Validation of role of CdtB subunit of toxin in the pathogenicity of Salmonella enterica serovar Typhi and assessment of its potential as a vaccine candidate

Abstract

Typhoid fever caused by Salmonella enterica serovar Typhi (S. Typhi) continues to be a major problem, especially in developing countries. Moreover, due to the rapid emergence of multi-drugresistant (MDR) strains as well as problems associated with the existing vaccines, efforts are being made to develop effective prophylactic agents. CdtB subunit of typhoid toxin was selected for assessing its potential as a vaccine candidate as it was found to be conserved in almost all the Typhi strains. Before the evaluation of CdtB as a vaccine candidate, its role in the pathogenesis of S. Typhi was investigated. From the information obtained from in-vivo, ex-vivo and in-vitro studies, two main observations were derived: i) the cloned and purified typhoid toxin (holotoxin) induces typhoid-fever like symptomatology in mice. ii) CdtB subunit is the main catalytic unit of holotoxin through which typhoid toxin exerts genotoxic effects on host DNA; which leads to cell death mainly by apoptosis, thus, validating the role of typhoid toxin in Salmonella pathogenicity. After evaluating the role of CdtB protein in pathogenesis, its immunoprophylactic potential was studied. Immunization with the protein conferred 75% protection against the lethal dose of S. Typhi with a reduction in bacterial burden, levels of pro-inflammatory cytokines and restoration of histoarchitecture of the organs. The protein elicited humoral as well as cellular immune response, which provided the proof of concept of immunogenic and immunoprotective nature of CdtB protein, thereby, establishing the relevance of this protein for developing it as a prophylactic option against S. Typhi. newline