The Role of Myeloid Cell Activation and Arginine Metabolism in the Pathogenesis of Virus-Induced Diseases

Abstract

When an antiviral immune response is generated, a balance must be reached between two opposing pathways: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS) and arginase 1 (Arg1). Nitric oxide (NO) production by iNOS is an important proinflammatory mediator, whereas Arg1-expressing macrophages contribute to the resolution of inflammation and wound repair. In the context of viral infections, expression of these enzymes can result in a variety of outcomes for the host. NO has direct antiviral properties against some viruses, whereas during other virus infections NO can mediate immunopathology and/or inhibit the antiviral immune response to promote chronic infection. Arg1 activity not only has important wound healing functions but can also inhibit the antiviral immune response during some viral infections. Thus, depending on the specific virus and the tissue(s) involved, the activity of both of these arginine-hydrolyzing enzymes can either exacerbate or limit the severity of virus-induced disease. In this review, we will discuss a variety of viral infections, including HIV, SARS-CoV, LCMV, HCV, RSV, and others, where myeloid cells influence the control and clearance of the virus from the host, as well as the severity and resolution of tissue damage, via the activities of iNOS and/or Arg1. Clearly, monocyte/macrophage activation and arginine metabolism will continue to be important areas of investigation in the context of viral infections.

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…Several cross-inhibitory interactions have been reported between the Arg1 and iNOS pathways (12,13,125). Arg1 has a lower affinity for L-Arg, but catalyzes the reaction faster than iNOS, and thus, their overall rates of conversion of L-Arg are relatively similar (12).…”

“…For example, NO is known to have antimicrobial and antiparasitic activity (71,102). In the context of viral infections, NO production or arginine depletion can alter/inhibit viral replication, cause immunopathology, and/or promote viral persistence, in part, by modifying innate and/or adaptive immune responses (13).…”

Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis

“…Oxidative stress and/or altered immune response could be involved in VEE viral infection. In this regard, pro-oxidant and immune modulator properties of NO have been reported (Burrack and Morrison, 2014;Mannick, 1995); therefore, approaches to inhibit the effect of NO on viral replication and oxidative stress need to be used appropriated compounds. Melatonin (MTL), a molecule with antioxidant properties, has shown to have protective effects on experimental murine VEE virus infection (Bonilla et al, 2003(Bonilla et al, , 2004Valero et al, 2004Valero et al, , 2007Valero et al, , 2009).…”

“…During an anti-viral immune response a balance between two opposing pathways is observed: the production of pro-inflammatory cytokines and cytotoxic cells to limit the viral infection and regulators to control the excessive immune response and avoid tissue damage. Nitric oxide (NO) can mediate immunopathology and/or inhibit the antiviral immune response to promote chronic infection (Burrack and Morrison, 2014). In this regard, NO has been implicated in the experimental spread of Venezuelan equine encephalitis (VEE) virus and other viruses (Bonilla et al, 2004;Perrone et al, 2013;Mannick, 1995).…”

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

“…Arg is also catabolised by a third enzyme, inducible NO synthase (NOS2), to produce NO and l ‐citrulline. NO enhances the differentiation of monocytes to ‘classically activated’ macrophages whilst increased ARG1 expression has been linked with prohomeostatic ‘alternatively activated’ macrophages that do not produce NO 10, 11. Arg is required for the production of TNF‐α 12, 13.…”