For the vast majority of microbial pathogens, the first encounter with a host occurs on the mucosal surfaces of the respiratory, genital or gastrointestinal tracts. Once contact has been initiated, there ensues a complex molecular interplay between the host and microbe that ultimately determines the success or failure of the infection process. Nowhere is the battle between host and microbe more intense than on the epithelial surfaces of the gastrointestinal tract. Enteric pathogens, such as Salmonella typhimurium, Shigella flexneri, E.coli O157:H7, and Vibrio cholerae, secrete a panoply of molecular "weapons", including toxins, that enable them to adhere to, colonize, and invade intestinal epithelial cells. To defend itself against these invaders, the intestinal epithelium is aligned closely with the innate and adaptive immune systems. The innate immune system consists of broadly reactive and relatively non-specific barriers to infection, including antimicrobial peptides, proteases, and mucus, that deter (but rarely prevent) bacterial attachment to epithelial cells surfaces. The adaptive immune response, on the other hand, is exquisitely more sophisticated, responding to infection through the local production and transport onto epithelial surfaces of secretory IgA (SIgA) antibodies capable of neutralizing even the most potent microbial pathogens and toxins.
Research in my laboratory is aimed at understanding how SIgA, alone and in combination with other components of the innate and adaptive immune systems, disarms microbial pathogens and neutralizes toxins on the mucosal surfaces of the gastrointestinal tract. We study S.typhimurium and S.flexneri as model enteroinvasive pathogens, and are particularly interested in the effects of anti-LPS IgA antibodies on bacterial colonization, attachment and invasion. Another focus of my laboratory is ricin, an extremely potent member of the shiga family of toxins that is considered a potential bioterrorism agent. Using cell culture and mouse models of ricin intoxication, we are investigating the mechanisms by IgA and IgG antibodies neutralize ricin in both mucosal and systemic compartments. Ultimately, the results from these studies will be applied to the development of much needed mucosal vaccines and therapeutics against naturally acquired infections and potential bioterrorism agents.