Research in my laboratory is focused on the virulence factors and pathogenic mechanisms of the gram-negative bacterium Burkholderia cepacia. B. cepacia has recently emerged as an important opportunistic pathogen of the lower respiratory tract, affecting immunocompromised individuals and particularly cystic fibrosis (CF) patients.
Projects in My Laboratory:
Type III Secretion Pathogenesis in a growing number of gram-negative bacteria is dependent on the secretion of virulence proteins via a conserved secretory system, termed type III. We have identified and characterized a genetic locus encoding multiple type III secretion genes in B. cepacia. Using allelic exchange mutagenesis, we generated defined null mutations in central components of the type III secretion system, and demonstrated that a type III mutant is severely attenuated in virulence in a murine model of infection. We are currently pursuing proteomic and genomic-based approaches to identify the secreted substrates of the B. cepacia type III translocon, as well as further characterize the role of type III secretion in modulating the host response to B. cepacia infection. Cable Pilus Biogenesis Cable pili are unique peritrichous adherence organelles expressed by certain strains of B. cepacia. Cable pili have been shown to mediate binding to both cellular and acellular receptors, and likely promote B. cepacia colonization of the respiratory tract of compromised hosts. We have undertaken a genetic analysis of cable pili and have identified and characterized a locus ( cbl) encoding structural, accessory, and regulatory components of the cable pilus biosynthetic pathway. We have also initiated studies to define the regulatory control of cable pilus gene expression, and have evidence that control is manifested at both the transcriptional and posttranscriptional levels. We have recently identified within the cbl locus three additional genes, designated cblS, cblT and cblR, predicted to encode new members of the superfamily of environmentally responsive two-component signal transduction systems. We are currently utilizing a combined genetic and biochemical approach to characterize the function of these genes and to define the signal transduction events controlling cable pilus gene expressionElectron micrographs of macrophages infected with Burkholderia cepaciaElectron micrographs of wild-type Burkholderia cepacia expressing cable pili (A-D) and a cblA mutant strain (E,F) blocked in cable pilus expression
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