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

Abstract

BackgroundSalmonella 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 FindingsWe 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 adjuvantConclusions and SignificanceSalmonella 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.

Structural and Functional Characterization of the Type Three Secretion System (T3SS) Needle of Pseudomonas aeruginosa

“…For instance, Salmonella typhimurium , assembles between 10 and 100 NCs per cell (Kubori et al, 1998), while only a few NCs were detected on the surface of Pseudomonas aeruginosa (Perdu et al, 2015). Notably, the T3SS needle is formed by a single polymerized protein that has been studied in the context of vaccine development against several pathogens (Charro and Mota, 2015; Jneid et al, 2016; Koroleva et al, 2017). It has been shown that immunization with needle proteins induces specific humoral and T cell responses and abrogates bacterial pathogenicity in animal models (Koroleva et al, 2017).…”

Overview of the Nontyphoidal and Paratyphoidal Salmonella Vaccine Pipeline: Current Status and Future Prospects

“…Taking advantage of widely conserved Salmonella antigens may offer one potential solution to increase the cross-reactivity of vaccine candidates. Outer membrane proteins (eg, OmpC, OmpD, OmpF) [ 32 , 33 ], siderophores (enterobactin) [ 34 ], and type III secretion system proteins (eg, SipB, SipD, SseB, SseC, and PrgI) [ 35–37 ] have been explored as vaccine antigens in mice, demonstrating robust immunogenicity and protective efficacy against homologous strains. Alternatively, access to conserved membrane antigens can be enhanced for live-attenuated and OMV platforms.…”

Pathogenic signature of invasive non-typhoidal Salmonella in Africa: implications for vaccine development

“…180 Lee and colleagues 181 reported that the SPI-2-T3SS translocon subunit SseB was only modestly protective in C57BL/6 mice, but that co-administration of flagellin markedly improved vaccine efficacy in comparison with immunization with SseB or flagellin alone, possibly owing to flagellin-induced boosting of the SseB-specific CD4 + T cell response. The group of Jneid 182 found that four oral administrations of the SPI-1-T3SS component SipD adjuvanted with cholera toxin induced 72% protection against a lethal dose of S. Typhimurium, thus identifying for the first time an SPI-1-T3SS component as a potential candidate for protein-based iNTS vaccines. Kurtz and colleagues 183 demonstrated that immunization with the SPI-2-T3SS peptide SseI was able to reduce mortality upon S. Typhimurium SL1344 challenge.…”