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

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.

Spheres of Influence: Insights into Salmonella Pathogenesis from Intestinal Organoids

“…Using enteroids with reversed polarity, the authors showed that S. Typhimurium invades and induces actin ruffles more efficiently at the apical surface compared to the basolateral surface. The authors observed a more diffuse process of epithelial invasion rather than invasion only or predominantly at the M cells [144], which confirmed the S. Typhi observations by Nickerson, KP et al [71].…”

“…The fidelity of organoid-derived data in representing human disease was further demonstrated in 2018 by Nickerson, KP and colleagues [71], who compared infection of human tissue biopsies and human intestinal enteroid-derived monolayers seeded on a 2D Transwell system, and observed that the enteroid-derived epithelial monolayers recapitulated S. Typhi infection observations made in the tissue biopsy model. The authors also carried out transcriptional profiling of both the host tissue and the bacteria in order to determine early critical interactions.…”

“…Organoids/enteroids have been utilized for improving the basic understanding of tissue homeostasis, organogenesis, and physiological functions [4,69]. The systems have also been used to model diseases [49,51], to study host-pathogen interactions [59,65,70,71] and cancer [72], and to test potential vaccines and drugs [73][74][75]. The organoids/enteroids are also used as new tools for personalized medicine, where patient-derived models can serve as platforms for testing treatment options.…”

Quantitative Assessment of an Artificial Neural Network for the Variation in Immunity to Salmonella Infection Among Sudanese and Chinese Populations and the Relationship Between HLA-DQB1 and Antibody: A Preliminary Study

“…Cases of the disease among African children decrease, and increase in the acquisition of the antibody to start all complement-dependent killing of Salmonella, and subsequently, more effective blood phagocytes and opsoniza-tion (4)(5)(6). Measuring and detecting serum antibody markers in the clinical laboratory to evaluate a patient's health status is an important and valuable issue (6)(7)(8)(9)(10)(11). The affinity of an antibody to its antigen describes and characterizes the strength of the interaction between the antibody and the antigen and plays a critical role in the recovery of infection.…”

Host-pathogen interactions in typhoid fever: the model is the message

“…In a recent study, the early stages of S. Typhi infection have been investigated in intestinal biopsies and in organoids derived from human intestinal epithelial tissue (7). Infected biopsies were used to monitor transcriptional changes in the host and the pathogen, to determine cytokine profiling, and to perform electron microscopy observation.…”