Varicella-zoster virus isolates, but not the vaccine strain OKA, induce sensitivity to alpha-1 and beta-1 adrenergic stimulation of sensory neurones in culture.
The reactivation of varicella-zoster virus (VZV) from its persistent state in sensory neurones causes shingles and induces severe, long-lasting pain and hyperalgesia that often lead to postherpetic neuralgia. To investigate the VZV-induced neuropathic changes, we established conditions for the active infection of sensory neurones from rat dorsal root ganglia in vitro. After 2 days of culture, up to 50% of the cells expressed viral antigens of the immediate-early and late replication phase. The intracellular calcium ion concentration was monitored in individual cells by microfluorimetry. Whereas the calcium response to capsaicin was preserved, the VZV-infected neurones gained an unusual sensitivity to noradrenaline stimulation in contrast to non-infected cells. The adrenergic agonists phenylephrine and isoproterenol had a similar efficacy demonstrating that both alpha(1)- and beta(1)-adrenoreceptors were involved. The sensitivity to adrenergic stimulation was observed after infection with different wildtype isolates, but not with the attenuated vaccine strain OKA. The lack of noradrenaline sensitivity of vaccine-infected neurones demands a structural comparison of wildtype and vaccine viruses with and without phenotype. A partial sequence evaluation (26 kb) of the European OKA vaccine strain surprisingly revealed a series of nucleotide exchanges in comparison to presumably identical OKA strains from other sources, although VZV is generally considered genetically stable. In summary, we report that the infection with wildtype VZV isolates, but not with the vaccine strain, induces noradrenaline sensitivity in sensory neurones, which correlates with clinical and experimental observations of adrenergic effects involved in VZV-induced neuralgia.
Schmidt
Michaela
M
Abteilung Virologie, Hygiene-Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
Kress
Michaela
M
Heinemann
Stefanie
S
Fickenscher
Helmut
H
D000818:Animals; D002478:Cells, Cultured; D019433:Chickenpox Vaccine; D006562:Herpes Zoster / Q000209:etiology / Q000503:physiopathology / Q000821:virology; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology* / Q000821:virology*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D014776:Virus Cultivation
D019433:Chickenpox Vaccine; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D010656:Phenylephrine; D007545:Isoproterenol; D009638:Norepinephrine