Elsevier

EBioMedicine

Volume 31, May 2018, Pages 92-109
EBioMedicine

Research Paper
Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes Aimed at Evading Host Mucosal Immune Defense During Early Infection of Human Intestinal Tissue

https://doi.org/10.1016/j.ebiom.2018.04.005Get rights and content
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Highlights

  • Salmonella Typhi targets human-specific pathways by inducing host transcriptional changes.

  • These pathways include cytoskeletal rearrangement, polarized cytokine release, and hampering host immune defense system

  • The overall outcome of Salmonella interaction with the target human host is to avoid immune response in order to efficiently infect and propagate.

Salmonella remains a severe human health threat without sufficient therapeutic options, which is mainly due to the lack of key information about the steps in early pathogenesis that lead to infection. Using human ex vivo models, we have identified key steps in S. Typhi's early development, suggesting that S. Typhi exploits human host machinery, not only to invade, but also to avoid a robust immune response. These findings identify possible targets for the development of more efficient vaccine candidates against human salmonellosis.

Abstract

Commensal microorganisms influence a variety of host functions in the gut, including immune response, glucose homeostasis, metabolic pathways and oxidative stress, among others. This study describes how Salmonella Typhi, the pathogen responsible for typhoid fever, uses similar strategies to escape immune defense responses and survive within its human host. To elucidate the early mechanisms of typhoid fever, we performed studies using healthy human intestinal tissue samples and “mini-guts,” organoids grown from intestinal tissue taken from biopsy specimens. We analyzed gene expression changes in human intestinal specimens and bacterial cells both separately and after colonization. Our results showed mechanistic strategies that S. Typhi uses to rearrange the cellular machinery of the host cytoskeleton to successfully invade the intestinal epithelium, promote polarized cytokine release and evade immune system activation by downregulating genes involved in antigen sampling and presentation during infection. This work adds novel information regarding S. Typhi infection pathogenesis in humans, by replicating work shown in traditional cell models, and providing new data that can be applied to future vaccine development strategies.

Abbreviations

STY
Salmonella Typhi
STM
Salmonella Typhimurium
M cells
Microfold cells
CFU
colony forming units
LB
Luria Burtoni broth
DMEM
Dulbecco's Modified Eagle Medium
PBS
phosphate buffered saline
DTT
dithiothreitol
EDTA
ethylenediaminetetraacetic acid
ISC
intestinal stem cell
DAPT
N-[2S-(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl-1,1-dimethylethyl ester-glycine
qPCR
quantitative reverse transcriptase polymerase chain reaction
FITC
fluorescein isothiocyanate
TEER
trans-epithelial electrical resistance
RNA
ribonucleic acid
LDH
lactate dehydrogenase
H&E
hematoxylin and eosin
PAS
periodic acid Schiff
TEM
transmission electron microscopy
IL
interleukin

Keywords

Typhoid fever
Salmonella
Snapwell™ system
Human tissue
Terminal ileum
Immune system
Innate immunity
Immune evasion
Host-pathogen interaction
Vaccine development
Intestinal organoids
Organoid monolayer

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