Inflammation, Toxin Responses and Infectious Pathogenesis
Inflammatory responses are natural consequences of many infections and can be a key protective response. However, in some cases, inflammation can cause devastating effects on the host. The Thorpe lab uses several model systems to understand how the serious consequences of inflammation are mediated.
One major area of interest is to understand the role of Shiga toxin in the pathogenesis of diseases associated with Shiga toxin-producing E. coli infection, such as hemorrhagic colitis and hemolytic uremic syndrome (HUS). Her group linked the proinflammatory effects of Shiga toxins on intestinal epithelial cells to alteration in host signal transduction via a mechanism called the ribotoxic stress response. Since then, the Thorpe laboratory has focused on characterizing how Shiga toxins exert their proinflammatory effects on host cells via this response. Previous work in the Thorpe laboratory has shown that by damaging the 28S rRNA, both Shiga toxin and ricin can stimulate production of the proinflammatory cytokine IL-8, despite overall inhibition of protein synthesis. This phenomenon involved activation of host stress activated protein kinase pathways involving p38 and JNK. c-fos and c-jun mRNAs are induced, and IL-8 is expressed at both the mRNA and protein level. Through work designed to more fully understand how this pathway operates, Dr. Dakshina Jandhyala has developed data suggesting that the MAP3Kinase mixed lineage kinase ZAK plays a major role. Understanding these pathways in more detail is a major goal of our work.
Shiga toxin plays a central role in the severe disease caused by some strains of enterohemorhagic E. coli or (STEC). This pathogen is associated with increasing numbers of food-borne disease outbreaks. Although some cases of this infection can be relatively mild, others can lead to severe and life-threatening disease. The Thorpe laboratory collaborates with Dr. Tom Obrig at University of Maryland, Baltimore Campus, to develop therapeutics for Shiga toxin-associated diseases. Approaches to inhibiting the ribotoxic stress response are the focus of this area.
Another interest in the laboratory is to understand the potential role of subtilase cytotoxin (SubAB) in HUS. This molecule is an AB(5) cytotoxin and is produced by some strains of Shiga toxigenic E. coli. In collaboration with James and Adrienne Paton at the University of Adelaide, South Australia, the Thorpe lab is working to understand how this toxin works. Recent information reveals that endoplasmic reticulum stress is important for the function of the molecule. Jennifer Wolfson and the group are now focused on understanding the signal transduction events that occur in host cells following exposure to SubAB, and how co-exposure to this molecule and Shiga toxin impacts host cells.
The Thorpe lab also collaborates with Dr. Patricia Hibberd and Dr. David Snydman at Tufts Medical Center on several different clinical and translational projects, assessing the potential immunomodulatory effects of the probiotic Lactobacillus rhamnosus GG.