Identification of an important immunological difference between virulent varicella-zoster virus and its avirulent vaccine: viral disruption of dendritic cell instruction.
Virulent varicella-zoster virus (VZV) can spread in immunocompetent humans, resulting in symptoms mostly of the skin. In contrast, vaccine Oka (V-Oka), the attenuated VZV vaccine strain, only rarely causes clinical reactions. The mechanisms underlying these pathogenetic differences are unclear. In this study, we comparatively analyzed the ability of virulent VZV and V-Oka to modulate instruction of dendritic cells (DCs) by innate signals. DCs isolated from normal human skin were susceptible to infection with VZV and V-Oka. Moreover, inflammatory DCs, which play a crucial role in the stimulation of Th1 immune responses, accumulated in herpes zoster lesions. Infection of inflammatory DCs generated in vitro with virulent VZV or V-Oka resulted in upregulation of CD1c. Upon coculture with CD1c-restricted innate cells, DCs developed a mature phenotype whether infected with virulent VZV or V-Oka. Intriguingly, a striking difference was detected on the functional level. The release of IFN-gamma and IL-12, the signature cytokines of Th1 responses, was enhanced by V-Oka but blocked by virulent VZV. V-Oka and virulent VZV efficiently synergized with CD40L, eliminating the possibility that CD40 signaling was a target of VZV-associated immune evasion. Instead, virulent VZV selectively interfered with signaling through TLR2, which is known to sense VZV. Thus, virulent VZV subverts Th1-promoting instruction of human DCs by blocking TLR2-mediated innate signals that prime IL-12 production by DCs. Taken together, our results demonstrate a novel immune-evasion mechanism of virulent VZV that has been lost during the attenuation process leading to the VZV vaccine strain.
Institute of Virology, Venerology and Allergology, Charité-Universitätsmedizin Berlin, Germany.
Cindy
C
Gutzeit
Martin J
MJ
Raftery
Matthias
M
Peiser
Karsten B
KB
Tischer
Martina
M
Ulrich
Melanie
M
Eberhardt
Eggert
E
Stockfleth
Thomas
T
Giese
Andreas
A
Sauerbrei
Craig T
CT
Morita
Günther
G
Schönrich
D002478:Cells, Cultured; D019433:Chickenpox Vaccine / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D006562:Herpes Zoster / Q000276:immunology / Q000821:virology; D014645:Herpesvirus 3, Human / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity*; D022283:Herpesvirus Vaccines / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000821:virology; D014613:Vaccines, Attenuated / Q000276:immunology; D014774:Virulence
D019433:Chickenpox Vaccine; D022283:Herpesvirus Vaccines; D014613:Vaccines, Attenuated; D018664:Interleukin-12