Infection dynamics in L. major autophagic machinery is regulated by ATG9-PI3P negative feedback loop

Abstract

Autophagy is a self-destructing mechanism of cell via lysosomal degradation, which helps to degrade/ destroy hazardous substances, proteins, degenerating organelles and recycling nutrient. It plays an important role in cellular homeostasis and regulates internal environment of cell, moreover, when needed causes non-apoptotic programmed death of cell. Its usually detailed with ageing and nutritional stress, but recent researches provide support for its role in innate as well as adaptive immunity. Autophagy has been observed as one of the major factors in parasite clearance in leishmaniasis. Due to intra-cellular pathogen, the cell mediated response is only alternative for adaptive immunity against Leishmania in host. T-cells have been observed as main component of cell mediated immunity in leishmaniasis. The differentiation of T-cells generates either destruction or proliferation of parasite as different kind of cytokine mediate different results. Pro-inflammatory cytokine IL12 and TNF generate Th2 response which helps in active phagocytosis of parasite whereas an anti-inflammatory cytokine like IL10 mediate parasite promotion by blocking autophagic pathways and inhibiting phagocytic actions. TLR2/6 mediated signaling stimulated by LPG produces many pro-inflammatory cytokines like IL12, TNF and IL6 etc. In macrophages, it is found that TNF via autocrine signaling induce autophagy and help in parasite killing of Toxoplasma gondii via JNK phosphorylation in macrophages. The phosphorylated JNK induces Beclin by phosphorylating Bcl2, which inhibits Beclin action, thus releasing Beclin and promoting VpS34 which recruits PI3P for autophagosome formation. Recruitment of PI3P is controlled by ATG9 protein, autophagy related gene protein, which in normal condition is inhibited by mTOR via ULK/ ATG1. IL10 has been observed to inhibit autophagy via starvation induced AKT-PI3K pathway in macrophages and result in inducing mTOR. Thus, we can conclude that IL10 inhibits recruitment of PI3P via mTOR. Through systems aspect, here, we decipher that Atg9-PI3P acts as a negative feedback loop in autophagic machinery of leishmaniasis.