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Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in
Franklin R Toapanta1, Paula J Bernal2, Stephanie Fresnay2
1Center 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.
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.
Insights
Innate immune cells like monocytes and dendritic cells show distinct activation and migration patterns in humans who develop typhoid fever after Salmonella Typhi challenge. These changes in immune cell responses correlate with disease outcome.
Area of Science:
- Immunology
- Infectious Diseases
- Human Challenge Models
Background:
- A novel human oral challenge model using wild-type Salmonella Typhi (S. Typhi) was established, inducing typhoid fever in 65% of subjects after ingesting 10^4 CFU.
- Previous studies in murine models indicated changes in monocytes and dendritic cells (DCs) during S. Typhimurium infection, but human data were lacking.
- Understanding innate immune cell responses in humans challenged with S. Typhi is crucial for deciphering typhoid pathogenesis.
Purpose of the Study:
- To investigate alterations in circulating monocytes and DCs in human volunteers following oral challenge with wild-type S. Typhi.
- To compare immune cell profiles between subjects who developed typhoid diagnosis (TD) and those who did not (NoTD).
- To explore differential immune cell activation, migration, and signaling pathways related to typhoid fever development.
Main Methods:
- Analysis of monocytes and DCs from a subset of volunteers (5 TD, 3 NoTD) in a human S. Typhi oral challenge model.
- Flow cytometry was used to assess the expression of surface markers like CD38, CD40, integrin α4β7, and CD21.
- Monocyte activation was evaluated by measuring S. Typhi binding and intracellular signaling pathway phosphorylation (p38MAPK, NFkB, Erk1/2) upon stimulation.
Main Results:
- TD volunteers exhibited upregulated CD38 and CD40 on monocytes and DCs, and increased integrin α4β7 on monocytes during disease progression (0-96h post-challenge).
- CD21 was upregulated on DCs in TD volunteers, a change not seen in NoTD subjects.
- NoTD volunteers showed enhanced S. Typhi binding and robust p38MAPK, NFkB, and Erk1/2 phosphorylation in monocytes post-challenge, unlike the moderate Erk1/2 phosphorylation in TD volunteers.
Conclusions:
- This study reveals distinct activation, migration, and signaling profiles of monocytes and DCs in humans that correlate with clinical outcomes after S. Typhi challenge.
- The findings highlight differential innate immune responses contributing to typhoid fever development or resistance.
- These insights advance our understanding of human Salmonella Typhi infection pathogenesis and potential therapeutic targets.
