PP2Ac Modulates AMPK-Mediated Induction of Autophagy in Mycobacterium bovis-Infected Macrophages.

Hussain Hussain,Yao Yao,Song Song,Wang Wang,Zhao Zhao,Shah Shah,Liao Liao,Hussain Mangi Hussain Mangi,Sabir Sabir,Yang Yang,Dong Dong,Zhou Zhou

doi:10.3390/ijms20236030

Abstract

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis in cattle population across the world. Human beings are at equal risk of developing tuberculosis beside a wide range of M. bovis infections in animal species. Autophagic sequestration and degradation of intracellular pathogens is a major innate immune defense mechanism adopted by host cells for the control of intracellular infections. It has been reported previously that the catalytic subunit of protein phosphatase 2A (PP2Ac) is crucial for regulating AMP-activated protein kinase (AMPK)-mediated autophagic signaling pathways, yet its role in tuberculosis is still unclear. Here, we demonstrated that M. bovis infection increased PP2Ac expression in murine macrophages, while nilotinib a tyrosine kinase inhibitor (TKI) significantly suppressed PP2Ac expression. In addition, we observed that TKI-induced AMPK activation was dependent on PP2Ac regulation, indicating the contributory role of PP2Ac towards autophagy induction. Furthermore, we found that the activation of AMPK signaling is vital for the regulating autophagy during M. bovis infection. Finally, the transient inhibition of PP2Ac expression enhanced the inhibitory effect of TKI-nilotinib on intracellular survival and multiplication of M. bovis in macrophages by regulating the host’s immune responses. Based on these observations, we suggest that PP2Ac should be exploited as a promising molecular target to intervene in host–pathogen interactions for the development of new therapeutic strategies towards the control of M. bovis infections in humans and animals.

Highlights

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis and distributed worldwide affecting cattle population and causing huge economic losses to farming communities in many countries
We found a significantly increased expression of PP2Ac at mRNA level in Bone marrow derived macrophages (BMDM) cells infected with different multiplicity of infections (MOIs) of M. bovis (Figure 1C)
We asked whether the duration of M. bovis infection might affect the expression of PP2Ac in macrophages

Summary

Introduction

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis and distributed worldwide affecting cattle population and causing huge economic losses to farming communities in many countries. M. bovis is the only member of the Mycobacterium tuberculosis complex (MTBC) that affects a wide range of animal species and human beings. Besides Mycobacterium tuberculosis (M. tuberculosis), M. bovis is the most common etiological agent of human TB responsible for approximately 5% of the global tuberculosis burden [1,2]. Contaminated milk or milk products are the other major source of infection in human population. It has been documented that M. bovis is an important zoonotic pathogen [3], it should be considered as a major threat to the human population and proper security measures should be adopted to prevent the spread of infection

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Results

Conclusion