Oxidative stress in malarial diseases: Plasmodium-human host interactions and therapeutic interventions

Abstract

Oxidative stress is a major contributor of disease aetiology, progression and outcomes. Host systems and parasite infectivity play critical roles in the generation and manipulation of oxidative stress in malaria. Host systems involve the immunological and inflammatory responses that generate free radical species as host signalling processes as well as parasite combating and destructive entities. Parasites trigger molecules with inherent free radical generation in the host. Without the ability to synthesize amino acids, the parasite depends on the breakdown of haemoglobin to salvage the same within the food vacuole. This creates a highly oxidative stress environment from the Fenton reaction through the central ferrous moiety. Elimination of host oxidative stress process, from haemoglobin degradation product haeme, has critically evolved to protect parasites from the hostile intracellular compartment where it is an obligatory inhabitant. Parasites produce antioxidant species from both enzymatic and non-enzymatic molecules which cushions the parasites proteins from oxidation. The parasite also converts haeme, through biocrystallization, to haemozoin, a seemingly biologically inert molecule. In the presence of parasite DNA, haemozoin induces oxidative and inflammatory mediators (cytokines, chemokines, inducible nitric oxide synthase, nitric oxide, oxygen free radical, nitrogen free radicals, peroxynitrite etc.) with a high propensity toward oxidative stress able to override host antioxidant defence systems. Other parasite proponents, e.g. glycosylphosphotidylinositol, are instrumental in negatively modulating host oxidative stress. Without intervention, the disease machineries of oxidative stress go into a vicious cycle of self-propagation mode that leads to host debilitation, cachexia and death. Current drugs are mainly antiparasitic and relieve the " disease” aspect of malaria sparingly. Phytotherapeutics and phytochemicals (asiatic acid, maslinic acid oleanolic acid), which display anti-oxidant and pro-oxidant properties, have shown both " antiparasite” and " anti-disease” effects promising efficacy in combating malaria. These pleiotropic properties are displayed in different environments with potential to buffer malarial disease syndrome.