Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease.

Franklin R Toapanta,Myron M Levine,Laurence S Magder,Marcelo B Sztein,Claire Jones,Stephanie Fresnay,Paula J Bernal,Brian Angus,Thomas C Darton,Claire S Waddington,Andrew J Pollard,Christoph J Blohmke

doi:10.1371/journal.pntd.0004766

Abstract

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.

Highlights

To gain new insights into the host-pathogen interactions, which could aid in novel vaccine design, an improved human oral challenge model with wild-type Salmonella Typhi
Various other changes were identified in other B cell subsets (e.g., switched memory (Sm) CD27+, SmCD27- and naïve) including upregulation of activation molecules (e.g., CD40) and downregulation of co-stimulators (e.g., CD21) that might indicate that each subset plays a different role during typhoid disease
Non-PB cells were further categorized into various B memory (BM) subsets using the IgD/ CD27 classification scheme as proposed by Sanz et al [12], which delineates four subpopulations: (i) Sm CD27+ [CD27+IgD-], (ii) Sm CD27- [CD27-IgD-], (iii) unswitched memory (Um) [CD27+IgD+] and (iv) naïve [CD27-IgD+] cells

Summary

Introduction

Typhi, which allowed studying various aspects of the host-pathogen interaction as well as test vaccines and alternative treatment options, was developed forty years at the University of Maryland [4, 6,7,8,9,10]. Typhi was recently developed at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford (Oxford Vaccine Group). In this new model, participants were challenged with up to 104 CFU of S. Typhi (Quailes strain) in a sodium bicarbonate buffered solution. This dose resulted in 65% of participants being diagnosed with typhoid fever (referred here as typhoid diagnosis -TD-) [11]

Methods

Results

Discussion

Conclusion