Uncovering Mechanisms of Varicella Zoster Virus Pathogenesis Using a Rhesus Macaque Model
- Author(s): Arnold, Nicole Justine
- Advisor(s): Messaoudi, Ilhem
- et al.
Varicella Zoster Virus is neurotropic alpha herpesvirus that causes varicella (chickenpox) and establishes latency in the sensory ganglia. Reactivation results in herpes zoster (HZ, shingles), a painful and debilitating disease that affects 1 million people in the US each year. FDA approved vaccines reduce the incidence of both varicella and HZ; however, they induce short-lived immunity and are contraindicated for individuals who are immunosuppressed. The development of more efficacious vaccines has been hampered by the fact the VZV is a strictly human pathogen which has hindered the development of a robust translational animal model. Previous studies from our laboratory have shown that intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), the homolog of VZV, recapitulates the hallmarks of VZV infection in humans. In this dissertation, we use this animal model to investigate the host-pathogen interactions in the lung and sensory ganglia (sites of primary infection and latency) as well as the role that T cells play in SVV tropism and reactivation. First, we show that SVV infection causes severe lung damage characterized initially by significant immune infiltration, an up-regulation of genes involved in antiviral immunity and a down-regulation of genes involved in lung development. This robust host response correlates with a decrease in viral loads and is then followed by an increase in genes important for tissue repair. Next, we show that SVV DNA and transcripts are detected in the ganglia 3 days post-infection (DPI), before the development of varicella. Interestingly, CD4 and CD8 T cells were also shown to infiltrate the sensory ganglia 3 DPI; before the development of cell mediated immunity, which suggests a role for T cells in SVV tropism into the ganglia. SVV acute infection of the ganglia induces robust gene expression changes indicative of an innate antiviral immune response along with a down-regulation of genes that play a role in the nervous system function. Interestingly, genes important for neuron development remained down-regulated 100 days post infection suggesting that SVV latency leads to a long-lived remodeling of the ganglia transcriptional profile. Next, given the crucial role that T cell play in SVV dissemination, we characterized the transcriptional changes that SVV infection induces within them. This analysis revealed that SVV alters expression of several genes that may support viral replication and dissemination. Lastly, we report that the decline of both CD4 and CD8 T cell immunity followed by stress can lead to SVV reactivation, which also causes long-lasting gene expression changes in the ganglia transcriptome, indicative of neuronal damage. These findings provide novel insights into the host pathogen interactions of VZV during acute infection and guide efforts toward more efficacious vaccines and therapeutics.