Abstract

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN2) is implicated in the formation of MAMs, but, the roles of mitochondria and MFN2 in MTB infection have not been elucidated. Using mircroarry profiling of TB patients and in vitro MTB stimulation of macrophages, we observed an up-regulation of MFN2 in the peripheral blood mononuclear cells of active TB patients. Furthermore, we found that MTB stimulation by MTB-specific antigen ESAT-6 or lysate of MTB promoted MFN2 interaction with NLRP3 inflammasomes, resulting in the assembly and activation of the inflammasome and, subsequently, IL-1β secretion. These findings suggest that MFN2 and mitochondria play important role in the pathogen-host interaction during MTB infection.

Highlights

  • Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children

  • We found that mitofusin 2 (MFN2) expression was both up-regulated in peripheral blood mononuclear cell (PBMC) and THP-1 monocyte-derived macrophages upon MTB stimulation and IL-1b secretion was increased (Fig. 2, d–f)

  • We found higher expression of MFN2 in a subset of 15 genes, which is capable of distinguishing TB patients from healthy controls

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Summary

Introduction

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. We first reported that mitochondrial MFN2 interacts and activates NLRP3 inflammasome and promotes IL-1b secretion upon MTB stimulation. We found that MFN2 expression was both up-regulated in PBMCs and THP-1 monocyte-derived macrophages upon MTB stimulation (including MTB lysate and ESAT-6) and IL-1b secretion was increased (Fig. 2, d–f). MTB stimulation alters both mitochondrial membrane potential and MFN2 localization in THP-1 macrophages

Results
Conclusion

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