title: Importance ofSalmonellaTyphi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model.
abstract: Typhoid fever, caused by the human-restricted organismSalmonella entericaserovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels ofS. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~104CFU) wild-typeS. Typhi. Typhoid fever development was associated with higher multifunctionalS. Typhi-responsive CD8+ T effector memory cells at baseline. Early decreases of these cells in circulation following challenge were observed in bothS. Typhi-responsive integrin α4β7- and integrin α4β7+ CD8+ T effector memory (TEM) cells, suggesting their potential to home to both mucosal and extra-intestinal sites. Participants with higher baseline levels ofS. Typhi-responsive CD8+ T memory cells had a higher risk of acquiring disease, but among those who acquired disease, those with a higher baseline responses took longer to develop disease. In contrast, protection against disease was associated with low or absentS. Typhi-responsive T cells at baseline and no changes in circulation following challenge. These data highlight the importance of pre-existingS. Typhi-responsive immunity in predicting clinical outcome following infection with wild-typeS. Typhi and provide novel insights into the complex mechanisms involved in protective immunity to natural infection in a stringent human model with a high challenge dose. They also contribute important information on the immunological responses to be assessed in the appraisal and selection of new generation typhoid vaccines.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fresnay
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA.
authors.forename: Monica A
authors.initials: MA
authors.lastname: McArthur
authors.affiliation: Department of Epidemiology and Public Health, University of Maryland School of Medicine , Baltimore, MD , USA.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Magder
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre , Oxford , UK.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre , Oxford , UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre , Oxford , UK.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre , Oxford , UK.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Nuffield Department of Medicine, University of Oxford , Oxford , UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre , Oxford , UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine , Baltimore, MD , USA.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
keywords: CD8+ T cells; Salmonella Typhi; cell-mediated immunity; cytokines; cytotoxicity; multifunctional; typhoid fever