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Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease.

Toapanta FR, Bernal PJ, Fresnay S, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM, Pollard AJ, Sztein MB - PLoS Negl Trop Dis (2015)

Bottom Line: Typhi bacteremia) endpoints.Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation.Typhi.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Ability of DCs to bind S. Typhi following wild-type challenge.Time courses of the binding ability of circulating DCs from TD (A) and NoTD (C) volunteers for S. Typhi (killed-fluorescently labeled). Shown in panels B and D are the data of individual volunteers at peak time of binding in TD (TD-48h and TD-96h) and NoTD (D1 Post-challenge) volunteers, respectively. Each volunteer is indicated by a defined symbol and color, as in Fig 4. The horizontal line indicates the means.
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pntd.0003837.g007: Ability of DCs to bind S. Typhi following wild-type challenge.Time courses of the binding ability of circulating DCs from TD (A) and NoTD (C) volunteers for S. Typhi (killed-fluorescently labeled). Shown in panels B and D are the data of individual volunteers at peak time of binding in TD (TD-48h and TD-96h) and NoTD (D1 Post-challenge) volunteers, respectively. Each volunteer is indicated by a defined symbol and color, as in Fig 4. The horizontal line indicates the means.

Mentions: The ability of DCs to bind S. Typhi was evaluated as described above. In TD volunteers an increase in the interaction of S. Typhi with DCs was evident after typhoid diagnosis with a peak at TD-96h (Fig 7A). A more detailed analysis at this time point revealed that all 5 volunteers evaluated showed increased avidity for the bacteria (Fig 7B). Remarkably, in NoTD volunteers, as was observed in monocytes, a spike in the interaction with S. Typhi was present immediately after challenge (D1), with varying degrees depending on the individual participants (Fig 7D).


Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease.

Toapanta FR, Bernal PJ, Fresnay S, Darton TC, Jones C, Waddington CS, Blohmke CJ, Dougan G, Angus B, Levine MM, Pollard AJ, Sztein MB - PLoS Negl Trop Dis (2015)

Ability of DCs to bind S. Typhi following wild-type challenge.Time courses of the binding ability of circulating DCs from TD (A) and NoTD (C) volunteers for S. Typhi (killed-fluorescently labeled). Shown in panels B and D are the data of individual volunteers at peak time of binding in TD (TD-48h and TD-96h) and NoTD (D1 Post-challenge) volunteers, respectively. Each volunteer is indicated by a defined symbol and color, as in Fig 4. The horizontal line indicates the means.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4465829&req=5

pntd.0003837.g007: Ability of DCs to bind S. Typhi following wild-type challenge.Time courses of the binding ability of circulating DCs from TD (A) and NoTD (C) volunteers for S. Typhi (killed-fluorescently labeled). Shown in panels B and D are the data of individual volunteers at peak time of binding in TD (TD-48h and TD-96h) and NoTD (D1 Post-challenge) volunteers, respectively. Each volunteer is indicated by a defined symbol and color, as in Fig 4. The horizontal line indicates the means.
Mentions: The ability of DCs to bind S. Typhi was evaluated as described above. In TD volunteers an increase in the interaction of S. Typhi with DCs was evident after typhoid diagnosis with a peak at TD-96h (Fig 7A). A more detailed analysis at this time point revealed that all 5 volunteers evaluated showed increased avidity for the bacteria (Fig 7B). Remarkably, in NoTD volunteers, as was observed in monocytes, a spike in the interaction with S. Typhi was present immediately after challenge (D1), with varying degrees depending on the individual participants (Fig 7D).

Bottom Line: Typhi bacteremia) endpoints.Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation.Typhi.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus