The unifying themes of my research program are seeking to understand the underlying mechanisms that control the pathogenesis and disease associated with Salmonella, as well as developing control strategies for the bacteria or its associated disease. The main focus of the work that can be divided into 3 areas (below) is on the Salmonella A2B5 Toxins: Biology, Pathogenesis, and Neutralization.
Project 1. Molecular evolution and the roles in virulence of Salmonella A2B5 toxins.
Project 2. Salmonella persistent infection.
Project 3. Prophylactic and therapeutic development protecting against Salmonella A2B5 toxins.
Background: The gram-negative bacteria Salmonella enterica serovar Typhi (S. Typhi) is a human host-restricted pathogen that is the cause of typhoid fever, affecting 10.9 million people annually. Typhoid toxin is an A2B5 toxin that is secreted exclusively by S. Typhi bacterial cells that have invaded the host cells, and become localized in a specialized vacuole that is called the “Salmonella-containing vacuole (SCV)”. The tissue tropism of the bacteria, intracellular localization, along with toxin secretion are all required for typhoid fever disease progression and the establishment of persistent infection. Typhoid toxin consists of three subunits: two enzymatic ‘A’ subunits that intoxicate host cells, CdtB (nuclease) and PltA (mono ADP-ribosyltransferase), and a homopentamer of the receptor-binding ‘B’ subunit PltB, serving as the first example of A2B5 toxin. Some nontyphoidal Salmonella serovars (NTS) that cause self-limiting gastroenteritis in humans and/or animals also encode typhoid toxin orthologues in their genomes, which are predicted to play significant roles in NTS pathogenesis. My research program primarily focuses on defining the roles of Salmonella A2B5 toxins in pathogenesis and virulence, using typhoid toxin and its orthologues as examples. We also put our efforts into the development of intervention strategies against these toxins, particularly the use of anti-toxin antibodies and vaccines targeting toxins, and the understanding of their underlying protection mechanisms.