Nitric Oxide Influences HSV-1-Induced Neuroinflammation

Abstract

Herpes simplex virus type 1 (HSV-1) has the ability to replicate in neurons and glial cells and to produce encephalitis leading to neurodegeneration. Accumulated evidence suggests that nitric oxide (NO) is a key molecule in the pathogenesis of neurotropic virus infections. NO can exert both cytoprotective as well as cytotoxic effects in the central nervous system (CNS) depending on its concentration, time course exposure, and site of action. In this study, we used an in vitro model of HSV-1-infected primary neuronal and mixed glial cultures as well as an intranasal model of HSV-1 in BALB/c mice to elucidate the role of NO and nonapoptotic Fas signalling in neuroinflammation and neurodegeneration. We found that low, nontoxic concentration of NO decreased HSV-1 replication in neuronal cultures together with production of IFN-alpha and proinflammatory chemokines. However, in HSV-1-infected glial cultures, low concentrations of NO supported virus replication and production of IFN-alpha and proinflammatory chemokines. HSV-1-infected microglia downregulated Fas expression and upregulated its ligand, FasL. Fas signalling led to production of proinflammatory cytokines and chemokines as well as induced iNOS in uninfected bystander glial cells. On the contrary, NO reduced production of IFN-alpha and CXCL10 through nonapoptotic Fas signalling in HSV-1-infected neuronal cultures. Here, we also observed colocalization of NO production with the accumulation of β-amyloid peptide in HSV-1-infected neurons both in vitro and in vivo. Low levels of the NO donor increased accumulation of β-amyloid in uninfected primary neuronal cultures, while the NO inhibitor decreased its accumulation in HSV-1-infected neuronal cultures. This study shows for the first time the existence of a link between NO and Fas signalling during HSV-1-induced neuroinflammation and neurodegeneration.

Viral Involvement in Alzheimer’s Disease

“… 97 iNOS increases inflammation within AD brains because it leads to both lipid peroxidation and functional alteration of proteins (these modifications are molecular markers of AD). 98 NF-kβ activity upregulates cytokine and proinflammatory molecules, such as IL-1β, TNF-α, ROS, and COX2. 92 The production of PGE2 has been shown to stimulate the production of Aβ ( Figure 4 ).…”

Nitric Oxide Circumvents Virus-Mediated Metabolic Regulation during Human Cytomegalovirus Infection

“…Nitric oxide has been demonstrated to be inhibitory toward both RNA and DNA viruses (reviewed in reference 15 ), including those that establish lifelong infection such as herpesviruses. Herpes simplex virus 1 (HSV-1) replication was demonstrated to be inhibited by exogenous nitric oxide exposure ( 16 ), yet nitric oxide is implicated in immunopathogenesis during HSV-1 infection ( 17 – 19 ). Nitric oxide inhibits HSV-2 replication in vitro and in vivo ( 20 ).…”

Recent Progress of Nanomedicine in the Treatment of Central Nervous System Diseases

“…But NO might also induce neurodegeneration. In summary, differences in concentration and time exposure allow NO to act simultaneously on cytoprotective and cytotoxic effects in the CNS . For NO, there is a novel NIR‐responsive sandwich nanostructure based on GO nanosheets and BNN6 ( N , N ′‐di‐sec‐butyl‐ N , N ′‐dinitroso‐1,4‐phenylenediamine), which is combined through π–π stacking.…”