Salmonella enterica Serovar Typhi conceals the invasion-associated type three secretion system from the innate immune system by gene regulation.

Sebastian E Winter,Geraldo E S Alves,Victor Poon,Fabiane Cassou,A Marijke Keestra,Luciana F Costa,Franziska Faber,Renato L Santos,Torsten Sterzenbach,Andreas J Bäumler,Erica A Costa,Maria G Winter,Tatiane A Paixão

doi:10.1371/journal.ppat.1004207

Sebastian E Winter, Geraldo E S Alves + Show 11 more

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https://doi.org/10.1371/journal.ppat.1004207

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Abstract

Delivery of microbial products into the mammalian cell cytosol by bacterial secretion systems is a strong stimulus for triggering pro-inflammatory host responses. Here we show that Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, tightly regulates expression of the invasion-associated type III secretion system (T3SS-1) and thus fails to activate these innate immune signaling pathways. The S. Typhi regulatory protein TviA rapidly repressed T3SS-1 expression, thereby preventing RAC1-dependent, RIP2-dependent activation of NF-κB in epithelial cells. Heterologous expression of TviA in S. enterica serovar Typhimurium (S. Typhimurium) suppressed T3SS-1-dependent inflammatory responses generated early after infection in animal models of gastroenteritis. These results suggest that S. Typhi reduces intestinal inflammation by limiting the induction of pathogen-induced processes through regulation of virulence gene expression.

Highlights

One function of the innate immune system in the intestinal tract is to generate temporary inflammatory responses against invasive enteric pathogens while avoiding detrimental overreaction against harmless commensal bacteria under homeostatic conditions
Bacterial pathogens translocate effector proteins into the cytoplasm of host cells to manipulate the mammalian host. These processes, e.g. the stimulation of small regulatory GTPases, activate the innate immune system and induce pro-inflammatory responses aimed at clearing invading microbes from the infected tissue
Upon entry into host tissue, Salmonella enterica serovar Typhi, the causative agent of typhoid fever, rapidly represses expression of a virulence factor required for entering tissue to avoid detection by the host innate immune surveillance

Summary

Introduction

One function of the innate immune system in the intestinal tract is to generate temporary inflammatory responses against invasive enteric pathogens while avoiding detrimental overreaction against harmless commensal bacteria under homeostatic conditions. Typhimurium), an invasive enteric pathogen associated with human gastroenteritis, triggers acute intestinal inflammation in the terminal ileum and colon, thereby producing symptoms of diarrhea and abdominal pain within less than one day after ingestion [3]. In contrast to Salmonella-induced gastroenteritis, only a third of patients develop diarrhea that is characterized by a dominance of mononuclear cells in the stool [6]. The dominant cell type in intestinal infiltrates is mononuclear, while neutrophils are infrequent [9,10,11]. Typhi does not elicit this response [13] These observations suggest that invasion of the intestinal mucosa by S. Typhi elicits little intestinal inflammation during early stages of infection, the molecular mechanisms underlying these apparent differences are poorly defined

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