Salmonella Effector SpvB Disrupts Intestinal Epithelial Barrier Integrity for Bacterial Translocation.

Lanqing Sun,Qifeng Deng,Sidi Yang,Yuanyuan Li,Kedi Dong,Shuyan Wu,Rui Huang

doi:10.3389/fcimb.2020.606541

Lanqing Sun, Qifeng Deng + Show 5 more

Open Access

https://doi.org/10.3389/fcimb.2020.606541

Copy DOI

Abstract

Salmonella are common enteric bacterial pathogens that infect both humans and animals. Intestinal epithelial barrier, formed by a single layer of epithelial cells and apical junctional complex (AJC), plays a crucial role in host defense against enteric pathogens to prevent bacterial translocation. However, the underlying mechanisms of intestinal epithelial barrier dysfunction caused by Salmonella are poorly understood. It is found that a locus termed Salmonella plasmid virulence (spv) gene exists extensively in clinically important Salmonella serovars. SpvB is a key effector encoded within this locus, and closely related to Salmonella pathogenicity such as interfering with autophagy and iron homeostasis. To investigate the interaction between SpvB and intestinal epithelial barrier and elucidate the underlying molecular mechanism, we used the typical foodborne disease agent Salmonella enterica serovar Typhimurium (Salmonella typhimurium) carrying spvB or not to construct infection models in vivo and in vitro. C57BL/6 mice were orally challenged with S. typhimurium wild-type strain SL1344 or spvB-deficient mutant strain SL1344-ΔspvB. Caco-2 cell monolayer model, as a widely used model to mimic the human intestinal epithelium in vitro, was infected with SL1344, SL1344-ΔspvB, or spvB complementary strain SL1344-c-ΔspvB, respectively. The results showed that SpvB enhanced bacterial pathogenicity during S. typhimurium infection in vivo, and contributed to intestinal epithelial barrier dysfunction in both infection systems. This SpvB-mediated barrier dysfunction was attributed to the cellular redistribution of Claudin-1, Occludin, and E-cadherin junctional proteins. Moreover, by using pharmacological inhibitors, we found that F-actin rearrangement and suppression of protein kinase C (PKC) signaling pathway were involved in SpvB-mediated barrier dysfunction. In conclusion, the study reveals the contribution of Salmonella effector SpvB to the dysfunction of intestinal epithelial barrier integrity, which facilitates bacterial translocation via the paracellular route to promote Salmonella systemic dissemination. Our findings broaden the understanding of host–pathogen interactions in salmonellosis, and provide new strategies for the therapy in limiting bacterial dissemination during infection.

Highlights

Salmonella enterica (S. enterica) are facultative intracellular pathogens that can cause both localized and disseminated disease
Since it is previously known that Salmonella effector SpvB could function on preventing actin polymerization (Tezcan-Merdol et al, 2001), which is of vital importance in maintenance of apical junctional complex (AJC), we focus on the interaction between SpvB and intestinal epithelial barrier to further described its role during Salmonella infection
Previous studies have identified that a few bacterial effectors secreted by type three secretion system (T3SS) are associated with intestinal epithelial barrier dysfunction in Salmonella infection (Boyle et al, 2006; Lin et al, 2016)

Summary

Introduction

Salmonella enterica (S. enterica) are facultative intracellular pathogens that can cause both localized and disseminated disease. Consisting of more than 2,600 different serovars, S. enterica can be divided into typhoidal and non-typhoidal S. enterica serovars according to species specificity and diverse clinical manifestations. Typhoidal S. enterica serovars are human host–restricted pathogens, and typically result in typhoid and paratyphoid fevers (collectively referred to as enteric fever). Whereas non-typhoidal S. enterica serovars, such as Typhimurium and Enteritidis (Salmonella typhimurium and S. enteritidis), are global causes of diarrheal diseases with lifethreatening bacteremia occurring sometimes both in humans and animals (Zhang et al, 2018; Collaborators, 2019). Despite the different disease outcomes determined by conflicts between host and pathogen, all these Salmonella serovars have to overcome the same intestinal barrier in order to successfully colonize the host (Hume et al, 2017). We used S. typhimurium to study host–pathogen interactions in salmonellosis because it acts as a typical foodborne disease agent with a high mortality rate, which is widely used to establish infection models both in vitro and in vivo (Wotzka et al, 2017)

Methods

Results

Conclusion