Protective Host Immune Responses to
            <i>Salmonella</i>
            Infection

Pham, Oanh H.; McSorley, Stephen J.

doi:10.2217/fmb.14.98

Cited by 106 publications

(92 citation statements)

References 88 publications

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“…Interleukin-17A-producing CD4+ T cells are the core component of the Th17 helper subset which is thought to mediate protection against several organisms, including intracellular bacteria [12, 13, 37]. Therefore, we next investigated whether immunization with Ty21a induces S .…”

Section: Resultsmentioning

confidence: 99%

Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a

Wahid

Fresnay

Levine

et al. 2016

Clinical Immunology

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The live oral typhoid vaccine Ty21a elicits predominantly CD8+, as well as CD4+ T cells mediated immune responses. Clinical field studies showed that Ty21a is moderately effective against S. Typhi and S. Paratyphi B, but not S. Paratyphi A infections. In this study we describe the in depth characterization of S. Typhi, S. Paratyphi A and S. Paratyphi B cross-reactive CD4+ T cell responses elicited following immunization with Ty21a. PBMC samples were collected from 16 healthy volunteers before and 42/84 days after Ty21a immunization and stimulated ex-vivo with Salmonella-infected targets. Multiparametric flow cytometry was used to detect the vaccine elicited Salmonella-specific responses in T effector/memory (TEM) and CD45RA+ T effector/memory (TEMRA) CD4+ cell subsets, by measuring CD4+ multifunctional (MF) cells that concomitantly produced IFN-γ, TNF-α, IL-2, MIP-1β, IL-17A and/or expressed CD107a. Post-vaccination increases in S. Typhi-specific MF cells were observed in CD4+ TEM and TEMRA subsets which predominantly produced IFN-γ and/or TNF-α, while IL-2 was produced by a smaller cell subset. A small proportion of those MF cells also produced MIP-1β, IL-17A and expressed CD107a (a marker associated with cytotoxicity). Approximately one third of these specific MF cells have the potential to migrate to the gut mucosa, as evidenced by co-expression of the gut-homing molecule integrin α4β7. In contrast to our previous observations with CD8+T cells, MF CD4+ T cell responses to the different Salmonella serovars evaluated were similar in magnitude and characteristics. We conclude that although induction of cross-reactive CD4+ MF effector T cells suggest a possible role in Salmonella-immunity, these responses are unlikely to provide an immunological basis for the observed efficacy of Ty21a against S. Typhi and S. Paratyphi B, but not to S. Paratyphi A.

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Section: Resultsmentioning

confidence: 99%

Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a

Wahid

Fresnay

Levine

et al. 2016

Clinical Immunology

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“…Salmonella enterica is a facultative intracellular bacterium implicated in a variety of illnesses, from gastric disorders to cancer, and is the leading cause of food borne illnesses in humans 12 . S. enterica infects over 90 million people worldwide, including 1.2 million annually in the United States 3 .…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ in Salmonella pathogenesis: New tricks for an old dog

2017

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Salmonella enterica is a facultative intracellular bacterium that is the leading cause of food borne illnesses in humans. The cytokine IFN-γ has well-established antibacterial properties against Salmonella and other intracellular microbes, for example its capacity to activate macrophages, promote phagocytosis, and destroy phagocytosed microbes by free radical-driven toxification of phagosomes. But IFN-γ induces the expression of hundreds of uncharacterized genes, suggesting that this cytokine deploys additional antimicrobial strategies that await discovery. Recently, one such mechanism, mediated by a family of IFN-inducible small GTPases called Guanylate Binding Proteins (GBPs) has been uncovered. GBPs were shown to facilitate the pyroptotic clearance of Salmonella from infected macrophages by rupturing the protective intracellular vacuole this microbe forms around itself. Once this protective vacuole is lost, exposed Salmonella activates pyroptosis, which destroys the infected cell. In this review, we summarize such emerging roles for IFN-γ in restricting Salmonella pathogenesis.

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“…These results highlight the importance of mucosal immunity for protection against Salmonella infection already described as the first line of defense before dissemination of the pathogen [41]. Although many studies have already demonstrated the importance of cellular immunity in the control of intracellular Salmonella infection [42], there is also converging evidence of the importance of humoral immunity in the fight against Salmonella [34, 43–45]. Evidence from humans studies suggest that severe infection and bacteremia occur when specific antibody is lacking, whose role is essential to protect against extracellular growth of NTS in the blood [46, 47].…”

Section: Discussionmentioning

confidence: 63%

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

et al. 2016

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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.

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Protective Host Immune Responses to Salmonella Infection

Cited by 106 publications

References 88 publications

Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a

Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a

Interferon-γ in Salmonella pathogenesis: New tricks for an old dog

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

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