Program Shepherds: Alison O'Brien (USUHS) and Erik Hewlett (UVA)
The central theme of Research Program IV is to study how toxins of various NIAID Category A-C microorganisms and certain emerging pathogens interact with host cells, the consequences of those interactions, and the development of methods to block or ameliorate the impact of these virulence factors on the target cells and the host.
All categories of Select Agent toxins, as defined by mechanism of action, are represented in this program, i.e., Shiga toxin and ricin, Clostridium perfringens epsilon, and Staphylococcus aureus enterotoxins. An additional project centers on Toxins A and B from Clostridium difficile, both of which are considered to be key virulence components in the pathogenesis of C. difficile colitis. Several projects in Program IV are focused on the toxin-intestinal cell interface and therefore are a natural bridge to Program III.
Shiga toxin (Stx) of Shigella dysenteriae type 1, Stx1 and Stx2 of Escherichia coli O157:H7, and other Shiga toxin-producing E. coli (STEC), and ricin from the castor bean plant cause depurination of a critical residue in the 28S rRNA of 60S ribosomes and, hence, inhibition of protein synthesis, apoptosis, and cell death.
Clostridium perfringens epsilon toxin (ETX) is a class B CDC/USDA overlap toxin and a major virulence factor in natural veterinary infections caused by ETX-producing C. perfringens isolates. Currently there are no ETX therapeutics (NIH prefers ETX therapeutics over vaccines because natural ETX-related disease in humans is uncommon).
C. difficile colitis is a toxin-mediated disease, which is dependent on the actions of Toxin A (TcdA) and/or Toxin B (TcdB). Although the molecular mechanisms by which TcdA and TcdB modify Rho-subfamily GTPases are well defined, the pathways connecting those events to colitis and inflammatory diarrhea remain elusive.
Bacterial superantigens (SAg) are exotoxins that trigger an excessive immune response that may lead to lethal shock. Because of their ability to induce incapacitation at exceedingly low concentrations and to elicit shock, their ease of production and their exceptional stability, SAgs are classified as Category B biological weapons.