# Mechanisms of varicella virus dissemination

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $123,974

## Abstract

SUMMARY
Varicella zoster virus (VZV) is a highly contagious, neurotropic alpha herpes virus that causes varicella
(chickenpox). VZV establishes latency in the sensory ganglia from which it can reactivate to cause herpes zoster
(shingles), a painful disease that affects almost 1 million individuals in the United States annually. During primary
infection VZV is transmitted through the inhalation of viral particles, but the mechanisms by which VZV traffics
from the initial site of infection to the ganglia and skin remain unclear. Data from in vitro assays as well as in vivo
studies using severe-combined immunodeficient mice implanted with human fetal tissues (SCID-hu) strongly
suggest that T cells are highly susceptible to VZV infection and may play a critical role in VZV dissemination to
the skin and ganglia. However, the SCID-hu mouse model has two major limitations: 1) the lack of an adaptive
immune system and 2) the possibility that the strict human host specificity of VZV could have altered viral
behavior in this murine model. Additionally, in vitro studies of human tonsillar T cells were carried out using the
attenuated Oka vaccine strain, which may not adequately model the outcome of infection with wild type viral
strains. In this application, we propose to define the mechanisms by which VZV usurps T cells to spread by using
a rhesus macaque model that recapitulates the hallmarks of VZV infection. In this model, rhesus macaques are
intra-bronchially infected with Simian varicella virus (SVV), a homolog of VZV. We have demonstrated that lung-
resident T cells are susceptible and permissive to SVV infection. Additionally, memory T cells are detected in
the ganglia as early as 3 days post-infection, at the same time as viral DNA and before the detection of a viral-
specific T cell response. Although these observations establish a significant role for T cells in SVV spread
to the ganglia, as has been suggested for VZV, the mechanism by which varicella viruses hijack the
host's T cells to disseminate to latency sites remain poorly defined. In this application, we will address this
critical knowledge gap by first identifying transcriptional changes induced by SVV infection in T cells isolated
from the lung during acute infection using high throughput single cell RNA sequencing. Then, we will assess
alterations in metabolic and migratory function of SVV-infected T cells in vitro. Completion of the studies
proposed in this application will yield novel insight into viral-host interactions at the single cell level and will serve
as a model to investigate the pathogenesis of other T cell tropic viruses.

## Key facts

- **NIH application ID:** 9932898
- **Project number:** 5R21AI143301-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Ilhem Messaoudi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $123,974
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932898

## Citation

> US National Institutes of Health, RePORTER application 9932898, Mechanisms of varicella virus dissemination (5R21AI143301-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9932898. Licensed CC0.

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