Molecular Mechanisms of Bacterial Pathogenicity
The threat of bacterial infections and antibiotic-resistant microorganisms is omnipresent. Therefore, research needs to be carried on, focusing on molecular characterization and lifestyle of microbial pathogens. The outcome of these investigations will result in the discovery of specific targets aiming on the development of novel anti-microbial treatment and prevention strategies. We are interested in investigating molecular pathogenesis with an emphasis on bacterial adaptation in response to environmental and host conditions. Our research is focused on specialized physiology/regulatory pathways and membrane located structures, which facilitate adaptation, colonization, persistence, and optimized growth for two human pathogens, namely Vibrio cholerae and Haemophilus influenzae.
My group is interested in bacterial communication. In one area of research we investigate the role of interactions between the normal intestinal microbiota and pathogens in human health and disease. Our current work is focused on antibiotic associated hemorrhagic colitis caused by the opportunistic infection activities of Klebsiella oxytoca. In another primary activity we study a specific (type iv) process of protein and DNA transfer performed by bacteria to deliver effector molecules directly into other cells, such as other bacteria or the mammalian host. We apply genetics, biochemistry and structural biology to study (1) conjugative gene transfer and antibiotic resistance gene spread, (2) bacterial attachment and biofilm development on surfaces including medical implants such as urinary tract catheters (E. coli, Proteus mirabilis, Klebsiella spp) and (3) Infection activities of bacterial pathogens in human and animal hosts (Campylobacter fetus).
The Schild lab studies the molecular mechanisms of bacterial pathogenesis and bacterial adaptation in response to environmental and host conditions. The outer membrane and associated structures of Gram-negative bacteria are emphasized including their impact on virulence and vaccine development. Selected model organisms are a variety of Gram-negative bacteria that act as human pathogens (e.g. Vibrio cholerae and Haemophilus influenzae).
The facultative human pathogen V. cholerae is the causative agent of the secretory diarrheal disease cholera. We use a temporally controlled reporter-system of transcription to investigate differences in gene regulation under changing environmental and host conditions along the lifecycle of V. cholerae. Novel proteins were thus linked to the regulation of flagellar motility, chemotaxis, metabolism and extracellular matrix production, which have been shown to be important for several stages in the lifecycle of V. cholerae (e.g.: biofilm formation, virulence and transmission of cholera).
Knowledge of outer membrane physiology and host colonization have enabled our group to successfully initiate a vaccine project based on outer membrane vesicles and we currently hold two patents on this subject. Recently we successfully extended the investigation of outer membrane vesicles as vaccine candidates to other Gram-negative bacteria with high demand for a vaccine, e. g. members of the Pasteurellaceae family.
We collaborate with several groups to share our expertise on biofilms as well as animal models and to develop suitable in vivo and colonization studies for other bacterial pathogens.
Horizontal gene transfer (HGT) is an essential feature in the evolution of bacteria. One mechanism by which HGT can be achieved is bacterial conjugation. Bacterial conjugation is cell-cell contact dependent transfer of single stranded DNA through a cell-envelope localized type IV secretion system (T4SS). Genes for this type of HGT reside on conjugative plasmids (CPs) or integrated conjugative elements (ICEs). Bacterial conjugation is ubiquitous in the bacterial and archaebacterial world and facilitates efficient gene transfer within populations of the same species and across species boundaries. It is responsible for rapid spread and persistence of virulence and antibiotic resistance genes in pathogenic bacteria causing increasing problems in treatment of diseases using antibiotics.
In our lab we study the complex regulation of DNA transfer genes as well as structure-function relationships of various proteins important for bacterial conjugation. Our model plasmid is an enterobacterial, F-related conjugative resistance plasmid.
Furthermore, we investigate activation of cellular stress systems by expression of DNA transfer genes and the link between cell division and the heat-shock regulon in Escherichia coli.