title: Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71.
abstract: BACKGROUND
  Enterovirus 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Liao
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Min
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jen-Ren
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chun-Keung
authors.initials: CK
authors.lastname: Yu
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Liu
mesh_terms: D001341:Autonomic Nervous System / Q000187:drug effects / Q000821:virology; D001933:Brain Stem / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D045744:Cell Line, Tumor; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D004660:Encephalitis / Q000097:blood / Q000188:drug therapy / Q000821:virology; D004770:Enterovirus / Q000472:pathogenicity*; D004769:Enterovirus Infections / Q000097:blood / Q000188:drug therapy / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D004837:Epinephrine / Q000097:blood*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D009638:Norepinephrine / Q000097:blood*; D011654:Pulmonary Edema / Q000188:drug therapy / Q000821:virology
chemical_list: D016207:Cytokines; D009638:Norepinephrine; D004837:Epinephrine