virus pathogenicity.
Our experimental approach to this question is centered on comparing cellular responses to infection with non-pathogenic/low virulence arenaviruses (e.g. Tacaribe) and their genetically closely related but highly pathogenic relatives (e.g. Junín virus). Receptor usage, regulation of cell death (apoptosis) and cytokine regulation have all been implicated as contributing factors to the difference in pathogenic phenotype; however, the details of how these factors actually contribute to infection outcome at a molecular level remains unknown.
To clarify this, we are seeking to understand how infection of the host cell is sensed through various mechanisms, what role this plays in shaping the downstream host responses to that infection, and how this may contribute to either control of infection or immunopathology. Recently, we have been exploring the mechanisms by which virus infection triggers apoptotic cell death and the interferon response, mechanisms by which some arenaviruses can subvert these processes, and how the regulation of kinase pathways involved in apoptosis regulation may also influence downstream cytokine expression (including of interferons) through common host factors.
We have also been combining mass spectrometry efforts in our recent work, in particular to help us better understand the interaction of the viral nucleoprotein with host factors that may on the one hand be related to its diverse activities in antagonizing antiviral responses, but also its role in viral RNA synthesis. In this respect we are particularly interested in exploring the role of protein modification in these functions.
Experimentally, much of our work relies on the application of reverse genetics-based tools, including both lifecycle modelling systems (i.e. minigenome and trVLP assays) that allow us to recapitulate specific subsets of steps in the virus lifecycle, and full-length clone systems that let us generate recombinant viruses, and thereby study the effects of specific mutations on virus biology. Such systems allow us to study arenaviruses both under BSL2 and BSL4 conditions, and also to generate reporter-expressing viruses, which we use to visualize virus infection in our studies.
Overall, our work unravelling the molecular details of virus-host interaction and its relation to pathogenesis will help to 1) assess the risks currently posed by novel arenaviruses, 2) predict under what conditions they might emerge to pose a threat for public health and 3) rationally develop novel indirectly-acting and/or host-directed antiviral therapies.
- Mapping host cell kinase pathway activation in response to arenavirus infection
- Characterizing cytokine responses to arenavirus infection
- Understanding the roles of NP in regulating the activation of antiviral response pathways
- Characterizing the role of kinase activation and viral protein phosphorylation in viral RNA synthesis
- Visualization of virus infection using reporter-expressing viruses
- MS-based identification of novel host cell interaction partners of viral proteins