Nitric oxide in parasitic infections: a friend or foe?

Abstract

The complex interaction between the host and the parasite remains a puzzling question. Control of parasitic infections requires an efficient immune response that must be balanced against destructive pathological consequences. Nitric oxide is a nitrogenous free radical which has many molecular targets and serves diverse functions. Apart from being a signaling messenger, nitric oxide is critical for controlling numerous infections. There is still controversy surrounding the exact role of nitric oxide in the immune response against different parasitic species. It proved protective against intracellular protozoa, as well as extracellular helminths. At the same time, it plays a pivotal role in stimulating detrimental pathological changes in the infected hosts. Several reports have discussed the anti-parasitic and immunoregulatory functions of nitric oxide, which could directly influence the control of the infection. Nevertheless, there is scarce literature addressing the harmful cytotoxic impacts of this mediator. Thus, this review provides insights into the most updated concepts and controversies regarding the dual nature and opposing sides of nitric oxide during the course of different parasitic infections.

Keywords: Immune response; Isoenzymes; Nitric oxide; Nitric oxide synthase; Parasitic infections.

Fig. 1

Biochemical pathway of nitric oxide (NO) synthesis. In the mammalian cells, the nitric oxide synthase (NOS) enzyme mediates the conversion of L-arginine to L-citrulline and (NO), using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a co-factor. Oxidative degradation of (NO) results in the formation of the breakdown products, nitrate (NO3-) and nitrite (NO2-)

Fig. 2

Opposing roles of macrophages during parasitic infections. Macrophages play vital roles in the immune response to different parasites, both as effector anti-parasitic (M1) and as immunoregulatory (M2). Classical activation of the macrophages is associated with (Th1)-immune response. Through the triggering action of (IFN-γ), (M1) macrophages express (iNOS) enzyme, with subsequent high level of (NO), which directly kills different pathogens. Instead of mediating the parasite killing, (M2) macrophages modulate the immune response and control the inflammation by expressing the enzyme arginase-1. The arginase pathway limits the arginine availability for (NO) synthesis, resulting in low (NO) output

Fig. 3

The dichotomous nature of (NO) during different parasitic infections. In the immune response against various parasitic species, (NO) switches between two faces; one is protective or (friendly), and the other is detrimental (inimical). Through its cytotoxic potential and microbicidal abilities, (NO) was proved protective against the Leishmania parasite. A single dose of (NO)-releasing chitosan nanoparticles (NONPs) showed high efficiency in reducing L.amazonensis parasite burden. During experimental (T.gondii) infection, (iNOS) enzyme inhibited tachyzoite proliferation in the brain sections of the infected mice. Also, increased expression of (nNOS) has largely contributed to the clearance of (G.lamblia) protozoan through enhancing intestinal motility. Yet, (NO) was incriminated in triggering several pathological sequelae, which reflect the deleterious side of this molecule. In (S.haematobium) infection, a strong association was observed between (iNOS) expression and urothelial carcinomas (UCs). Furthermore, over (NO) production has worsened the cardiac electromechanical functions in mice experimentally infected with (T. cruzi). In cerebral malaria (CM), (TNF-a)-induces high amounts of (NO), which in turn stimulates the expression of intercellular adhesion molecule 1 (ICAM-1) by the brain endothelium. (ICAM-1) triggers the binding of infected erythrocytes to endothelial cells, a factor which contributes considerably to the pathogenesis of (CM)