S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

Abstract

Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P Ͻ 0.0001), despite higher parasite burdens (P Ͻ 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P Ͻ 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4 ϩ and CD8 ϩ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P Ͻ 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.

Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria

“…Rapid reversibility of cerebral swelling has also been observed in adults and children after anti-malarial treatment and highlights the need for new malarial treatments that that can rapidly prevent and reverse neuronal cytotoxicity [ 71 ]. These findings are in agreement with neuroprotective effects observed with triterpenoids used in pre-clinical models of Huntington’s disease and induced neurotoxicity [ 74 , 75 ].…”

“…CDDO and its derivatives are currently being investigated in murine models of neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS) and Huntington’s disease where improvements to memory and motor impairments have been observed [ 33 , 75 ]. Whether the improved survival in ECM observed with adjunctive CDDO-EA will also be accompanied by reduced cognitive and motor impairments in surviving mice is unknown.…”

Cysteamine, an Endogenous Aminothiol, and Cystamine, the Disulfide Product of Oxidation, Increase Pseudomonas aeruginosa Sensitivity to Reactive Oxygen and Nitrogen Species and Potentiate Therapeutic Antibiotics against Bacterial Infection

“…CYS can also readily react with nitric oxide (NO) donors to form a new adduct with characteristics suggestive of S -nitrosocysteamine. S-nitrosothiols are a family of compounds with an emerging role in immunity ( 25 ), including maintenance of cell barrier integrity against infection and repair ( 26 , 27 ) and cell signaling ( 28 ). CYS also impairs bacterial virulence at subinhibitory levels, with striking effects on bacterial pigment production, including phenazines in P. aeruginosa and pyomelanin in BCC.…”

Detection of trace concentrations of S-nitrosothiols by means of a capacitive sensor

“…There are many examples demonstrating that this type of signaling occurs across a broad range of biological systems ( Table 1 , [ 1 , 36 ]). Disorders of protein S-nitrosylation are relevant to the pathophysiology of many diseases [ 1 , 33 , 34 , 37 ], and S-nitrosylation is emerging as a field relevant to many biological disciplines [ 1 ] ( Table 1 ). In addition, intermediate low molecular weight SNOs ( Fig 7A ) appear to act as ligands in many signaling reactions.…”