Impact of Varicella-Zoster Virus on Dendritic Cell Subsets in Human Skin during Natural Infection

University of Sydney, Discipline of Infectious Diseases and Immunology, Blackburn Building, Room 601, New South Wales 2006, Australia.
Journal of Virology (Impact Factor: 4.44). 04/2010; 84(8):4060-72. DOI: 10.1128/JVI.01450-09
Source: PubMed


Varicella-zoster virus (VZV) causes varicella and herpes zoster, diseases characterized by distinct cutaneous rashes. Dendritic
cells (DC) are essential for inducing antiviral immune responses; however, the contribution of DC subsets to immune control
during natural cutaneous VZV infection has not been investigated. Immunostaining showed that compared to normal skin, the
proportion of cells expressing DC-SIGN (a dermal DC marker) or DC-LAMP and CD83 (mature DC markers) were not significantly
altered in infected skin. In contrast, the frequency of Langerhans cells was significantly decreased in VZV-infected skin,
whereas there was an influx of plasmacytoid DC, a potent secretor of type I interferon (IFN). Langerhans cells and plasmacytoid
DC in infected skin were closely associated with VZV antigen-positive cells, and some Langerhans cells and plasmacytoid DC
were VZV antigen positive. To extend these in vivo observations, both plasmacytoid DC (PDC) isolated from human blood and Langerhans cells derived from MUTZ-3 cells were shown
to be permissive to VZV infection. In VZV-infected PDC cultures, significant induction of alpha IFN (IFN-α) did not occur,
indicating the VZV inhibits the capacity of PDC to induce expression of this host defense cytokine. This study defines changes
in the response of DC which occur during cutaneous VZV infection and implicates infection of DC subtypes in VZV pathogenesis.

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    • "DC resident in the skin are almost exclusively of the myeloid lineage. Recently, a distinctly different subset, plasmacytoid dendritic cells (pDC), normally absent in skin, were shown to migrate to inflamed skin lesions of autoimmune reactions such as psoriasis (Albanesi et al., 2010; Nestle et al., 2005) and lupus erythematosus (Farkas et al., 2001; Meller et al., 2005), as well as to virally induced lesions of herpes simplex (Donaghy et al., 2009; Peng et al., 2009) and varicella (Gerlini et al., 2006; Huch et al., 2010). pDC are thought to play a central role in the response to viruses through their capacity to produce high amounts of IFNα, which is primarily induced by microbial nucleic acids signalling via Toll-Like Receptor (TLR) 7 and 9 (Gilliet et al., 2008). "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are rarely present in normal skin but have been shown to infiltrate lesions of infections or autoimmune disorders. Here, we report that several DC subsets including CD123(+) BDCA-2/CD303(+) pDCs accumulate in the dermis in indurations induced by the tuberculin skin test (TST), used to screen immune sensitization by Mycobacterium tuberculosis. Although the purified protein derivate (PPD) used in the TST did not itself induce pDC recruitment or IFN-α production, the positive skin reactions showed high expression of the IFN-α-inducible protein MxA. In contrast, the local immune response to PPD was associated with substantial cell death and high expression of the cationic antimicrobial peptide LL37, which together can provide a means for pDC activation and IFN-α production. In vitro, pDCs showed low uptake of PPD compared with CD11c(+) and BDCA-3/CD141(+) myeloid DC subsets. Furthermore, supernatants from pDCs activated with LL37-DNA complexes reduced the high PPD uptake in myeloid DCs, as well as decreased their capacity to activate T-cell proliferation. Infiltrating pDCs in the TST reaction site may thus have a regulatory effect upon the antigen processing and presentation functions of surrounding potent myeloid DC subsets to limit potentially detrimental and excessive immune stimulation.
    Full-text · Article · Aug 2011 · Journal of Investigative Dermatology
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    ABSTRACT: L’infection primaire au VZV et la réactivation du VZV latent sont fréquemment observées à la suite d’une GMO ou d’une GSCO, ce qui cause de sérieuses complications chez le patient. Pour prévenir ces infections, une prophylaxie antivirale est administrée systématiquement chez tous les greffés de MO ou de SCO, alors qu’il n’existe aucun consensus sur la durée optimale d’une telle prophylaxie. Pour résoudre ce problème, notre objectif est de développer et valider une méthode ELISpot-VZV-IFN- qui permettra de suivre la reconstitution de l’immunité à médiation cellulaire anti-VZV chez les receveurs de GMO ou de GSCO et ainsi déterminer le moment opportun pour réduire ou interrompe la prophylaxie chez les receveurs de greffes de CSH. Dans un premier temps, des valeurs-seuil de la réponse à médiation cellulaire anti-VZV chez la population pédiatrique saine ont dû être générées. À la lumière de nos résultats, un enfant avec un résultat ELISpot-VZV-IFN- > 190.0 SFU/106 PBMC devrait être protégé contre une possible infection à VZV. Pour valider cette étude, une étude prospective de la reconstitution immunitaire anti-VZV a été effectuée chez 9 enfants greffés de MO ou de SCO. Nos résultats préliminaires ont montré qu’il n’y avait eu aucune reconstitution significative de l’immunité à médiation cellulaire anti-VZV dans les 18 premiers mois post-transplantation chez 8 de ces 9 enfants. Les résultats de ces expériences vont fournir d’importantes informations quant à la reconstitution de l’immunité anti-VZV à la suite d’une GMO ou d’une GSCO et pourraient permettre l’amélioration des soins apportés aux receveurs de GMO ou de GSCO. Primary infection with VZV and reactivation of latent VZV are commonly observed following BMT and UCBT, leading to serious complications in patients. As a result, antiviral prophylaxis is systematically administered to BMT and UCBT recipients, yet there is no consensus that defines its optimal duration. To resolve this problem, our objective was to develop and validate a VZV-IFN--ELISpot with which reconstitution of VZV immunity can be followed in BMT and UCBT recipients, providing clinicians a practical tool to gauge the need for and adjust antiviral prophylaxis in individual HSCT recipients. First of all, threshold values for anti-VZV immunity in healthy pediatric subjects were generated. Based on our results, a child exhibiting > 190.0 VZV-specific SFU /106 PBMC should be protected against a possible VZV infection. To validate these results, a prospective study on the recovery of VZV-specific T cell immunity was performed on 9 children following BMT or UCBT. Preliminary results demonstrated that there was no significant recovery of VZV-specific T cell immunity in the first 18 months post-transplantation in 8 of 9 cases. Results of these experiments will yield important new information regarding reconstitution of anti-VZV immunity following BMT and UCBT and could lead to improvements in clinical management of BMT and UCBT recipients.
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    ABSTRACT: The capacity of varicella zoster virus (VZV) to cause varicella (chickenpox) relies upon multiple steps, beginning with inoculation of the host at mucosal sites with infectious virus in respiratory droplets. Despite the presence of a powerful immune defense system, this virus is able to disseminate from the site of initial infection to multiple sites, resulting in the emergence of distinctive cutaneous vesiculopustular lesions. Most recently, it has been proposed that the steps leading to cutaneous infection include VZV infecting human tonsillar CD4(+) T cells that express skin homing markers that allow them to transport VZV directly from the lymph node to the skin during the primary viremia. It has also been proposed that dendritic cells (DC) of the respiratory mucosa may be among the first cells to encounter VZV and these cells may transport virus to the draining lymph node. These various virus-host cell interactions would all need to occur in the face of an intact host immune response for the virus to successfully cause disease. Significantly, following primary exposure to VZV, there is a prolonged incubation period before emergence of skin lesions, during which time the adaptive immune response is delayed. For these reasons, it has been proposed that VZV must encode functions which benefit the virus by evading the immune response. This chapter will review the diverse array of immunomodulatory mechanisms identified to date that VZV has evolved to at least transiently limit immune recognition.
    No preview · Article · Jan 2010 · Current topics in microbiology and immunology
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