title: Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease.
abstract: A new human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently developed. In this model, ingestion of 104 CFU of Salmonella resulted in 65% of subjects developing typhoid fever (referred here as typhoid diagnosis -TD-) 5-10 days post-challenge. TD criteria included meeting clinical (oral temperature ≥38°C for ≥12 h) and/or microbiological (S. Typhi bacteremia) endpoints. One of the first lines of defense against pathogens are the cells of the innate immune system (e.g., monocytes, dendritic cells -DCs-). Various changes in circulating monocytes and DCs have been described in the murine S. Typhimurium model; however, whether similar changes are present in humans remains to be explored. To address these questions, a subset of volunteers (5 TD and 3 who did not develop typhoid despite oral challenge -NoTD-) were evaluated for changes in circulating monocytes and DCs. Expression of CD38 and CD40 were upregulated in monocytes and DCs in TD volunteers during the disease days (TD-0h to TD-96h). Moreover, integrin α4β7, a gut homing molecule, was upregulated on monocytes but not DCs. CD21 upregulation was only identified in DCs. These changes were not observed among NoTD volunteers despite the same oral challenge. Moreover, monocytes and DCs from NoTD volunteers showed increased binding to S. Typhi one day after challenge. These monocytes showed phosphorylation of p38MAPK, NFkB and Erk1/2 upon stimulation with S. Typhi-LPS-QDot micelles. In contrast, monocytes from TD volunteers showed only a moderate increase in S. Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation. This is the first study to describe different activation and migration profiles, as well as differential signaling patterns, in monocytes and DCs which relate directly to the clinical outcome following oral challenge with wild type S. Typhi.
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Franklin R
authors.initials: FR
authors.lastname: Toapanta
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Bernal
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fresnay
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D012485:Salmonella typhi; D014435:Typhoid Fever / Q000276:immunology* / Q000382:microbiology*; D055815:Young Adult
chemical_list: D015415:Biomarkers