Systems biology of autophagy in leishmanial infection and its diverse role in precision medicine

Abstract

Autophagy is a contentious issue in leishmaniasis and is emerging as a promising therapeutic regimen. Published research on the impact of autophagic regulation on Leishmania survival is inconclusive, despite numerous pieces of evidence that Leishmania spp. triggers autophagy in a variety of cell types. The mechanistic approach is poorly understood in the Leishmania parasite as autophagy is significant in both Leishmania and the host. Herein, this review discusses the autophagy proteins that are being investigated as potential therapeutic targets, the connection between autophagy and lipid metabolism, and microRNAs that regulate autophagy and lipid metabolism. It also highlights the use of systems biology to develop novel autophagy-dependent therapeutics for leishmaniasis by utilizing artificial intelligence (AI), machine learning (ML), mathematical modeling, network analysis, and other computational methods. Additionally, we have shown many databases for autophagy and metabolism in Leishmania parasites that suggest potential therapeutic targets for intricate signaling in the autophagy system. In a nutshell, the detailed understanding of the dynamics of autophagy in conjunction with lipids and miRNAs unfolds larger dimensions for future research.

Synthetic biology for combating leishmaniasis

“…Cellular response such as autophagy and apoptosis in leishmaniasis may be regulated by bistable switch to regulate BCL2 and Beclin1. Alternate expression of both genes may control homeostasis of cell to achieve parasite elimination and creating less impact on host cells ( Guhe et al, 2023 ; Figure 2A ). Hence, incorporation of a regulatory toggle switch ( Soni and Singh, 2021b ; Figure 2G ) or bistable expression system, would necessitate administering only an inducer dose and boosters to the host to activate the immune response for the sustained development of long-term memory ( Figure 2 ).…”

Assessment of autophagy inLeishmaniaparasites

“…Many cells require autophagy to recycle damaged or stressed intracellular components for the purpose of maintaining homeostasis and cell health through both selective or non-selective degradative mechanisms (3,4). The autophagic process is activated when the cell senses a need for nutrients, growth or energy (5)(6)(7) or to eliminate invasive pathogens (8)(9)(10). All cells are known to engage in basal levels of autophagy to perform basic hemostatic processes that include protein or organelle turnover (8,11).…”

“…The autophagic process is activated when the cell senses a need for nutrients, growth or energy (5)(6)(7) or to eliminate invasive pathogens (8)(9)(10). All cells are known to engage in basal levels of autophagy to perform basic hemostatic processes that include protein or organelle turnover (8,11). In mammals, the induction of autophagy is a complicated process that involves a myriad of autophagy-like proteins, ATGs, which induce the formation of the autophagic organelle, autophagosome.…”

“…In addition to evading host immune responses, Leishmania parasites have been shown to hijack the host cell's autophagic machinery (8). It has been suggested that the continued survival of Leishmania parasites in their host is due to their ability to modulate host mTORregulated autophagy processes (27), which helps them to obtain essential nutrients in their harsh intracellular host environment (28).…”