Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71

Abstract

BackgroundEnterovirus 71 (EV71) infections may be associated with neurological complications, including brainstem encephalitis (BE). Severe EV71 BE may be complicated with autonomic nervous system (ANS) dysregulation and/or pulmonary edema (PE). ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release.ObjectiveThe aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines.Study DesignPlasma levels of norepinephrine (NE) and epinephrine (EP) in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs) on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs) were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP.ResultsThe plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE.ConclusionThe plasma levels of NE and EP elevated in EV71-infected patients with ANS dysregulation and PE. Both NE and EP enhanced the percentages of infected cells and virus titers in EV71 infection in vitro. NE and EP may play a role in the pathogenesis of EV71 BE complicated with ANS dysregulation and PE.

Mechanism for the lethal effect of enterovirus A71 intracerebral injection in neonatal mice

“…In vivo, the analysis of homogenized brainstem tissue also demonstrated the upregulation of cytokines, including IL-6 and IL-8, and adrenaline, in infected neonatal mice, but not in the inactivated antigen-treated group. These findings are consistent with our previous findings [8] and those of other studies [22][23][24]. In our previous study [8], to investigate the potential interaction of astrocytes and neurons during EV-A71 infection, we designed a double-layer coculture system consisting of an upper layer of EV-A71-infected human astrocytes and a lower layer of uninfected human neurons from the brainstem.…”

Milrinone in Enterovirus 71 Brain Stem Encephalitis

“…Once the surge of sympathetic over-activity resulted in PE, the cardiopulmonary failure followed. The plasma levels of epinephrine in EV71-infected patients with ANS dysregulation and PE were markedly high ( Liao et al, 2015 ). Furthermore, the percentages EV71-infected cells were increased in THP-1 and Jurkat cells via treatment with epinephrine.…”

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

“…The reason for such diverse tropism by EV-A71 remains largely unknown. However, encephalitis of the midbrain, pons and medulla occurs in 62% of patients with neurological complications during EV-A71 infection (Wang et al, 1999) and, due to the role of the brainstem in autonomic regulation, encephalitis of this anatomical region is typically associated with pulmonary edema and fluctuating blood pressure (Liao et al, 2015). In terms of CVs, a mouse model designed to imitate neonatal CVB3 infections found lesions in the hippocampus and cortex, although viral RNA was detected throughout the brain .…”