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

ABSTRACT: 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 wtS. 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 (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. 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. Vaccines are lacking against several of the major causes of invasive Salmonella disease, such as invasive nontyphoidal Salmonella and S. Paratyphi A. These studies demonstrate that T memory cell effector responses generated after human wtSalmonella Typhi mucosal infection are multifunctional and cross?reactive against S. Paratyphi A, S. Paratyphi B and an invasive nontyphoidal Salmonella Typhimurium strain, yet the specific functional characteristics of the memory T?cell responses are significantly impacted by serovar. These data provide a rationale for strain?specific vaccination against invasive Salmonella for next?generation T?cell?based vaccines.

SUBMITTER: Rapaka R

PROVIDER: S-EPMC7512505 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Background: Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period.Methods: We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms.Results: Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates.Conclusions: Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy.

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

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