L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi

Abstract

Chagas disease caused by Trypanosoma cruzi is a neglected disease that affects about 7 million people in Latin America, recently emerging on other continents due to migration. As infection in mice is characterized by depletion of plasma L-arginine, the effect on infection outcome was tested in mice with or without L-arginine supplementation and treatment with 1400W, a specific inhibitor of inducible nitric oxide synthase (iNOS). We found that levels of L-arginine and citrulline were reduced in the heart and plasma of infected mice, whereas levels of asymmetric dimethylarginine, an endogenous iNOS inhibitor, were higher. Moreover, L-arginine supplementation decreased parasitemia and heart parasite burden, improving clinical score and survival. Nitric oxide production in heart tissue and plasma was increased by L-arginine supplementation, while pharmacological inhibition of iNOS yielded an increase in parasitemia and worse clinical score. Interestingly, electrocardiograms improved in mice supplemented with L-arginine, suggesting that it modulates infection and heart function and is thus a potential biomarker of pathology. More importantly, L-arginine may be useful for treating T. cruzi infection, either alone or in combination with other antiparasitic drugs. Author summaryTrypanosoma cruzi is the causative agent of the neglected Chagas disease in humans. During infection in mice, depletion of plasma L-arginine is correlated with mortality. L-arginine is a semi-essential amino acid needed for cell proliferation, and is the substrate of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS), which is involved in the immune response against infections. Observed L-arginine depletion is likely caused by increased Arg-1 activity, but the effect on immune response are still unknown. Our PLOS Neglected Tropical Diseases | https://doi

Regulatory Lymphoid and Myeloid Cells Determine the Cardiac Immunopathogenesis of Trypanosoma cruzi Infection

“…Moreover, after a global metabolomic analysis we found elevated levels of asymmetric+symmetric dimethyl-arginine (ADMA+SDMA) after infection in heart and plasma (Gironès et al, 2014 ) and confirmed elevated levels of ADMA in plasma (Carbajosa et al, 2018 ). ADMA is a product nuclear proteolysis by arginine methyltransferases (Teerlink, 2005 ), and is an endogenous inhibitor of iNOS that in combination with L-arginine regulates NOS activity (Blackwell, 2010 ).…”

“…It is worth mentioning that a decrease in L-arginine causes down regulation iNOS expression (Konig et al, 2009 ) and reduces NO production by substrate competition. Notably, L-arginine administration to infected mice incremented plasma L-arginine and NO levels, significantly decreased parasitemia, heart parasite burden and clinical score, while increasing mice survival and cardiac performance (Carbajosa et al, 2018 ). In this direction, L-arginine treatment has been also shown to be beneficial in preventing Trypanosoma cruzi vertical transmission in rats (da Costa et al, 2014 ) and in patients affected by Dilated Cardiomyopathy, which clinically is the most similar to Chagas cardiomyopathy (Kralova et al, 2015 ).…”

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

“…The cardiac expansion of MDSCs is related to tissular damage and parasite persistence, because these cells were the most important source of NO leading to the immune response suppression . Based on this data, it has been proposed a new therapeutic approach against this disease, consisting in the administration of L‐arginine . Interestingly, the treatment with L‐arginine in mice improves survival rates and parasite clearance, preventing an excessive cardiac damage …”

“…103,104 Based on this data, it has been proposed a new therapeutic approach against this disease, consisting in the administration of L-arginine. 105 Interestingly, the treatment with L-arginine in mice improves survival rates and parasite clearance, preventing an excessive cardiac damage. 105 Toxoplasma gondii is an obligate intracellular parasite that belongs to the Apicomplexa phylum.…”

“…105 Interestingly, the treatment with L-arginine in mice improves survival rates and parasite clearance, preventing an excessive cardiac damage. 105 Toxoplasma gondii is an obligate intracellular parasite that belongs to the Apicomplexa phylum. 106 It is transmitted orally and has the ability to successfully cross the intestinal epithelial barrier to spread throughout the body.…”