Neutralizing Antibodies to Typhoid Toxin

Principal Investigator: Jeongmin Song

Department of Microbiology and Immunology
Sponsor: NIH-National Institute of Allergy and Infectious Diseases (NIAID)
Grant Number: 1R03AI135767-01
Title: Neutralizing Antibodies to Typhoid Toxin
Project Amount: $92,878
Project Period: December 2017 to November 2018

DESCRIPTION (provided by applicant): 

Typhoid fever is a major global health concern, with ongoing occurring outbreaks in some developing countries. The causative agent of typhoid fever is the gram-negative bacterium, Salmonella Typhi. It was recently discovered that S. Typhi produces an unusual toxin known as typhoid toxin. The goal of this research program is to generate the first B cell epitope map of typhoid toxin, with a particular focus on identification of regions associated with the onset of toxin-neutralizing antibodies. In Specific Aim 1 we will generate a collection of murine monoclonal antibodies (MAbs) against all of the three components of typhoid toxin, CdtB, PltA and PltB and characterize them to identify potent MAbs by performing ELISA, cell-based toxin-neutralization assays, competition ELISA, pepscan analysis, mutagenesis, and surface plasmon resonance. In Specific Aim 2 a select number of toxin-neutralizing MAbs generated in Aim 1 will be evaluated for the ability to passively protect mice against lethal dose typhoid toxin challenge. We will test whether the MAbs with the most potent toxin-neutralizing activity in vitro are also protective in vivo. Additionally, we will begin to define the mechanism(s) by which the most potent MAbs neutralize typhoid toxin in vitro. The MAbs generated as part of this study will be powerful tools for more detailed mechanistic studies to better understand the biology of typhoid toxin and may even have potential applications for therapeutics uses in humans.