Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

Siqi Yuan,Jingmin Yan,Yao Fang,Xiaoyi He,Chenglong Rao,Yupei Xia,Zhiqiang Hu,Qian Li,Xuhu Mao,Bin Tang,Jiangao Chen,Jianping Xie,Meijuan Zhang,Mengling Tang

doi:10.1186/s12866-021-02199-x

Abstract

BackgroundBurkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent.ResultsWe demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo.ConclusionTaken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.

Highlights

Burkholderia pseudomallei, a gram-negative bacillus, is the causative agent of a broad spectrum of clinical manifestations collectively known as melioidosis
This study indicates that eIF2α/CHOP pathway contributes to Mycobacterium tuberculosis (Mtb) intracellular survival of in macrophages [19]
All phosphate-buffered saline (PBS) treated mice in the survival experiment died by day 6 after inoculation, but mortality was delayed and reduced in tauroursodeoxycholic acid (TUDCA) treated mice, of which 42% survived until the end of the 10 days observation period (Fig. 1a)

Summary

Introduction

Burkholderia pseudomallei, a gram-negative bacillus, is the causative agent of a broad spectrum of clinical manifestations collectively known as melioidosis. TUDCA reduces ER stress, effectively protects hepatocytes and restores glucose homeostasis in the pathogenesis of obesity, insulin resistance and diabetes mellitus and infectious diseases. In the treatment of infectious diseases, TUDCA is implicated as a therapy for hepatitis B and C virus infection [8, 9], and inhibits influenza A viral infection by disrupting viral M2 or IRE1 stress pathway [10, 11]. Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. No effective vaccine is available currently, and the drug resistance is a major problem in the treatment of melioidosis. Finding new clinical treatment strategies in melioidosis is extremely urgent

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Conclusion