Hantavirus reverse genetics and innate immune responses

Hantaviruses are a group of viruses that cause lifelong infections mice, rats and other rodents without causing disease. However, if humans become infected by inhaling infected-rodent urine contaminated dust, they can become very ill with severe diseases called haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Death rates can be as high as 35%. We want to understand details of how hantaviruses grow at the molecular level and how they deal with the cell?s defence mechanisms. To aid these studies we will develop methodology to apply recombinant DNA techniques to make viruses containing defined genetic changes in their genomes that are debilitated in their growth properties and could be used as potential vaccines. In addition, our studies will provide important new information that may help in the design of new antiviral drugs.

Hantaviruses comprise one genus within the family Bunyaviridae and include some of the most important human pathogens in that family, including those causing haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Hantaviruses have a worldwide distribution and are recognised as posing an increasing threat to human helath. Despite the significant medical impact of hantaviruses, many aspects of their replication and interaction with host cells are incompletely understood. A major impediment to the study of hantaviruses is the lack of a reverse genetics system. In addition, hantaviruses grow less well in tissue culture compared to, for example, orthobunyaviruses, presenting technical difficulties. Thus, in this project we will (a) investigate cell lines that should allow improved growth of hantaviruses; (b) develop reverse genetics systems for hantaviruses; (c) investigate aspects of hantavirus RNA synthesis; (d) attenuate hantavirus replication in cell culture via reverse genetics; and (e) investigate the interactions of strongly pathogenic, weakly pathogenic and apathogenic hantaviruses with host innate immune systems. These studies will lead to an increased understanding of hantavirus replication and lay the foundation for future work to develop novel hantaviruses as potential vaccines.