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New Evidence that Catecholamines Increase Enterovirus 71 Infectivity

Enterovirus 71
Catecholamines – enterovirus-71 infectivity

Outbreaks of Human Enterovirus 71 (EV71) are often reported in Asia. EV71 is responsible for syndromes like hand-foot and mouth disease, but is also involved in pulmonary edema (PE) and in neurological complications, like brainstem encephalitis (BE) and autonomic nervous system dysregulation (ANS).

During cases of EV71 associated encephalitis, an elevated plasma level of epinephrine and norepinephrine was observed, raising the issue of interconnections between catecholamines and EV 71 infection. The authors have investigated the impact of catecholamines on EV 71 infection and vice-versa. They confirmed elevated plasma levels of epinephrine and norepinephrine in patients with BE compared to controls. The difference was more notable with norepinephrine. Catecholamine levels were even higher in BE complicated with ANS and PE than in uncomplicated BE.

The effects of epinephrine and norepinephrine on infection were studied.  The authors used immune progenitor cell lines expressing α1A and β2 adrenergic receptors such as THP-1 monocytes cell line, Jurkat lymphocytes cell line and HL-60 myeloid cell line. Appropriate stimuli induced their differentiation into immune cells which increased the proportion of infected cells when they were exposed to EV71.

Norepinephrine or epinephrine treatment was able to further enhance the infection of differentiated cells of human peripheral blood mononuclear cells (PBMC) and of pulmonary (A549) and neuroblastoma (SK-N-SH) cell lines as well. In contrast, the rate of infection was lower when adrenergic receptors were blocked by using a neutralizing antibody.

Infected human PBMC treated with epinephrine or norepinephrine showed in increase in IL-6 production. However, the production of other cytokines, such as IL-10, IL-1β, IL-8 and IL-12p70 was unaffected.

These data suggest that catecholamines enhance the infection with EV71. During brainstem encephalitis, an increased release of epinephrine and norepinephrine is observed, resulting in a vicious circle where EV71 enhances its own infection.

Blocking adrenergic receptors with neutralizing antibodies resulted in a reduced infection. Whether blocking these receptors would be useful to avoid the worsening of brainstem encephalitis deserves further investigation.


Commentary

on the study by Liao YT et al. PLoS One, 10(8):e0135154. doi: 10.1371/journal.pone.0135154.
Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71
The 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 Design: Plasma 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.
The 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. Conclusion: The 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.

Authors Affiliations:

Antoine Bertin and Didier HoberUniversité de Lille et CHU de Lille, Laboratoire de virologie, EA 3610 Bâtiment P Boulanger, Hôpital A Calmette CHRU Lille, France ; Email: didier.hober@chru-lille.fr

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