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

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 crossreactive against other invasive Salmonella. Conclusion. Gaps in crossreactive 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.

Controlled human infectious models, a path forward in uncovering immunological correlates of protection: Lessons from enteric fevers studies

“…Paratyphi B and invasive non-typhoidal S . Typhimurium using the typhoid CHIM ( Rapaka et al, 2020 ). We observed that S .…”

Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis

“…For typhoid fever, a live-attenuated vaccine, Ty21a, offers moderate protection, and the recent rollout of a protein-conjugated capsular Vi antigen subunit vaccine (TCV) has shown improved (albeit still incomplete) protection than Vi capsular polysaccharide vaccines [ 6 ]. On the other hand, no human vaccines are currently licensed for non-typhoidal serovars, which lack the Vi capsular antigen [ 7 ], and T cell-based mechanisms are thought to represent a strong target for vaccine development [ 8 ].…”

Global and regional associations of enteric infections and asthma

“…Our present analyses only cover 4 main types of enteric infections, diarrheal diseases, typhoid, paratyphoid, and iNTS. In contrast to these diseases which show no clear bias towards a Th2 phenotype [13, 14], critical for asthma pathogenesis, some intestinal helminth infections, like gastric helminthiasis in children, were positively associated with asthma [15], possibly because of the Th2 responses mounted upon infections. Hence, more detailed interrogations regarding the types of infectious agent and the severity of enteric infections are needed to decipher the potential underlying mechanistic links.…”