Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia.
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.


OBJECTIVE
Many 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.
Graduate Program in Microbiology, University of California-Riverside, Riverside, California, USA.
Nicole
N
Arnold
Department of Botany and Plant Sciences, University of California-Riverside, Riverside, California, USA.
Thomas
T
Girke
Graduate Program in Genetics, Genomics and Bioinformatics, University of California-Riverside, Riverside, California, USA.
Suhas
S
Sureshchandra
Graduate Program in Microbiology, University of California-Riverside, Riverside, California, USA ilhem.messaoudi@ucr.edu.|Graduate Program in Genetics, Genomics and Bioinformatics, University of California-Riverside, Riverside, California, USA.|Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, California, USA.
Ilhem
I
Messaoudi
D000208:Acute Disease; D000818:Animals; D001370:Axonal Transport; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002644:Chickenpox / Q000821:virology; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D017950:Ganglia, Sensory / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D015870:Gene Expression; D006566:Herpesviridae Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000472:pathogenicity; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta; D055495:Neurogenesis; D018140:Varicellovirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D014779:Virus Replication
D004279:DNA, Viral
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