Severe gastroenteritis in both developed and less developed countries is caused by rotaviruses and currently there is only one licensed vaccine available. Disease aspect of rotavirus results from rapid replication of the virus in intestinal cells, outstripping the ability of the intestine to replace damaged cells. The virus is a 70 nm non-enveloped virus containing 11 segments of double stranded RNA genome. To date three structural proteins (VP3, VP4 and VP7) and two non-structural proteins (NSP2 and NSP4) have been shown to be associated with pathogenicity and one nonstructural protein, NSP1 was shown to be associated with host range. The NSP4 is associated with diarrhea and cytotoxicity. Past activities 1. Mission-oriented research We have produced novel mutant forms of human rotavirus NSP4 that have potential in using as toxoid vaccines. Studies are underway to fully characterize the mutants. In addition, we have cloned and sequenced several important rotavirus strain-specific genes (VP4, VP5, VP8, NSP4, NSP5 and NSP6 to identify their role in viral pathogenesis and vaccine associated adverse reactions. 2. Lab-based regulatory research Lab was set-up to perform rotavirus potency testing; Rotavirus plaque-assay for potency testing was developed. Several vaccine lots have been released based on in-house potency testing and by review of submitted lot release protocols. This is an on-going CBER mission-related activity. Recently this lab activity has been transferred to the QC lab within DVP. PROGRESS Recently we identified a peroxisomal targeting signal tri-peptide in rotaviral VP4 protein. This is a seminal discovery to the entire virology field, since functional peroxisomal targeting tri-peptide sequences were not reported before in any viral proteins. Since peroxisomal biogenesis associated disorders were known, we are currently pursuing the idea that the rotaviral protein targeting to the organelle may have serious implications in viral pathogenesis and possibly associated with the vaccine induced adverse reactions in infants.
