Richard Novick, M.D.
Staphylococcus aureus; superantigens; mobile genes; pathogenicity islands, signal transduction, regulation of virulence, microbial pathogenesis; MRSA; bacterial genetics
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RESEARCH INTERESTS: Our lab is focused on the study of staphylococcal virulence, its genetic and regulation. There are two major areas:
1. Global regulation of virulence genes by agr. Virulence in S. aureus is regulated by a complex network of regulatory determinants, the most important of which is the agr locus, which we have identified and characterized. The agr locus contains a two-component signaling module that is autoinduced by a small semi-cyclic peptide (AIP), that is encoded within the locus, is secreted, and then binds to AgrC, the signal receptor, activating the system. agr operates by autoinduction and is therefore a quorum sensor.
Agr has undergone a striking evolutionary differentiation into 4 specificity groups in S. aureus. Heterologous AIP-receptor interactions are generally inhibitory, blocking virulence gene expression (but not growth). This inhibition has been shown to block an experimental abscess in mice. We are currently developing one of the inhibitory peptides for potential therapeutic use. Additionally, we are purifying the receptor in collaboration with the Skirball Structural Biology Group, in order to determine its structure which will reveal the mechanism of signal transduction.
2. Mobile pathogenicity islands encoding superantigens. Our second major area is the study of mobile, phage-related pathogenicity islands (SaPIs) that encode and are responsible for the dissemination of genes encoding superantigens, such as toxic shock toxin and the enterotoxins. These elements, 15-20 kb in length, reside quiescently at specific chromosomal locations under the control of a repressor and are induced to excise and replicate by certain temperate phages, with which they severely interfere. Following replication, they are packaged in small, SaPI-induced infective phage-like particles that can infect other cells, thus spreading superantigen and other toxins. We have recently found that helper phages, but not non-helpers, produce specific bifunctional “moonlighting” proteins that induce SaPI reproduction by binding and inactivating the SaPI repressor. Current studies involve determination of the mechanism of SaPI interference with phage reproduction and identification of the SaPI genes involved. Additionally, we are very interested in similar elements carried by other bacteria, especially since an experiment to test for SaPI transfer to other species revealed efficient phage-mediated transfer, to Listeria monocytogenes, a serious food-borne pathogen, which is not known to produce superantigens.