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Simian varicella virus causes robust transcriptional changes in T cells that support viral replication.

ABSTRACT: Varicella zoster virus (VZV) causes varicella (chickenpox) during acute infection. Several studies have shown that T cells are early and preferential targets of VZV infection that play a critical role in disseminating VZV in to the skin and ganglia. However, the transcriptional changes that occur in VZV-infected T cells remain unclear due to limited access to clinical samples and robust translational animal models. In this study, we used a nonhuman primate model of VZV infection where rhesus macaques are infected with the closely related Simian Varicella Virus (SVV) to provide novel insights into VZV-T cell interactions. RNA sequencing of bronchial alveolar lavage-resident T cells isolated from infected rhesus macaques show that SVV infection alters expression of genes important for regulation of gene expression, cell cycle progression, metabolism, and antiviral immunity. These data provide insight into cellular processes that may support viral replication, facilitate SVV dissemination, and evade host defense.

SUBMITTER: Arnold N

PROVIDER: S-EPMC7114558 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Simian varicella virus causes robust transcriptional changes in T cells that support viral replication.

Arnold Nicole N Messaoudi Ilhem I

Virus research 20170601

Varicella zoster virus (VZV) causes varicella (chickenpox) during acute infection. Several studies have shown that T cells are early and preferential targets of VZV infection that play a critical role in disseminating VZV in to the skin and ganglia. However, the transcriptional changes that occur in VZV-infected T cells remain unclear due to limited access to clinical samples and robust translational animal models. In this study, we used a nonhuman primate model of VZV infection where rhesus mac ...[more]

PMID: 28698046

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Project description:Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression.ImportanceMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection.

Project description:Primary infection with varicella-zoster virus (VZV) causes varicella and the establishment of lifelong latency in sensory ganglion neurons. In one-third of infected individuals VZV reactivates from latency to cause herpes zoster, often complicated by difficult-to-treat chronic pain. Experimental infection of non-human primates with simian varicella virus (SVV) recapitulates most features of human VZV disease, thereby providing the opportunity to study the pathogenesis of varicella and herpes zoster in vivo. However, compared to VZV, the transcriptome and the full coding potential of SVV remains incompletely understood. Here, we performed nanopore direct RNA sequencing to annotate the SVV transcriptome in lytically SVV-infected African green monkey (AGM) and rhesus macaque (RM) kidney epithelial cells. We refined structures of canonical SVV transcripts and uncovered numerous RNA isoforms, splicing events, fusion transcripts and non-coding RNAs, mostly unique to SVV. We verified the expression of canonical and newly identified SVV transcripts in vivo, using lung samples from acutely SVV-infected cynomolgus macaques. Expression of selected transcript isoforms, including those located in the unique left-end of the SVV genome, was confirmed by reverse transcription PCR. Finally, we performed detailed characterization of the SVV homologue of the VZV latency-associated transcript (VLT), located antisense to ORF61. Analogous to VZV VLT, SVV VLT is multiply spliced and numerous isoforms are generated using alternative transcription start sites and extensive splicing. Conversely, low level expression of a single spliced SVV VLT isoform defines in vivo latency. Notably, the genomic location of VLT core exons is highly conserved between SVV and VZV. This work thus highlights the complexity of lytic SVV gene expression and provides new insights into the molecular biology underlying lytic and latent SVV infection. The identification of the SVV VLT homolog further underlines the value of the SVV non-human primate model to develop new strategies for prevention of herpes zoster.

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Simian varicella virus causes robust transcriptional changes in T cells that support viral replication.

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Simian varicella virus causes robust transcriptional changes in T cells that support viral replication.

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