The host mTOR pathway and parasitic diseases pathogenesis

Abstract

The mechanistic (or mammalian) target of rapamycin (mTOR) is considered as a critical regulatory enzyme involved in essential signaling pathways affecting cell growth, cell proliferation, protein translation, regulation of cellular metabolism, and cytoskeletal structure. Also, mTOR signaling has crucial roles in cell homeostasis via processes such as autophagy. Autophagy prevents many pathogen infections and is involved on immunosurveillance and pathogenesis. Immune responses and autophagy are therefore key host responses and both are linked by complex mTOR regulatory mechanisms. In recent years, the mTOR pathway has been highlighted in different diseases such as diabetes, cancer, and infectious and parasitic diseases including leishmaniasis, toxoplasmosis, and malaria. The current review underlines the implications of mTOR signals and intricate networks on pathogen infections and the modulation of this master regulator by parasites. Parasitic infections are able to induce dynamic metabolic reprogramming leading to mTOR alterations in spite of many other ways impacting this regulatory network. Accordingly, the identification of parasite effects and interactions over such a complex modulation might reveal novel information regarding the biology of the abovementioned parasites and might allow the development of therapeutic strategies against parasitic diseases. In this sense, the effects of inhibiting the mTOR pathways are also considered in this context in the light of their potential for the prevention and treatment of parasitic diseases.

The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages

“…mTOR inhibition has been associated with hematological adverse effects ( 38 ). However, it is worth noting that targeting human mTOR complex 1 has been proposed as an adjunctive host-directed therapy for cerebral malaria aimed at modulating the host immune response ( 39 ). Understanding the pharmacokinetic/pharmacodynamic drivers of efficacy and the corresponding dosing requirements and therapeutic window for malaria, which may differ from indications in oncology, will be crucial for future optimization and development of this compound.…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…Interestingly, changes in the environment that includes sleep loss can decrease memory formation in the hippocampus by affecting autophagy proteins [24,122,[143][144][145][146]. At the cellular level, loss of homeostasis [84,119,147] affects circadian rhythm that impairs cognition [14,23,58,86,140,148]. Activation of autophagy with circadian proteins may be protective during stroke.…”

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

“…Previous studies also suggest in experimental studies with AD that a baseline cyclic circadian rhythm that controls autophagy is necessary to reduce A β deposition and prevent memory loss [ 129 , 148 ]. Alterations in environmental homeostasis [ 82 , 129 , 149 ] can alter circadian rhythm that results in loss of cognitive ability [ 2 , 19 , 49 , 50 , 84 , 150 ]. Sleep fragmentation also can produce changes in hippocampal autophagy proteins and decrease memory function [ 4 , 127 , 151 – 154 ].…”