Rv3722c Promotes Mycobacterium tuberculosis Survival in Macrophages by Interacting With TRAF3.

Yingying Lei,Wei Zhou,Weize Xu,Rohit Tyagi,Xiaojian Cao,Bing Yang,Shuhong Zhao,Khaista Rahman,Shuang Dong,Xi Chen,Gang Cao,Qijun Wu,Yangyang Xu

doi:10.3389/fcimb.2021.627798

Yingying Lei, Wei Zhou + Show 11 more

Open Access

https://doi.org/10.3389/fcimb.2021.627798

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Abstract

Mycobacterium tuberculosis (M.tb) secretes numerous proteins to interfere with host immune response for its long-term survival. As one of the top abundant M.tb secreted proteins, Rv3722c was found to be essential for bacilli growth. However, it remains elusive how this protein interferes with the host immune response and regulates M.tb survival. Here, we confirmed that Rv3722c interacted with host TRAF3 to promote M.tb replication in macrophages. Knock-down of TRAF3 attenuated the effect of Rv3722c on the intracellular M.tb survival. The interaction between Rv3722c and TRAF3 hampered MAPK and NF-κB pathways, resulting in a significant increase of IFN-β expression and decrease of IL-1β, IL-6, IL-12p40, and TNF-α expression. Our study revealed that Rv3722c interacted with TRAF3 and interrupted its downstream pathways to promote M.tb survival in macrophages. These findings facilitate further understanding of the mechanism of M.tb secreted proteins in regulating the host cell immune response and promoting its intracellular survival.

Highlights

Tuberculosis, caused by the bacillus Mycobacterium tuberculosis (M.tb), remains the leading cause of morbidity and mortality from a single infectious pathogen throughout the world
We identified TNF receptor-associated factor 3 (TRAF3), an important multifunctional immune regulator involved in mitogen-activated protein kinase (MAPK) and NFkB pathways as an interaction target of Rv3722c
To explore the signaling pathways that might be involved in Rv3722c altered cytokine expression, we examined MAPK and nuclear factor-kB (NF-kB) pathways, which have been described to be involved in the production of numerous inflammatory cytokines (Koul et al, 2004; Jung et al, 2006; Méndez-Samperio, 2010)

Summary

Introduction

Tuberculosis, caused by the bacillus Mycobacterium tuberculosis (M.tb), remains the leading cause of morbidity and mortality from a single infectious pathogen throughout the world. An estimated 10.0 million people fell ill with tuberculosis and around 1.4 million deaths worldwide in 2019 As an aerosol transmitted pathogen, M.tb is firstly recognized by alveolar macrophages and persists in infected macrophages. The infection can trigger a wide range of host cells immune defenses, such as inflammation, phagocytosis, autophagy, and apoptosis, to eliminate invaded M.tb (Lerner et al, 2015). M.tb has developed numerous strategies to escape from host immune clearance for long-term persistence (Hmama et al, 2015; Liu et al, 2017).

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