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The ambiguous role of glutathione in malaria

October 3, 2015 - 19:41 -- Pierre Lutgen

Parasites are endowed with powerful and host-independant mechanisms which de novo synthesize or regenerate reduced glutathione (GSH) and protect the parasites from oxidative damage. GSH can penetrate from the extracellular space into the host cytosol but the parasite membrane is impermeable to peptides (H Atamna et al., Eur J Biochem 1997, 15, 670-9).. Glutathione is one of the most powerful anti-oxidants. It is a tripeptide formed by the amino acids glycine, cysteine and glutamic acid. It inhibits the action of arginine which produces NO and expels it from the food vacuole.

Plasmodium falciparum at the trophozoite stage in human erythrocytes exhibits a huge capacity for synthesis of GSH and an intense glutathione metabolism which maintains the reducing environment of the cytosol. The apicoplast of the parasite eventually plays a major role. During the growth cycle in the RBC the parasites obtain the majority of their amino acids through the digestion of hemoglobin. Glutathione also protects the gametocytes against oxidative stress (E Lasonder et al., Letters to Nature, 2002, 419537-43).

GSH takes part in detoxifiing heme, the product of hemoglobin digestion, by polymerizing some of it to insoluble hemozoin. But only 30% oft he heme is converted into hemozoin. Some authors suggest that nonpolymerized heme exits the food vacuole and is subsequently degraded by glutathione. Marginal amounts of free heme could be detected in the membrane of infected cells but nowhere else. Chloroquine and amodiaquine inhibit heme polymerization and thereby increase the efflux of heme out of the food vacuole (H Ginsburg et al., Biochem Pharmacol, 1998, 15, 1305-13). These drugs also competitevely inhibit the degradation of heme by glutathione, thus allowing toxic heme to accumulate in membranes. Heme has been shown to disrupt the barrier properties of membranes. It has strong pro-oxidant properties and damages the vascular endothelium. The hemoglobin release from fractured parasitized cells leads to anemia (K Mohan et al, Annals of Hematology, 1992, 65, 131-34).

After rupture the digestive vacuoles DVs are selectively phagocytosed by leukocytes. The fragments of DVs generate also a lot of ROS and induce systemic inflammatory responses. All this leads to a significant reduction of the capacity of the immune system and could explain why children affected with severe malaria frequently suffer from septicemia (P. Dasari et al., Blood, 2011 118-18, 49-60 & Dissertation zur Erlangung des Doktorgrades, Uni.Marburg 2013). The DV after schizont rupture appears to function as a decoy and is exploited by the parasite to perturb central elements of the innate immune system (Prasad Dasari et al., Med Microbiol Immunol 2014, 203, 383-393), and to divert leukocytes from the merozoites . Despite the fact, as occurs in vivo, that merozoites outnumber DVs by an order of magnitude, the leukocytes preferentially attack the DVs.

The pro-oxidant damage and inflammation created by excessive heme, hemozoin and DV fragments in blood vessels and plasma can be mitigated by glutathione. In other words, inside of the infected erythrocyte glutathione is beneficial to the parasite, outside of the erythrocyte it reduces the negative effects of the malarial infection.

The challenge seems to be to find the right balance between prophylaxis and therapy or the right balance of antioxidant levels at different stages of the malaria infection. A high oxidative stress will be detrimental for the survival of young parasites, but if this stress becomes too high in the case of severe malaria or after consumption of nutritional and antimalarial substances which enhance oxidative stress. Several cases of hemolytic anemia are described in the scientific literature after iv artesunate treatment.

The same mechanism works for gastrointestinal blood-feeding nematodes like Haemonchus contortus. With GSH they implement a detoxifying process against peroxidation and exogenous drugs. (A van Rossum et al., Infection and Immunity, 2004, 2780-2790). In schistosomiasis it is likely that glutathione depletion affects parasite survival (Hsin-Hung Huang et al., Curr Pharm Des 2012, 18, 3595-3611).

In leishmaniasis drugs which inhibit GSH enhance NO levels (P Kapoor et al., Trop Med Internat Health, 2000, 5, 438-441).

In many cancer types GSH levels are higher than in normal controls. Glutathione again is a protection of the rapidly multiplying cells against oxidative stress. In the case of cancer therapy the role of glutathione could be detrimental. Many anticancer chemotherapeutic drugs are pro-oxidants.

In summary, Artemisia annua tea could present the right balance of compounds (artemisinin, polysaccharides, amino acis, coumarines, phytosterols, potassium, nitrate…) to kill the malaria parasite and at the same time reduce inflammation. Interfering in this herbal polytherapy with stronger antioxidants like vitamin C, vitamin E, aspirin or paracetamol might inhibit the pro-oxidants which kill the parasite. It has been shown that vitamin E accumulates in the infected red cells reducing artemisinin effectiveness (K Mohan et al., Indian J Biochem Biophys, 1994, 6, 476-9).