Evaluation of Salmonella enterica serovar Typhimurium TTSS-2 deficient fur mutant as safe live-attenuated vaccine candidate for immunocompromised mice.

Abstract

Salmonella enterica serovar Typhimurium has been extensively exploited as live attenuated vaccines (LAV) which generally confers better protection than killed or subunit vaccines. However, many LAV are limited by their inherent ability to access systemic organs in many of the vaccinated hosts, especially those which are immunocompromised. We evaluated the efficacy of a live-attenuated SPI2-deficient (ΔssaV) S. Typhimurium vaccine candidate (MT13) that additionally devoids the ferric uptake regulator (fur). We used specific pathogen free (SPF) streptomycin-pretreated mouse colitis model that included healthy C57BL/6 and immunocompromised iNos(-/-), IL10(-/-) and CD40L(-/-) in the background of C57BL/6 mice to assess the efficacy of developed vaccine candidate. In our study, the S. Typhimurium MT13 strain was established as a safe vaccine candidate to be administered in immunocompromised mice as it was found to be systemically attenuated without conferring significant pathological signs and growth defect within the host. In bacterial challenge experiment, the MT13-vaccinated C57BL/6 mice were protected from subsequent wild-type S. Typhimurium infection by inducing proficient mucosal immunity. The MT13 strain elicited efficient O-antigen specific mucosal secretory IgA associated protective response which was comparable with its parental ssaV mutant. Vaccination with MT13 also showed proficient T-cell activation in host mice; which has direct relation with pathogen clearance from host tissues. Collectively, these data implicate the possible application of SPI-2 deficient fur mutant (MT13) as a novel live attenuated vaccine strain with adept immunogenicity and improved safety, even in immunocompromised hosts. Further, this vaccine candidate can be employed to express heterologous antigens targeted against several other diseases, especially related to enterocolitic pathogens.