| | Research Interests
Studies on rotavirus-cell binding and entry, cell signalling induced by rotavirus, and rotavirus modulation of type 1 diabetes development Rotaviruses are the major cause of severe acute diarrhoeal illness of infants and children. They are responsible for one-third of all hospitalizations for diarrhoea worldwide, and for an estimated 873,000 deaths/year, mostly in developing countries. Prevention of disease due to rotavirus is a major aim of paediatric medical research.
The quadrivalent live RRV-reassortant rotavirus vaccine showed 60-80% protection against severe diarrhoea in the USA and was the first rotavirus vaccine to have been licensed for use in humans. However, this vaccine was shown to be associated with a significant increase in incidence of intussusception in vaccinees, and was withdrawn in October, 1999. This vaccine also showed a lower efficacy in developing countries. Two new live attenuated vaccines are now being licensed worldwide. The use of oral rehydration therapy has led to decreased mortality rates, but no preventative therapies are available as yet.
A major interest of my group is the interaction of rotavirus with cellular receptors, as an understanding of rotavirus cell entry is likely to lead to development of improved vaccines and therapies. Rotavirus infection of cells appears to be a multi-step process involving virus binding, protease-dependent cleavage of the viral spike protein VP4 and pH-independent entry. The attachment of many rotaviruses to cells involves cellular sialic acids. Rotaviruses appear to enter cells in a novel mechanism involving direct penetration of the cell membrane.
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Our most recent results show that multiple members of the integrin family of heterodimeric adhesion molecules are important for rotavirus cell entry. We found that the rotavirus spike protein VP4 contains the alpha2beta1 integrin ligand sequence DGE. We showed that the DG residues are essential for binding of this protein, expressed as a GST fusion protein, to expressed alpha2 integrin subunit I domain, and the I domain is necessary for virus binding to alpha2beta1 integrin. In addition, we showed that the major outer capsid glycoprotein VP7 contains the alpha4beta1 ligand sequence LDV and the alphaxbeta2 ligand sequence in a region showing significant sequence homology to the snake venom disintegrin family of integrin counter-ligands. In our experiments, peptides containing these ligand sequences and monoclonal antibodies directed to these integrins blocked rotavirus infection of cells in a dose-dependent fashion. We also showed that cells permissive to rotavirus express the integrins alpha2beta1 and alphaxbeta2. Most clincially significant human rotaviruses use integrins alpha2beta1, alphaxbeta2 and alphavbeta3 during cell attachment or entry. Currently, we are studying the roles of integrins in rotavirus interactions with immune cells, and are mapping the I domain amino acids necessary for virus binding. We have concluded that these integrins can act as receptors or co-entry molecules for many rotaviruses.
We are collaborators with structural chemists in a program to determine the molecular basis of rotavirus VP4 binding to cell surface carbohydrates, and design sialylmimetics as rotavirus inhibitors. Compounds identified in this program (and those from elsewhere to integrins) that are potentially inhibitory to rotavirus cell binding and infection are being evaluated for their potential as anti-viral agents. We are also analysing the signalling pathways elicited in host cells by rotavirus binding and infection, and the nature of the cell death induced by rotavirus.
Another focus of our research is rotavirus modulation of type 1 diabetes. In collaboration with researchers at WEHI, we originally showed that rotavirus infection appears to trigger autoimmune responses to pancreatic antigens in children at high risk of developing type I diabetes. We have now shown that mouse, pig and monkey islets are susceptible to rotavirus infection, and are studying the effect of rotavirus infection in mouse models of type 1 diabetes development. Most recently, we determined that rotavirus infection delays diabetes onset in mice infected as infants or young adults. | |
