Multi-Functional MPT Protein as a Therapeutic Agent against Mycobacterium tuberculosis.

Jae-Sung Kim,Chul-Su Yang,Sun-Young Kim,Hyo-Keun Kim,Euni Cho,Sein Jang,Hye-In Jeon,Seok-Jun Mun,Hyun-Sung Kim,Young-Jin Jeong,Dong-Gyu Kim,Wooic Son,Sojin Kim

doi:10.3390/biomedicines9050545

Jae-Sung Kim, Chul-Su Yang + Show 11 more

Open Access

https://doi.org/10.3390/biomedicines9050545

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Journal: Biomedicines	Publication Date: May 13, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: Hanyang University, Anyang University

Abstract

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), avoids the host immune system through its virulence factors. MPT63 and MPT64 are the virulence factors secreted by MTB which regulate host proteins for the survival and proliferation of MTB in the host. Here, we found that MPT63 bound directly with TBK1 and p47phox, whereas MPT64 interacted with TBK1 and HK2. We constructed a MPT63/64-derived multifunctional recombinant protein (rMPT) that was able to interact with TBK1, p47phox, or HK2. rMPT was shown to regulate IFN-β levels and increase inflammation and concentration of reactive oxygen species (ROS), while targeting macrophages and killing MTB, both in vitro and in vivo. Furthermore, the identification of the role of rMPT against MTB was achieved via vaccination in a mouse model. Taken together, we here present rMPT, which, by regulating important immune signaling systems, can be considered an effective vaccine or therapeutic agent against MTB.

Highlights

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is one of the most important infectious diseases worldwide, due to its high mortality [1]
We found that MPT63 and MPT64 interacted with several proteins in host macrophages including TBK1, p47phox, and HK2
The purified recombinant MPT63 (rMPT63) complexes were identified by mass spectrometry analysis and included TANK-binding kinase (TBK1, 83K), receptor-interacting serine/threonine-protein kinase 1 (RIP1, 75K), RAC-alpha serine/threonine-protein kinase (AKT, 55K), Neutrophil cytosol factor 1 (p47phox, 45K), and p38 mitogen-activated protein kinase (p38MAPK, 38K) (Figures 1A and S1C)

Summary

Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is one of the most important infectious diseases worldwide, due to its high mortality [1]. MTB infects the host macrophages and survives through evading the host immune system. Lung granuloma is a representative lesion in TB [2,3]. MTB, which possesses several immunogenic proteins against the host cells [4], persists inside the granuloma for survival and proliferation, its function is still not clear. The function of numerous secretory proteins of MTB is still unknown. MTB’s secretory antigens are essential for interacting with host proteins and regulating the immune response, and for bacterial proliferation and survival [5]. These proteins secreted during infection can determine the pathways of the adaptive immune system, such as activating effector T-cells. Investigating the precise role of the secretory antigens is essential for understanding the pathogenicity of TB [6]

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