Research Interests

The symptoms of many bacterial diseases are due largely to the actions of toxic proteins released by the bacteria (diphtheria, anthrax, cholera, and tetanus toxins are well known examples). We study these toxins with the goals of understanding the biochemical basis of bacterial disease; gaining insight into how proteins cross membranes; and developing new pharmaceuticals. The most potent toxins act by penetrating into mammalian cells and modifying target substrates within the cytosol. Their actions generally involve four steps: (i) binding to receptors; (ii) endocytosis of the toxin-receptor complex; (iii) translocation of the enzymic part across a membrane, into the cytosol; and (iv) enzymic modification of a target substrate. We are currently focusing on diphtheria and anthrax toxins, applying a variety of methods to generate detailed models of each step in toxin action. How these structurally unrelated toxins insert into membranes under the influence of the low pH of the endosomal compartment, and translocate their enzymic moieties across the endosomal membrane represents a problem of broad interest. Crystallographic structures of the native proteins provide a framework for our studies. Genetically modified, nontoxic forms of these toxins may be used as transporters for heterologous proteins and peptides into cells. We are using anthrax toxin to engineer a new type of vaccines that stimulates the formation of cytotoxic T lymphocytic (CTL) responses, as opposed to antibody formation. CTL-based vaccines may be useful against a variety of diseases, which have heretofore been thought to be beyond the realm of vaccination.

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Section 44: Microbial Biology