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

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.

The flavonoids of Sophora flavescens exerts anti-inflammatory activity via promoting autophagy of Bacillus Calmette-Guérin-stimulated macrophages

“…assays to demonstrate autophagic activity in BCG and M.tb infected macrophages, 60,61 plays an indispensable role in autophagosome formation and processing of LC3, whereas knockdown of the protein results in impaired autophagy in gynecologic tumors. 37 These processes together with other up-regulated proautophagic regulatory genes AMBRA1, CTSS, FBXL20, and RAB24, participate in the autophagy flux by contributing to autophagy vesicle elongation, killing of pathogenic microorganisms, protein degradation, and cargo transport, respectively.…”

Pulmonary non-tuberculous mycobacterial infections: current state and future management

“…indicus pranii as a booster to BCG via the aerosol route showed protective effect in a mice model of TB, inducing proinflammatory cytokines like IFN-γ, IL-12 and IL-17, and increased frequency of multifunctional T-cells [275]. In vitro studies showed that M. indicus pranii modulates pro-inflammatory responses via the TLR-4 pathway, activate the innate immunity [276] and induced autophagy in TB infected macrophages [277]. Clinical trials as adjunct therapy showed that it is safe with no significant side effects and able to clear the pathogens in TB relapse patients [278].…”

Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages

“…Oleic acid, Catalase, Lowenstein-Jensen (LJ) Media were obtained from HiMedia Laboratories, India. GFP expressing M.tb was prepared by the method described in [11].…”

“…The protocol used in our previous publication was followed [11]. Briefly, macrophages were seeded on coverslips were infected with GFP expressing M.tb for 4 h with subsequent stimulation with MIP-LAM / M.tb-LAM for 4 h. This was followed by Lysotracker-Red staining.…”

“…Previously, we have reported that MIP is a potent inducer of autophagy in macrophages which resulted in enhanced co-localization of M.tb as well as its clearance from the infected macrophages [11]. The next question asked was whether MIP induced autophagy was exclusively by active mechanisms i.e.…”