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Structural Characterization of Membrane Proteins involved
in Bacterial Infections Structural Characterization of Membrane Proteins involved in Bacterial Infections Bacterial infections continue to remain a threat to public health, despite the current age of antibiotics. With progress of research techniques in the last decades, even certain traditionally non-infectious diseases have been recognized to have an infectious origin, such as peptic ulcers. Moreover, drug-resistant microorganisms have become a serious concern as some important human pathogens have acquired mechanisms that make them largely resistant to currently available treatments. Thus the medical and public health importance of bacterial infection fosters the necessity for understanding the molecular basis for infection and disease. A group of pathogenic bacteria employs an intracellular lifestyle, which provides them with an environment relatively shielded from the immune system and antibiotic exposure. These include bacteria such as Brucella, Chlamydia, Legionella, and Rickettsia, causing a wide range of disorders such as trachoma, chronic pelvic pain, infertility, pneumonia, thyphus and meningitis. As a successful infectious agent, intracellular pathogens require four steps: adherence, invasion, multiplication and dissemination. All of these steps involve interaction between pathogen and host cell components. Interactions can range from simple mechanical adherence prior to invasion, to subtle interference with host signaling systems as to sustain intracellular growth and replication. Membrane proteins play central roles in these bacteria-host interactions and prove pivotal for infection and intracellular replication. Outer membrane proteins form the first interface with the host, and serve roles in adherence, immune interaction or evasion. Various membrane spanning transport complexes, secrete or inject effector molecules into the host to alter normal cellular behaviour. Structural results of these membrane proteins either complexed with their interaction partner will be essential for a detailed understanding of the mechanism of disease. The aim of the proposed research is to structurally and biophysically characterize bacterial membrane proteins that are involved in pathogenicity and virulence. Legionella pneumophila will be targeted as a model system for intracellular infection. From this organism, membrane proteins involved in pathogen-host interaction will be targeted. The long term aim is to unravel the repertoire of molecular mechanisms that intracellular pathogenic bacteria employ to infect humans. This understanding may facilitate the development of pharmaceutical strategies targeting (intracellular) bacterial pathogens. The recent completion of the L. pneumophila genomic sequence (Chien et al., Science 2004), offers the opportunity to understand its b |
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