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

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

doi:10.1002/cti2.1178

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

Clin Transl Immunology. 2020 Sep 24;9(9):e1178. doi: 10.1002/cti2.1178. eCollection 2020.

Authors

Rekha R Rapaka^{1

2}, Rezwanul Wahid^{1

3}, Stephanie Fresnay^{1

3

4}, Jayaum S Booth^{1

3}, Thomas C Darton^{5

6}, Claire Jones⁵, Claire S Waddington^{5

7}, Myron M Levine^{1

2

3}, Andrew J Pollard⁵, Marcelo B Sztein^{1

2

3}

Affiliations

¹ Center for Vaccine Development and Global Health University of Maryland School of Medicine Baltimore MD USA.
² Department of Medicine University of Maryland School of Medicine Baltimore MD USA.
³ Department of Pediatrics University of Maryland School of Medicine Baltimore MD USA.
⁴ Present address: Stephanie Fresnay GlaxoSmithKline Rockville MD USA.
⁵ Oxford Vaccine Group Department of Paediatrics University of Oxford and the NIHR Oxford Biomedical Research Centre Oxford UK.
⁶ Present address: Thomas C Darton University of Sheffield Medical School Sheffield UK.
⁷ Present address: University of Cambridge Cambridge UK.

Abstract

Objective: There 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.

Methods: T 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).

Results: Blood T-cell effector memory (T_EM) responses after exposure to S. Typhi in humans evolve late, peaking weeks after infection in most volunteers. Induced multifunctional CD4⁺ Th1 and CD8⁺ T_EM cells elicited after S. Typhi challenge were cross-reactive with PA, PB and iNTSTy. The magnitude of multifunctional CD4⁺ T_EM cell responses to S. Typhi correlated with induction of cross-reactive multifunctional CD8⁺ T_EM cells against PA, PB and iNTSTy. Highly multifunctional subsets and T central memory and T effector memory cells that re-express CD45 (T_EMRA) demonstrated less heterologous T-cell cross-reactivity, and multifunctional Th17 elicited after S. Typhi challenge was not cross-reactive against other invasive Salmonella.

Conclusion: Gaps 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.

Keywords: Paratyphi; S. Typhi; T‐cell memory; human challenge; iNTS; invasive Salmonella.

Abstract

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