Manipulation of Salmonella Typhi Gene Expression Impacts Innate Cell Responses in the Human Intestinal Mucosa.

Rosângela Salerno-Gonçalves,Alessio Fasano,James E Galen,Marcelo B Sztein,Myron M Levine

doi:10.3389/fimmu.2018.02543

Rosângela Salerno-Gonçalves, Alessio Fasano + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2018.02543

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Abstract

Although immunity induced by typhoid fever is moderated and short-lived, typhoid vaccination with the attenuated Ty21a oral vaccine generates long-lasting protection rates reaching up to 92%. Thus, there are important differences on how wild-type Salmonella and typhoid vaccine strains stimulate host immunity. We hypothesize that vaccine strains with different mutations might affect gut inflammation and intestinal permeability by different mechanisms. To test this hypothesis, we used an in vitro organotypic model of the human intestinal mucosa composed of human intestinal epithelial cells, lymphocytes/monocytes, endothelial cells, and fibroblasts. We also used six Salmonella enterica serovar Typhi (S. Typhi) strains: the licensed Ty21a oral vaccine, four typhoid vaccine candidates (i.e., CVD 908, CVD 909, CVD 910, and CVD 915) and the wild-type Ty2 strain. We found that genetically engineered S. Typhi vaccine strains elicit differential host changes not only in the intestinal permeability and secretion of inflammatory cytokines, but also in the phenotype and activation pathways of innate cells. These changes were distinct from those elicited by the parent wild-type S. Typhi and depended on the genetic manipulation. In sum, these results emphasize the importance of carefully selecting specific manipulations of the Salmonella genome in the development of typhoid vaccines.

Highlights

It is widely accepted that immunity induced by typhoid fever is moderate and short-lived, and recurrences after re-exposure to the infection are typical [1, 2]
Salmonella enterica serovar Typhi (Typhi) exposure [8], we examined the presence of IL-1β, IL-6, IL-8, IL-17A, and tumor necrosis factor (TNF)-α cytokines in the supernatants of the 3-D model cultures after exposure to six different S
We found that IL-17A levels inversely correlated with TNF-α production in the group lacking cytokine responses induced by Center for Vaccine Development (CVD) 910 and CVD 915, it directly correlated with TNF-α production in the group containing cytokines responses induced by only CVD 910 and CVD 915 (Figure 3C)

Summary

Introduction

It is widely accepted that immunity induced by typhoid fever is moderate and short-lived, and recurrences after re-exposure to the infection are typical [1, 2]. Protection rates can reach up to 92% for the Ty21a oral vaccine depending on the number of vaccine doses and formulation and last for up to 7 years [3,4,5]. It is reasonable to hypothesize that there are significant differences on how wild-type Salmonella and attenuated typhoid vaccine strains stimulate the host immune responses. Gut innate cells are known to play a vital role in shaping adaptive immune responses. Migration of activated B and T cells is governed by cytokines and chemokines produced by innate cells, such as macrophages, endothelial and epithelial cells [6]. Analyses of the genes implicated in inflammatory bowel disease have highlighted several

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