Mycobacterium tuberculosis Rv0580c Impedes the Intracellular Survival of Recombinant Mycobacteria, Manipulates the Cytokines, and Induces ER Stress and Apoptosis in Host Macrophages via NF-κB and p38/JNK Signaling.

Md Kaisar Ali,Junqi Xu,Khushnood Abbas,Lambert Nzungize,Mohammed Asaad,Nzaou Stech Anomene Eckzechel,Ulrich Aymard Ekomi Moure,Aftab Alam,Jianping Xie,M. A. Abo-kadoum

doi:10.3390/pathogens10020143

Abstract

The Mycobacterium tuberculosis (M. tb) genome encodes a large number of hypothetical proteins, which need to investigate their role in physiology, virulence, pathogenesis, and host interaction. To explore the role of hypothetical protein Rv0580c, we constructed the recombinant Mycobacterium smegmatis (M. smegmatis) strain, which expressed the Rv0580c protein heterologously. We observed that Rv0580c expressing M. smegmatis strain (Ms_Rv0580c) altered the colony morphology and increased the cell wall permeability, leading to this recombinant strain becoming susceptible to acidic stress, oxidative stress, cell wall-perturbing stress, and multiple antibiotics. The intracellular survival of Ms_Rv0580c was reduced in THP-1 macrophages. Ms_Rv0580c up-regulated the IFN-γ expression via NF-κB and JNK signaling, and down-regulated IL-10 expression via NF-κB signaling in THP-1 macrophages as compared to control. Moreover, Ms_Rv0580c up-regulated the expression of HIF-1α and ER stress marker genes via the NF-κB/JNK axis and JNK/p38 axis, respectively, and boosted the mitochondria-independent apoptosis in macrophages, which might be lead to eliminate the intracellular bacilli. This study explores the crucial role of Rv0580c protein in the physiology and novel host-pathogen interactions of mycobacteria.

Highlights

Tuberculosis (TB) remains a formidable global public health concern and leading cause of death in adults, as compare to other infectious diseases [1]
To explore whether Ms_Rv0580c can induce hypoxia, we examined the expression of hypoxia-inducible factor, HIF-1α, after infection of macrophages with recombinant strains
The Rv0580c protein is conserved in the pathogenic mycobacterium strains

Summary

Introduction

Tuberculosis (TB) remains a formidable global public health concern and leading cause of death in adults, as compare to other infectious diseases [1]. Around 1.2 million people died from TB occurred in HIV-negative individuals (1.7 million people died in 2000), and 208,000 people died from TB occurred in HIV-positive individuals (678,000 people died in 2000) [2] Drug resistance makes this pathogen more deadly [1]. Macrophages have evolved several defense tactics to eliminate the intracellular pathogens, such as M. tb. These defense tactics include acidic environment, generation of free radicals, restriction of essential nutrients access to the microbes, as well as secretion of anti-microbial peptides and cytokines, which are able to induce the protective host immune response, recruitment of other immune cells, and activate the suicidal activities such as autophagy or apoptosis [5].

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Conclusion