Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model

Abstract

SummaryThe safe establishment of a protocol for a human challenge model for Salmonella Paratyphi A can be used to expedite the evaluation of novel vaccine candidates and provides insight into the clinical and immune response to paratyphoid infection.

Diagnostic host gene signature for distinguishing enteric fever from other febrile diseases

“…We detected significant differential expression (DE; FDR < 0.05, FC AE 1.25) of 4,308 and 4,501 genes in enteric fever patients with confirmed S. Typhi (n = 19) and S. Paratyphi A (n = 12) bacteraemia, respectively, when compared with healthy community controls (n = 47; Fig 1B). Similar numbers of genes were differentially expressed in samples collected at the time of enteric fever diagnosis in healthy adult volunteers challenged with either S. Typhi ("T1-ST") or S. Paratyphi A ("P1-SPT") in a CHIM (Fig 1B;Blohmke et al, 2016a;Dobinson et al, 2017).…”

“…Despite the multiple redundancies incorporated into human immune pathways driven by successful evolution (Nish & Medzhitov, 2011), our data suggest that the pattern of immune response activation is sufficiently specific to allow identification of the causative pathogen. For example, while immune responses during enteric fever and TB are broadly characterized by IFN signalling, we and others have reported that this response during acute S. Typhi infection appears to be skewed towards a type II pattern likely associated with neutrophils and NK cells rather than the type I-dominated profile found in TB (Manca et al, 2005;Thompson et al, 2009;Berry et al, 2010a;Spees et al, 2014;Blohmke et al, 2016aBlohmke et al, , 2017Dobinson et al, 2017). Application of computational methods to large datasets including host gene expression has been shown to be an effective approach to capture such differential activation of immune pathways (Herberg et al, 2016;Sweeney et al, 2016).…”

“…Typhi (“T1‐ST”) or S . Paratyphi A (“P1‐SPT”) in a CHIM (Fig B; Blohmke et al , ; Dobinson et al , ).…”

“…For example, while immune responses during enteric fever and TB are broadly characterized by IFN signalling, we and others have reported that this response during acute S . Typhi infection appears to be skewed towards a type II pattern likely associated with neutrophils and NK cells rather than the type I‐dominated profile found in TB (Manca et al , ; Thompson et al , ; Berry et al , ; Spees et al , ; Blohmke et al , , ; Dobinson et al , ). Application of computational methods to large datasets including host gene expression has been shown to be an effective approach to capture such differential activation of immune pathways (Herberg et al , ; Sweeney et al , ).…”

“…Clinical samples for paratyphoid infection were collected during a dose–escalation study, as previously described (P1; Dobinson et al , ). Briefly, 40 healthy adult volunteers were challenged with a single oral dose of virulent S .…”