The cGAS-STING mediated crosstalk between innate immunity and autophagy in leishmaniasis using mathematical modeling: Uncovering new therapeutic avenues

Abstract

The present paper deals with the investigation into the cGAS-STING pathway, focusing on the signaling of interferons through mathematical modeling and identifying a significant positive feedback loop regulated by STING for activation of type 1 interferons (IFN-1). Cyclic GMP-AMP synthase (cGAS) is responsible for detecting cytosolic DNA and initiating the STING (stimulator of interferon genes) pathway, which in turn causes the synthesis of pro-inflammatory cytokines and type I interferons. In addition to being crucial for pathogen identification, this route interacts with autophagy, a cellular mechanism that is necessary for immunological homeostasis and pathogen removal. In the context of Leishmania infection, the cGAS-STING signaling axis has come to light as a critical mediator of the crosstalk between innate immunity and autophagy. Further, the protein-protein interaction studies underscored the significance of two distinct domains in mediating interactions with IRF3 and LC3. Importantly, our findings suggest the possibility of manipulating STING concomitantly to regulate IRF3 and LC3 independently. This study remarkably advances our understanding of STING's multifaceted roles, particularly in regulating IFN-1 and autophagy, highlighting its pivotal role as a cross-talk point in leishmaniasis.