Matthias T Dittmar
We are seeking to identify novel antiviral targets to develop new treatment options, as well as predictive markers to manage infections more successfully. Viruses are obligatory cellular parasites, with their replication crucially depending on host cell functions. They have evolved strategies to modulate host cell cytoskeleton dynamics, activate signal transduction pathways to facilitate entry into new target cells and modify the proteome and RNAome to overcome cellular antiviral responses.
Therefore, viruses are ideal tools to study signalling and cytoskeleton networks and proteome/RNAome in an integrative way by comparing the dynamics of such virus exploited networks. With the increasing knowledge regarding the regulation of these networks it is now feasible to identify in more detail the host machineries that certain viruses hijack to further replication. Therefore, viruses like HIV and HCV will be tremendously useful in the emerging field of molecular systems biology leading to the identification of novel targets to develop new treatment options as well as predictive markers to manage infections more successfully.
Recent and ongoing research projects:
Virogenomics in HCV infection:
Hepatitis C virus (HCV) infection is globally widespread and is an increasing cause of severe liver disease and mortality (cirrhosis and hepatocellular carcinoma). In the UK at least 150,000 individuals are chronically infected and a large proportion will develop end stage liver disease without treatment. The UK HCV population is more diverse than that seen in other countries (reflecting ethnic heterogeneity) and, unlike other developed countries, genotype 3 is common. Recent research has identified a growing number of large and small noncoding RNA’s (ncRNA: large intergenic- and micro-RNA) that are expressed in mammalian cells. These noncoding RNA’s regulate a large fraction of the transcriptome and facilitate innate responses. This multi-gene regulatory capacity enables remodelling of the signalling landscape and innate responses to viral pathogens in a timely and translation-independent manner. Studying virus induced ncRNA profiles from patient cohorts infected with different HCV genotypes, grouped into progressor and non-progressor will reveal any significant differences in ncRNAs and has the potential to identify predictive markers for progression. Comparison of pre-treatment profiles of patients who did or did not respond to therapy may provide insights into profiles that predict treatment outcome.
Quantification of HIV and HCV envelope dependent changes in signalling and cytoskeleton networks:
This project focuses on integrated cellular responses upon viral envelope-receptor interactions. We compare cell-cell interaction as well as virus-cell interaction for two different viruses (Human Immunodeficiency Virus and Hepatitis C Virus, HIV and HCV) to identify common and distinct cellular responses. Exploiting state of the art imaging technologies we are currently characterising the dynamic changes (temporal and spatial) in cellular networks such as signalling pathways and cytoskeleton rearrangements. This knowledge will inform target identification to develop specific or broad acting antiviral drugs.