Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease.
A novel human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently established by the Oxford Vaccine Group. In this model, 104 CFU of Salmonella resulted in 65% of participants developing typhoid fever (referred here as typhoid diagnosis -TD-) 6-9 days post-challenge. TD was diagnosed in participants meeting clinical (oral temperature ≥38°C for ≥12h) and/or microbiological (S. Typhi bacteremia) endpoints. Changes in B cell subpopulations following S. Typhi challenge remain undefined. To address this issue, a subset of volunteers (6 TD and 4 who did not develop TD -NoTD-) was evaluated. Notable changes included reduction in the frequency of B cells (cells/ml) of TD volunteers during disease days and increase in plasmablasts (PB) during the recovery phase (>day 14). Additionally, a portion of PB of TD volunteers showed a significant increase in activation (CD40, CD21) and gut homing (integrin α4β7) molecules. Furthermore, all BM subsets of TD volunteers showed changes induced by S. Typhi infections such as a decrease in CD21 in switched memory (Sm) CD27+ and Sm CD27- cells as well as upregulation of CD40 in unswitched memory (Um) and Naïve cells. Furthermore, changes in the signaling profile of some BM subsets were identified after S. Typhi-LPS stimulation around time of disease. Notably, naïve cells of TD (compared to NoTD) volunteers showed a higher percentage of cells phosphorylating Akt suggesting enhanced survival of these cells. Interestingly, most these changes were temporally associated with disease onset. This is the first study to describe differences in B cell subsets directly related to clinical outcome following oral challenge with wild-type S. Typhi in humans.
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.
Franklin R
FR
Toapanta
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.
Paula J
PJ
Bernal
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.
Stephanie
S
Fresnay
Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Laurence S
LS
Magder
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Thomas C
TC
Darton
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Claire
C
Jones
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Claire S
CS
Waddington
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Christoph J
CJ
Blohmke
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Brian
B
Angus
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.
Myron M
MM
Levine
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
Andrew J
AJ
Pollard
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.
Marcelo B
MB
Sztein
D000293:Adolescent; D000328:Adult; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D016023:Integrins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology*; D017464:Receptors, Complement 3d / Q000235:genetics; D035842:Research Subjects; D012485:Salmonella typhi / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics; D014435:Typhoid Fever / Q000097:blood / Q000175:diagnosis* / Q000276:immunology* / Q000382:microbiology; D014436:Typhoid-Paratyphoid Vaccines / Q000276:immunology; D055815:Young Adult
D019013:CD40 Antigens; D016023:Integrins; D017464:Receptors, Complement 3d; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014436:Typhoid-Paratyphoid Vaccines; C071777:integrin alpha4beta7