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See detailORF9p phosphorylation by ORF47p is crucial for the formation and egress of the Varicella-zoster virus (VZV) viral particles.
Riva, Laura ULg; Thiry, Marc ULg; BONTEMS, Sébastien ULg et al

in Journal of Virology (2013), 87(5), 2868-2881

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully ... [more ▼]

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully assembled before being released from the infected cell. The Varicella-zoster virus (VZV) protein coded by ORF9 (ORF9p) is an essential tegument protein and, even though its mRNA is the most expressed during the productive infection, little is known about its functions. Using a GalK positive/negative selection technique, we modified a BAC containing the complete VZV genome creating viruses expressing mutant versions of ORF9p.We showed that ORF9p is hyper-phosphorylated during the infection, especially through its interaction with the viral Ser/Thr kinase ORF47p; we identified a consensus site within ORF9p recognized by ORF47p and demonstrated its importance for ORF9p phosphorylation. Strikingly, an ultra-structural analysis revealed that the mutation of this consensus site (Glutamate 85 to Arginine) strongly affects viral assembly and release, reproducing ORF47 kinase dead VZV phenotype. It also slightly diminishes the infectivity towards immature dendritic cells. Taken together, our results identify ORF9p as a new viral substrate of ORF47p and suggest a determinant role of this phosphorylation for viral infectivity, especially during the process of viral particle formation and egress. [less ▲]

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See detailPrimary Versus Secondary Failure After Varicella Vaccination: Implications for Interval Between 2 Doses
Bonanni, Paolo; Gershon, Anne; Gershon, Michael et al

in Pediatric Infectious Disease Journal (2013), 32(7), 305-313

Background: Two-dose varicella vaccination is recommended for optimal control of varicella in populations with high (>90%) 1-dose coverage. Optimal timing of the second dose may depend on whether ... [more ▼]

Background: Two-dose varicella vaccination is recommended for optimal control of varicella in populations with high (>90%) 1-dose coverage. Optimal timing of the second dose may depend on whether breakthrough varicella results from primary vaccine failure (no protective immunity after vaccination) or secondary vaccine failure (waning protective immunity). Methods: Published literature (1995 to 2012) on vaccine failure after varicella vaccination cited in PubMed and other online sources was reviewed. Results: Nineteen publications detailed 21 varicella outbreaks with breakthrough varicella rates ranging from 0% to 42%; the publications showed no consistent trend between breakthrough varicella rate and time since vaccination. Conclusions: Literature to date indicates a relatively high rate of primary vaccine failure and limited evidence of secondary vaccine failure among 1-dose varicella vaccine recipients, suggesting that a short interval between 2 doses might be preferable in countries considering implementation of universal varicella vaccination to reduce breakthrough varicella. However, any potential disruption to well-established vaccination schedules should be considered. [less ▲]

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See detailThe c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process
Lecat, Aurore ULg; Di Valentin, Emmanuel ULg; Somja, Joan ULg et al

in Journal of Biological Chemistry (2012), 287(35), 29213-26

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]

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See detailThe varicella-zoster virus ORF47 kinase interferes with host innate immune response by inhibiting the activation of IRF3.
Vandevenne, Patricia ULg; Lebrun, Marielle ULg; El Mjiyad, Nadia et al

in PLoS ONE (2011), 9(2),

The innate immune response constitutes the first line of host defence that limits viral spread and plays an important role in the activation of adaptive immune response. Viral components are recognized by ... [more ▼]

The innate immune response constitutes the first line of host defence that limits viral spread and plays an important role in the activation of adaptive immune response. Viral components are recognized by specific host pathogen recognition receptors triggering the activation of IRF3. IRF3, along with NF-kappaB, is a key regulator of IFN-beta expression. Until now, the role of IRF3 in the activation of the innate immune response during Varicella-Zoster Virus (VZV) infection has been poorly studied. In this work, we demonstrated for the first time that VZV rapidly induces an atypical phosphorylation of IRF3 that is inhibitory since it prevents subsequent IRF3 homodimerization and induction of target genes. Using a mutant virus unable to express the viral kinase ORF47p, we demonstrated that (i) IRF3 slower-migrating form disappears; (ii) IRF3 is phosphorylated on serine 396 again and recovers the ability to form homodimers; (iii) amounts of IRF3 target genes such as IFN-beta and ISG15 mRNA are greater than in cells infected with the wild-type virus; and (iv) IRF3 physically interacts with ORF47p. These data led us to hypothesize that the viral kinase ORF47p is involved in the atypical phosphorylation of IRF3 during VZV infection, which prevents its homodimerization and subsequent induction of target genes such as IFN-beta and ISG15. [less ▲]

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See detailVaricella zoster virus infection: not always benign...but preventable
Sadzot, Catherine ULg

Conference (2005, October 12)

Varicella-Zoster virus (VZV) is a Herpesvirus responsible for both varicella or chickenpox, a common and highly contagious childhood infectious disease and zoster or shingles, a clinical manifestation of ... [more ▼]

Varicella-Zoster virus (VZV) is a Herpesvirus responsible for both varicella or chickenpox, a common and highly contagious childhood infectious disease and zoster or shingles, a clinical manifestation of the viral reactivation, whose frequency increases with age. VZV infection is generally and wrongly regarded as a benign childhood disease: although it remains mild in the vast majority of cases, it can be associated with complications such as secondary skin bacterial infection, pneumonia, central nervous system dysfunction or Reye’s syndrome, and can even be occasionally fatal. The seriousness of VZV infection and its impact on health economic issues is becoming clearer as epidemiologic and pharmacoeconomic data become available. However, varicella is a vaccine preventable infectious disease since a live attenuated varicella vaccine based on the Oka Japanese VZV strain vaccine has been developed in the 1970s. The most widely used vaccine are Varilrix (GlaxoSmithKine) and Varivax (Merck & Co). A routine varicella vaccination programme targeting all healthy individuals over 1 year of age has been initiated in the US in 1995 and more recently in Canada and Australia. Vaccination is also recommended for susceptible healthy individuals at high risk if exposure. After a 10 years US experience, the vaccines have been shown to have a very good safety profile, to be well-tolerated and highly immunogenic and to provide around 85% protection against illness. When contracted after vaccination, what happens in a low percentage or cases, the disease remains mild and referred to as breakthrough. Immunity appears to assure a long-term protection. Although such a universal childhood vaccination as well as a vaccination of adults and adolescents without history of chickenpox is recommended by the WHO, Europe appears to be more reluctant to varicella vaccination. Due to health policies that are different from one European country to another, the situation is not yet uniform. Although varicella vaccine is actually licensed and recommended for high risk patients in most European countries, it has been included in a routine immunisation schedule solely in Germany in July 2004 and more recently in Sicily. The reluctance to the introduction of varicella vaccination is certainly due to the concern that low levels of coverage could increase the risk of delayed and thus more severe disease. The likelihood of achieving a high coverage rate, that could lead to a herd immunity and therefore avoid the problem of age-shift should be improved with a tetravalent vaccine which combine the existing measles-mums-rubella (MMR) vaccine for which high coverage levels are usually achieved with the varicella vaccine. Such a combined approach has already been approved by the FDA and has received a positive opinion at the European Medicines Agency. It will certainly help to implement, in the near future, the universal varicella vaccination. [less ▲]

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See detailVaricella-zoster virus IE63 protein represses the basal transcription machinery by disorganizing the pre-initiation complex
Di Valentin, Emmanuel ULg; Bontems, Sébastien ULg; Habran, Lionel ULg et al

in Biological Chemistry (2005), 386(3), 255-267

Using transient transfection assays, regulation properties of varicella-zoster virus (VZV)-encoded IE63 protein were analyzed on several VZV immediate early (ORF4), early (ORF28) and late (ORF67 ... [more ▼]

Using transient transfection assays, regulation properties of varicella-zoster virus (VZV)-encoded IE63 protein were analyzed on several VZV immediate early (ORF4), early (ORF28) and late (ORF67) promoters. IE63 was shown to repress the basal activity of most of the promoters tested in epithelial (Vero) and neuronal (ND7) cells to various extents. Trans -repressing activities were also observed on heterologous viral and cellular promoters. Since a construct carrying only a TATA box sequence and a series of wild-type or mutated interleukin (IL)-8 promoters was also repressed by IE63, the role of upstream regulatory elements was ruled out. Importantly, the basal activity of a TATA-less promoter was not affected by IE63. Using a series of IE63 deletion constructs, amino acids 151-213 were shown to be essential to the transrepressing activity in Vero cells, while in ND7 cells the essential region extended to a much larger carboxy-terminal part of the protein. We also demonstrate that IE63 is capable of disrupting the transcriptional pre-initiation complex and of interacting with several general transcription factors. The central and carboxy-terminal domains of IE63 are important for these effects. Altogether, these results demonstrate that IE63 protein is a transcriptional repressor whose activity is directed towards general transcription factors. [less ▲]

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