Autophagy induction by Mycobacterium indicus pranii promotes Mycobacterium tuberculosis clearance from RAW 264.7 macrophages.

Bindu Singh,Mohd Saqib,Ananya Gupta,Pawan Kumar,Sangeeta Bhaskar,Seyed Ehtesham Hasnain

doi:10.1371/journal.pone.0189606

Bindu Singh, Mohd Saqib + Show 4 more

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https://doi.org/10.1371/journal.pone.0189606

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Abstract

Mycobacterium indicus pranii (MIP) is a potent vaccine candidate against tuberculosis (TB) as it has demonstrated significant protection in animal models of tuberculosis as well as in clinical trials. Higher protective efficacy of MIP against TB as compared to BCG provoked the efforts to gain insight into the molecular mechanisms underlying MIP mediated protection against Mycobacterium tuberculosis (M.tb). Autophagy, initially described as a cell survival mechanism during starvation, also plays a key role in host resistance to M.tb. Virulent mycobacteria like M.tb, suppresses host autophagy response to increase its survival in macrophages. Since mycobacterial species have been shown to vary widely in their autophagy-inducing properties, in the present study, we examined the autophagy inducing efficacy of MIP and its role in MIP-mediated protection against M.tb. MIP was found to be potent inducer of autophagy in macrophages. Induced autophagy was responsible for reversal of the phagosome maturation block and phagolysosome fusion inhibition in M.tb infected macrophages, which ultimately lead to significantly enhanced clearance of M.tb from the macrophages. This is an important study which further delineated the underlying mechanisms for significant immunotherapeutic activity observed in TB patients / animal models of tuberculosis, given MIP therapy along with chemotherapy.

Highlights

Tuberculosis (TB), a chronic infectious disease, remains one of the world’s deadliest communicable diseases (WHO report 2016)
Since different mycobacterial species vary in their autophagy inducing potential, first we examined the efficacy of Mycobacterium indicus pranii (MIP) for induction of autophagy in RAW 264.7 macrophage cell line
Quantification of Microtubule-associated proteins 1A/1B light chain 3B (LC3)-II correlates with the extent of autophagy induced

Summary

Introduction

Tuberculosis (TB), a chronic infectious disease, remains one of the world’s deadliest communicable diseases (WHO report 2016). A lysosomal degradation pathway which contributes to maintenance of intracellular homeostasis, has been shown to be an integral part of both adaptive and innate immunity [6]. It was initially known as stress response involved in cell survival during nutrient starvation condition and for its role in maintaining intracellular homeostasis, by eliminating surplus or damaged organelles and degradation of superfluous, misfolded and damaged proteins [7]. Pharmacological or immunological means was found to reduce intracellular M.tb survival by targeting it for lysosomal degradation [13]. Studies in autophagy-deficient mice demonstrated that autophagy confers protection against active tuberculosis by reducing bacterial burden and inflammation [5,15]

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