Identification of an Important Immunological Difference between Virulent Varicella-Zoster Virus and Its Avirulent Vaccine: Viral Disruption of Dendritic Cell Instruction

Abstract

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-γ 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.

Manipulation of the Innate Immune Response by Varicella Zoster Virus

“…In the skin, a major site for VZV disease, it has been demonstrated via immunostaining of VZV infected skin lesions that there is a significantly reduced frequency of Langerhans cells (LCs) (113,127), extending an earlier case report which examined CD1a expression in VZV-infected skin (129). These observations suggest activation and migration of LCs to draining lymph nodes (113,127).…”

“…As discussed earlier, this may provide a transient advantage to the virus, allowing VZV to successfully disseminate during the first critical days after primary infection. Analogously, others have employed the in vitro MDDC infection model to demonstrate that the VZV vaccine strain (V-Oka) and virulent VZV clinical isolates equally infect these immune cells (127). Furthermore, Hu and Cohen utilized viruses unable to express VZV ORF10, ORF32, ORF57, or ORF66 proteins and demonstrated there was no impairment for infection of immature DCs.…”

Effects of virulent and attenuated transmissible gastroenteritis virus on the ability of porcine dendritic cells to sample and present antigen

“…Lassa virus infection of human DCs could inhibit the upregulation of surface marker expression and the development of an adaptive immune response, while the related naturally non-virulent arenavirus Mopeia virus (MV) infection of DCs could increase the transcription of type I IFN mRNA, IL-12 mRNA and CXCL-10 mRNA and induce stronger T-cell responses (Baize et al, 2004;Pannetier et al, 2011). Similarly, virulent varicella-zoster virus (VZV) subverted secretion of Th1 cytokines in human DCs by blocking TLR2mediated innate signals, while the attenuated VZV vaccine strain enhanced secretion of Th1 cytokines (Gutzeit et al, 2010). Thus, different responses of DCs to the virulent and attenuated virus may underlie the differences in pathogenicity between them.…”

Toll-like receptor sensing of human herpesvirus infection

“…DCs infected with the JoSt strain of VZV and stimulated with lipoteichoic acid (LTA), a TLR2 agonist, secreted dramatically less IL-12 than DCs infected with the vaccine strain and challenged with the same TLR2 agonist (Gutzeit et al, 2010). IL-12 secretion from DCs is critical for the development of adaptive immune responses to infection.…”