Human Salmonella Typhi exposure generates differential multifunctional cross‐reactive T‐cell memory responses against Salmonella Paratyphi and invasive nontyphoidal Salmonella

Rekha R Rapaka,Claire S Waddington,Claire Jones,Andrew J Pollard,Myron M Levine,Rezwanul Wahid,Stephanie Fresnay,Marcelo B Sztein,Thomas C Darton,Jayaum S Booth

doi:10.1002/cti2.1178

Abstract

ObjectiveThere are no vaccines for most of the major invasive Salmonella strains causing severe infection in humans. We evaluated the specificity of adaptive T memory cell responses generated after Salmonella Typhi exposure in humans against other major invasive Salmonella strains sharing capacity for dissemination.MethodsT memory cells from eleven volunteers who underwent controlled oral challenge with wt S. Typhi were characterised by flow cytometry for cross‐reactive cellular cytokine/chemokine effector responses or evidence of degranulation upon stimulation with autologous B‐lymphoblastoid cells infected with either S. Typhi, Salmonella Paratyphi A (PA), S. Paratyphi B (PB) or an invasive nontyphoidal Salmonella strain of the S. Typhimurium serovar (iNTSTy).ResultsBlood T‐cell effector memory (TEM) responses after exposure to S. Typhi in humans evolve late, peaking weeks after infection in most volunteers. Induced multifunctional CD4+ Th1 and CD8+ TEM cells elicited after S. Typhi challenge were cross‐reactive with PA, PB and iNTSTy. The magnitude of multifunctional CD4+ TEM cell responses to S. Typhi correlated with induction of cross‐reactive multifunctional CD8+ TEM cells against PA, PB and iNTSTy. Highly multifunctional subsets and T central memory and T effector memory cells that re‐express CD45 (TEMRA) demonstrated less heterologous T‐cell cross‐reactivity, and multifunctional Th17 elicited after S. Typhi challenge was not cross‐reactive against other invasive Salmonella.ConclusionGaps in cross‐reactive immune effector functions in human T‐cell memory compartments were highly dependent on invasive Salmonella strain, underscoring the importance of strain‐dependent vaccination in the design of T‐cell‐based vaccines for invasive Salmonella.

Highlights

Invasive Salmonella infection, caused by typhoidal Salmonella
Typhimurium isolated in Mali of the ST313 multilocus sequence type, as a representative invasive nontyphoidal Salmonella (iNTS) of serovar Typhimurium circulating in sub-Saharan Africa
At S. Typhi (ST) peak, CD8+ T-cell effector memory (TEM) cells were evaluated for simultaneous expression of two or more effector functions upon stimulation with BLCL infected with either Paratyphi A (PA), Paratyphi B (PB) or iNTSTy

Summary

INTRODUCTION

Invasive Salmonella infection, caused by typhoidal Salmonella Paratyphi A) or invasive nontyphoidal Salmonella (iNTS), is spread by faecal–oral route and is responsible for millions of infections yearly and over 600 000 deaths annually, with most mortality caused by iNTS.[1,2,3] There are no vaccines in clinical use known to prevent disease from S. Typhi strain by nondirected mutagenesis) does not confer crossprotection against PA disease,[29] but was moderately protective against PB.[30] After human Ty21a vaccination, low frequencies of highly multifunctional PA cross-reactive peripheral CD8+ T cells are elicited compared to frequencies of reactive CD8+ T cells against S. Typhi contains antigens able to elicit both cross-reactive CD4+ and CD8+ T-cell effector functions against other major invasive Salmonella for which vaccines are lacking, such as iNTS strains and PA, or how biologic differences between different invasive Salmonella strains impact T-cell priming and the development of T-cell memory and effector functions in humans. Typhimurium isolated in Mali of the ST313 multilocus sequence type (iNTSTy), as a representative iNTS of serovar Typhimurium circulating in sub-Saharan Africa

RESULTS

DISCUSSION

Participants and human challenge model

CONFLICTS OF INTEREST