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 goal of understanding the biochemical basis of bacterial disease; to gain insight into how proteins insert into and cross membranes; and to develop new vaccines and therapeutics based on properties of these toxins. The most potent bacterial toxins act by covalently modifying target substrates within the cytosol of mammalian cells. Their actions generally involve four steps: (i) binding to receptors; (ii) receptor-mediated endocytosis; (iii) translocation of the enzymic moiety across a membrane, into the cytosol; and (iv) enzymic modification of a target substrate. We are currently focusing on anthrax and diphtheria toxins, applying biophysical, biochemical, and cell biological methods to generate detailed models of each step. How these structurally unrelated toxins insert into bilayers under the influence of the low pH of the endosomal compartment, and translocate their enzymic moieties across the membrane represents a problem of interest from many perspectives. 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 have used anthrax toxin to engineer a new type of therapeutic, which also has the properties of a vaccine.

Selected Publications:

Mourez M, Lacy DB, Cunningham K, Legmann R, Sellman BR, Mogridge J, and RJ Collier. 2002. 2001: a year of major advances in anthrax toxin research. Trends Microbiol 10:287-293.

Mogridge J, Cunningham K, Lacy DB, Mourez M, and RJ Collier. 2002. The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen. Proc Natl Acad Sci USA 99:7045-7048.

Sellman BR, M Mourez, and RJ Collier. 2001. Dominant-negative mutants of a toxin subunit: an approach to therapy of anthrax. Science 292:695-697.

Benson, E.L., P.D. Huynh, A. Finkelstein, and R.J. Collier. 1998. Identification of residues lining the anthrax protective antigen channel. Biochemistry. 37:3941-3948.

Petosa, C., R. J. Collier, K. R. Klimpel, S. H. Leppla, and R. C. Liddington. (1997). Crystal structure of the anthrax toxin protective antigen. Nature. 385:833-838.

Ballard, J. D., R. J. Collier, and M. N. Starnbach. (1996). Anthrax Toxin-Mediated Delivery Of a Cytotoxic T-Cell Epitope In Vivo. Proc.Natl. Acad. Sci. USA 93:12531-12534.