An Outpatient, Ambulant-Design, Controlled Human Infection Model Using Escalating Doses of Salmonella Typhi Challenge Delivered in Sodium Bicarbonate Solution

Waddington, Claire S.; Darton, Thomas C.; Jones, Claire; Haworth, Kim E.; Peters, Anna; John, Tessa M.; Thompson, Ben; Kerridge, Simon; Kingsley, Robert A.; Zhou, Lei; Holt, Kathryn E.; Yu, Ly-Mee; Lockhart, Stephen; Farrar, Jeremy; Sztein, Marcelo B.; Dougan, Gordon; Angus, Brian; Levine, Myron M.; Pollard, Andrew J.

doi:10.1093/cid/ciu078

Cited by 128 publications

(269 citation statements)

References 34 publications

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“…Curiously, what appears to be a small reduction in the percentage of monocytes was observed immediately after typhoid diagnosis (TD), a finding consistent with the immunosuppression reported in animal models [32, 33] as well as with the decrease in white blood cell counts reported in the parent clinical trial [11]. However, the reductions in the percentages of monocytes as measured by flow cytometry or by WCC was not statistically different (S1A and S1B Fig).…”

Section: Discussionsupporting

confidence: 80%

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

et al. 2015

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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 ≥12h) 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 48h and 96h 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.

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Section: Discussionsupporting

confidence: 80%

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

et al. 2015

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“…9,10 The content of the arrays comprised an ORFeome library cloned previously with ∼63% coverage of the S. Typhi proteome supplemented with the additional S. Typhi open reading frames (ORFs) to provide full coverage. In addition, LPSs from Salmonella typhosa (S. Typhi), purified by gel filtration (L2387; Sigma-Aldrich, Dorset, United Kingdom), 11 was printed in four 3-fold serial dilutions from 0.1 to 0.003 mg/mL. Serum samples were shipped to UCI on dry ice and were probed onto proteome arrays as described previously.…”

Section: Methodsmentioning

confidence: 99%

Serodiagnosis of Acute Typhoid Fever in Nigerian Pediatric Cases by Detection of Serum IgA and IgG Against Hemolysin E and Lipopolysaccharide

Davies

Jain

Nakajima

et al. 2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. Inexpensive, easy-to-use, and highly sensitive diagnostic tests are currently unavailable for typhoid fever. To identify candidate serodiagnostic markers, we have probed microarrays displaying the full Salmonella enterica serovar Typhi (S. Typhi) proteome of 4,352 different proteins + lipopolysaccharides (LPSs), with sera from Nigerian pediatric typhoid and other febrile cases, Nigerian healthy controls, and healthy U.S. adults. Nigerian antibody profiles were broad (∼500 seropositive antigens) and mainly low level, with a small number of stronger "hits," whereas the profile in U.S. adults was < 1/5 as broad, consistent with endemic exposure in Nigeria. Nigerian profiles were largely unaffected by clinical diagnosis, although the response against t1477 (hemolysin E) consistently emerged as stronger in typhoid cases. The response to LPS was also a strong discriminator of healthy controls and typhoid, although LPS did not discriminate between typhoid and nontyphoidal Salmonella (NTS) disease. As a first step toward the development of a point-of-care diagnostic, t1477 and LPS were evaluated on immunostrips. Both provided good discrimination between healthy controls and typhoid/NTS disease. Such a test could provide a useful screen for salmonellosis (typhoid and NTS disease) in suspected pediatric cases that present with undefined febrile disease.

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“…For example, the incubation period for Typhi and Paratyphi A is typically 7-14 days (Crump et al, 2015). Likewise, rates of bacteremia observed for Salmonella Typhi range from 5% to 30%, depending on the dose of ingestion (Waddington et al, 2014), and gastrointestinal bleeding may develop in up to 10% of hospitalized patients (Crump et al, 2015). Likewise, Salmonella Napoli infection can also cause high fever as in the case of typhoid salmonellosis.…”

Section: Discussionmentioning

confidence: 99%

A Multischool Outbreak Due to Salmonella enterica serovar Napoli Associated with Elevated Rates of Hospitalizations and Bacteremia, Milan, Italy, 2014

Huedo

Gori

Amato

et al. 2016

Foodborne Pathogens and Disease

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A multischool outbreak of salmonellosis caused by Salmonella enterica serovar Napoli was investigated in the province of Milan from October to November 2014, following an increase in school absenteeism coinciding with two positive cases. Epidemiological studies detected 47 cases in four primary schools: 46 children and 1 adult woman (51.4% males and 48.6% females, median age 8.9). From these, 14 cases (29.8%) were severe and resulted in hospitalization, including 6 children (12.8%) who developed an invasive salmonellosis. The epidemic curve revealed an abnormally long incubation period, peaking 1 week after the first confirmed case. Twenty-five available isolates were typed by pulsed-field gel electrophoresis showing an identical pattern. The isolate belongs to ST474, an ST composed exclusively of Salmonella Napoli human strains isolated in France and Italy. Antibiotic resistance analysis showed resistance to aminoglycosides, correlating with the presence of the aminoglycoside resistance gene aadA25 in its genome. Trace-back investigations strongly suggested contaminated ham as the most likely food vehicle, which was delivered by a common food center on 21 October. Nevertheless, this ingredient could not be retrospectively investigated since it was no longer available at the repository. This represents the largest Salmonella Napoli outbreak ever reported in Italy and provides a unique scenario for studying the outcome of salmonellosis caused by this emerging and potentially invasive nontyphoidal serotype.

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An Outpatient, Ambulant-Design, Controlled Human Infection Model Using Escalating Doses of Salmonella Typhi Challenge Delivered in Sodium Bicarbonate Solution

Cited by 128 publications

References 34 publications

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

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

Serodiagnosis of Acute Typhoid Fever in Nigerian Pediatric Cases by Detection of Serum IgA and IgG Against Hemolysin E and Lipopolysaccharide

A Multischool Outbreak Due to Salmonella enterica serovar Napoli Associated with Elevated Rates of Hospitalizations and Bacteremia, Milan, Italy, 2014

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