Role of T3SS-1 SipD Protein in Protecting Mice against Non-typhoidal Salmonella Typhimurium

Abstract

Background

Salmonella enterica species are enteric pathogens that cause severe diseases ranging from self-limiting gastroenteritis to enteric fever and sepsis in humans. These infectious diseases are still the major cause of morbidity and mortality in low-income countries, especially in children younger than 5 years and immunocompromised adults. Vaccines targeting typhoidal diseases are already marketed, but none protect against non-typhoidal Salmonella. The existence of multiple non-typhoidal Salmonella serotypes as well as emerging antibiotic resistance highlight the need for development of a broad-spectrum protective vaccine. All Salmonella spp. utilize two type III Secretion Systems (T3SS 1 and 2) to initiate infection, allow replication in phagocytic cells and induce systemic disease. T3SS-1, which is essential to invade epithelial cells and cross the barrier, forms an extracellular needle and syringe necessary to inject effector proteins into the host cell. PrgI and SipD form, respectively, the T3SS-1 needle and the tip complex at the top of the needle. Because they are common and highly conserved in all virulent Salmonella spp., they might be ideal candidate antigens for a subunit-based, broad-spectrum vaccine.

Principal Findings

We investigated the immunogenicity and protective efficacy of PrgI and SipD administered by subcutaneous, intranasal and oral routes, alone or combined, in a mouse model of Salmonella intestinal challenge. Robust IgG (in all immunization routes) and IgA (in intranasal and oral immunization routes) antibody responses were induced against both proteins, particularly SipD. Mice orally immunized with SipD alone or SipD combined with PrgI were protected against lethal intestinal challenge with Salmonella Typhimurium (100 Lethal Dose 50%) depending on antigen, route and adjuvant .

Conclusions and Significance

Salmonella T3SS SipD is a promising antigen for the development of a protective Salmonella vaccine, and could be developed for vaccination in tropical endemic areas to control infant mortality.

Author Summary

Salmonella are bacteria responsible for a high global burden of invasive diseases, especially in South and South-East Asia (mainly enteric fever due to Salmonella Typhi) and sub-Saharan Africa (mainly invasive Non-Typhoidal Salmonella, iNTS). This iNTS disease has emerged as a prominent cause of systemic infection in children and immunocompromised African adults, with an associated case fatality of 20–25%. Because licensed vaccines only protect against enteric fever, there is a crucial need to develop a new broad-spectrum vaccine effective against enteric fever and iNTS that can be administered safely to children under 2 years old. The virulence of Salmonella depends on two type III secretion systems (T3SS-1 and T3SS-2) necessary for invasion, replication, intracellular survival and dissemination of the bacteria. Two structural proteins of T3SS-1 (essential for crossing the epithelial barrier) are highly conserved among Salmonella spp. and might be good candidates for a broad-spectrum vaccine. The current study describes the protective effect elicited by these proteins in a murine model. A specific immune response was generated against our antigens and provided protection against Salmonella Typhimurium oral infection. Such a candidate vaccine offers promising perspectives to control Salmonella diseases.