Microbiology, Immunology & Molecular Genetics Adjunct Faculty
Karl E. Klose, Ph.D.
My laboratory is interested in studying the molecular mechanisms involved in the pathogenesis of Vibrio cholerae, the bacterium that causes cholera. Cholera is a life-threatening diarrheal disease that remains a persistent problem for the developing world. Within the marine environment, V. cholerae is likely found within multi-cellular communities known as biofilms, within which no virulence factors are expressed. Inside the host, the bacteria adhere to the surface of intestinal epithelial cells and produce a number of virulence factors including cholera toxin. The action of the toxin leads to profuse watery diarrhea, the hallmark of this disease.
ToxT is the primary transcriptional activator of the major virulence genes in V. cholerae. Dr. Klose's lab has recently discovered that transcriptional activation by the ToxT protein also is modulated by environmental signals. Their efforts are focused on identifying the mechanism of ToxT modulation by environmental factors at the molecular level, in order to exploit this modulation and identify novel means to prevent virulence factor expression.
The outer membrane porins OmpU and OmpT are regulated by the transcriptional activator ToxR, which also regulates expression of ToxT. They have found that modulation of OmpU and OmpT contributes to the ability of the organisms to colonize the intestine, and are currently dissecting the role these porins play in pathogenesis.
Bacteria employ alternate sigma factors to confer different promoter specificities upon core RNA polymerase. They have found that the alternate sigma factor sigma54 (RpoN) is required for V. cholerae gene expression during both its free-swimming phase is required for flagellar synthesis and is also required for some aspect of the colonization process. They have recently elucidated the flagellar transcription hierarchy of V. cholerae, which will assist in our current genetic and biochemical approaches to identify the contribution of sigma54 and flagellar synthesis to virulence.
They are investigating the role of flagellar synthesis in the formation of biofilms, and how biofilm-specific gene expression affects the ability of V. cholerae to cause disease. The lab is also performing experiments that address the contribution of the O-side chain of the LPS to colonization of the intestinal epithelia. A better understanding of the pathogenic mechanisms employed by V. cholerae will hopefully lead to novel means of cholera therapy and ultimately prevention by the development of a safe and effective vaccine.
Another area of interest for his laboratory is the use of attenuated Salmonella typhimurium strains as vaccine vectors for the expression of heterologous antigens, and they are currently pursuing this strategy in vaccine approaches against both food-borne diseases and biowarfare agents.
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