Bacterial protein toxins, their interaction with host cells, their effects on intracellular signal transduction, and development of novel alternative anti-toxin therapeutics; human and nonhuman primate vaginal and gut microbial ecosystems (microbiomes) and their role in health and disease

Research in the Wilson laboratory involves studying the molecular interactions and biochemical mechanisms by which protein toxins produced by pathogenic bacteria cause their toxic effects on animal cells. When the bacterial toxins are released into the media of the host, they can interact with or even enter host cells and interfere with normal signal transduction and physiological function, thereby disrupting the delicate balance of cellular metabolism, often lethally. One project involves studying the structure, function and pathogenic mechanisms of the potent dermonecrotic toxins produced by Pasteurella multocida, Bordetella sp., E. coli, and Yersinia. Like many other toxins, these toxins are currently being used as potent tools for studying signal transduction pathways and physiological processes within cells. The laboratory is interested in understanding the underlying mechanism of how these toxins carry out their effects on these processes. For example, the laboratory has discovered that the pleiotropic effects on different tissue cells caused by the toxin from P. multocida is due to the diverse roles that the toxin’s targets have in different cell types, which in turn influence the cellular and organismic outcomes of toxin action. Research efforts for this project include

1. defining the cellular binding and uptake mechanisms that mediate toxin entry into host cell cytosol and translocation across vesicular membranes into the cytosol;
2. characterizing the determinants involved in intoxication and identifying additional toxin features that dictate differential intracellular trafficking among the PMT-CNF family members; and
3. screening and testing for functional activity additional putative CNF- and PMT-like domains found in a large number of bacterial genomes.

Of particular interest to the Wilson laboratory is translational biomedical research aimed at development of post-exposure anti-toxin therapeutics and development of toxin-based cargo-delivery platforms. This requires a global understanding of the downstream metabolic and signaling pathways that are affected by toxins, so as to identify potential sites for intervention. The Wilson lab has proteomic and metabolomic research projects to identify biomarkers of cellular toxicity (i.e. toxicogenomics). The Wilson lab is developing novel post-exposure anti-toxin therapeutics against botulinum neurotoxins as well as highly sensitive, high-throughput detection assays for distinguishing among botulinum neurotoxins. There is currently no effective antidote for preventing or reversing botulism or paralysis once exposure has occurred and symptoms of disease have initiated. A major goal of this translational biomedical research is to design novel anti-toxins for neuronal cell-specific delivery of post-exposure therapeutics. Another activity involves using toxins as cargo-delivery platforms for bacterial toxin-inspired drug delivery (BTIDD), particularly for cell-specific delivery of post-exposure therapeutics. We have designed and developed a prototype delivery platform. We are continuing to develop our inhibitor-cargo delivery vehicles, optimizing the delivery and cargo-release mechanism.

Dr. Wilson is also engaged in collaborative translational research to exploit comparative and functional genomic technologies to study the dynamic interactions between the host and its commensal as well as pathogenic microbes, i.e. the microbial ecology in the host environment (microbiomes). This research focuses on the complex ecosystem of the vaginal and gut microbiota and their impact on health and disease in human and nonhuman primates. A central goal is to elucidate pathogenic mechanisms of vaginal infections such as bacterial vaginosis and the role of normal and abnormal microbiota in disease susceptibility and progression. Studying both human and nonhuman primate vaginal ecosystems has the potential to address human biomedical questions by establishing an evolutionary and comparative biology context that considers environments, microbes, and host immune systems.