Molecular Microbiology and Immunology
615 N. Wolfe Street, Suite E2426
Baltimore , Maryland 21205
PhD, Technical University, 1996
Bacterial infections continue to pose a serious threat to public health. In addition, the emergence of antibiotic resistant bacterial strains has even further increased our need to understand the molecular mechanism by which bacteria cause disease. The long-term goal of our group is to understand the molecular interplay between pathogenic bacteria and the cells of their human or animal host. To study this interaction we use enteropathogenic Yersinia species as model systems and employ a multidisciplinary approach including microbial genetics, immunology, cell biology and structural biology. Upon entry into the host, enteropathogenic Yersinia species ultimately target and colonize human lymphoid tissues. In order to survive in the host environment, the bacteria have to evade the host’s immune system. This evasion is achieved by the injection of a lethal protein cocktail into the host cell effectively paralyzing the host defense. To inject the proteins into the cell, the bacteria use a sophisticated protein translocation machinery called type III secretion system. Since many other pathogenic bacteria such as Shigella, Salmonella, Chlamydia etc. use type III secretion systems, our results will also help to better understand bacterial infections in general and might ultimately help to develop new therapeutic anti-bacterial strategies. Our current work focuses on two aspects of this unique gram-negative infectious strategy. The first concerns the structure and function of the secretion machinery; the second concerns the regulation of the secretion process. More than 20 different proteins form the type III machinery. Using ultrastructural techniques we could recently show that one of these proteins forms a hollow needle-like structure during host cell contact. This needle is used by the bacterium to penetrate the host cell membrane providing a channel through which the toxic proteins are translocated. Using a combination of biochemical and ultrastructural techniques we are currently characterizing novel subcomplexes of the type III machinery and try, over time, to establish the whole architecture of this fascinating bacterial organelle. Another important aspect of type III secretion is its cell contact-dependant regulation. Upon attachment to a host cell Yersinia starts to express, assemble, and activate their type III secretion machineries. How the different chemical and physical aspects of the interaction translate into the activation of the type III secretion system is not yet fully understood. We use genetic screens and biochemical approaches to dissect this complex interaction and try to identify novel components of the underlying signal transduction events. This work should help to define bacterial pathogenesis at a molecular level and could open up new routes for the design of novel therapeutic schemes.
Molecular Microbiology and Immunology, bacterial pathogenesis, infectious disease, yersinia, type III secretion, host-pathogen interactions, signal transduction, structural biology