Keywords: Molecular genetic analysis of virulence of Klebsiella pneumoniae, as well as virulence gene regulation
My laboratory has used several Gram negative bacterial pathogens, Yersinia, Salmonella and Klebsiella as model systems to study bacterial pathogenesis. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level to learn how this interaction affects the pathogenesis of infections and to understand how these pathogens co-ordinate the expression of virulence determinants during an infection. To do this we use genetic, molecular and immunological approaches, in conjunction with the mouse model of infection.
Currently research in the Miller lab focusses on Klebsiella pneumoniae. Klebsiella pneumoniae (Kpn), is a bacterial pathogen that has a remarkable ability to cause a wide range of human diseases including pneumonia often accompanied with systemic spread to other organs. Kpn strains are broadly divided into two classes: Classical strains that are a notable problem in healthcare settings due to multidrug resistance, and hypervirulent strains that are drug sensitive, but able to establish disease in immunocompetent hosts. Alarmingly, there has been an increased frequency of clinical isolates that have both drug resistance and hv-associated genes. One such hv-associated locus is rmpADC that is required for maximal capsule gene (cps) expression and confers hypermucoviscosity (HMV). The capsule is required by all Kpn strains to cause disease and HMV has been tightly associated with hypervirulence. The lab recently found that RmpA autoregulates the expression of the promoter driving expression of the other two genes in the operon, rmpD and rmpC. The lab showed that RmpC is a transcriptional regulator that is required for maximal cps expression and RmpD is a small protein that is required for the HMV phenotype. Importantly, these analyses indicated that HMV and capsule are separable phenotypes and that HMV and capsule likely make distinct contributions to virulence in a mouse model of pneumonia. RmpC appears to regulate expression of ~200 genes in addition to regulating expression of capsule genes. We are currently employing a variety of approaches to investigate how RmpD and RmpC contribute to HMV, capsule and virulence.
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Training Program Affiliations:
- Microbiology and Immunology