# Temporal Functions of Interferon Lambda Signaling During Acute and Recurrent Herpes Simplex Virus Type 1 Skin Infection

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $35,552

## Abstract

PROJECT SUMMARY/ABSTRACT
 The skin is a complex physical and immunologic epithelial barrier responsible for protecting the host
from external threats, including viral pathogens. Specialized immune factors—including skin-specific immune
cells and cytokines—help mediate a balanced skin immune response that prevents pathogen invasion while
maintaining barrier integrity. Type III interferons (IFN-λ) are a class of antiviral cytokines that have been
characterized to mediate this balanced, antiviral immune response at epithelial barriers; however, their role in
the skin is not well-characterized. Herpes simplex virus type 1 (HSV-1) can infect the skin, and subsequently
sensory neurons where it causes a lifelong, persistent infection. HSV-1 infects more than half of US adults and
primarily manifests as orofacial lesions, but also causes keratitis, blindness, and encephalitis. We will examine
IFN-λ-mediated immunity in the skin against acute and recurrent HSV-1 skin infection.
 We found that mice lacking the IFN-λ receptor (Ifnlr1-/-) developed more severe acute skin disease
compared to WT mice, independent of a direct effect on viral replication, and that loss of IFN-λ signaling in
keratinocytes recapitulated this phenotype. We found also found that treating keratinocytes with IFN-λ induced
the production of the cytokine thymic stromal lymphopoietin (TSLP), a known promoter of regulatory T cell
(Treg) functions. In Aim 1, I will test my hypothesis that IFN-λ-induced TSLP production by keratinocytes
promotes regulatory T cell (Treg) function and restricts inflammatory pathology during acute disease. I will
evaluate the role of an IFN-λ-keratinocyte-Treg signaling axis in protecting from acute HSV-1 skin pathology,
identify skin immune populations modulated by IFN-λ signaling in keratinocytes, and define IFN-λ-dependent
transcriptional responses in primary murine keratinocytes.
 We also found that Ifnlr1-/- mice exhibited delayed viral clearance and developed more severe recurrent
HSV-1 skin lesions compared to WT mice, suggesting a role for IFN-λ signaling in promoting adaptive immune
responses in the skin. In Aim 2, I will test my hypothesis that IFN-λ signals through DCs to promote generation
of HSV-1-specific, skin-resident memory CD8+ T cells that restrict HSV-1 spread and virus-induced
inflammation during recurrent HSV-1 skin disease. I will determine how of IFN-λ signaling specifically in
leukocytes affects localization of reactivated HSV-1 throughout the dermatome, skin immunopathology, and
the skin-resident and infiltrating immune profiles during recurrent HSV-1 infection
 My proposed project will investigate viral immunology in the skin and our findings can be used to
develop therapies for viral- and immune-mediated skin pathologies. My proposed training plan, under guidance
from Dr. Helen Lazear and Dr. Jason Whitmire, will give me research experience in virology and immunology
while developing my teaching, mentoring, leadership, and project ma...

## Key facts

- **NIH application ID:** 10536270
- **Project number:** 1F31AI167502-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Drake Thomas Philip
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $35,552
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536270

## Citation

> US National Institutes of Health, RePORTER application 10536270, Temporal Functions of Interferon Lambda Signaling During Acute and Recurrent Herpes Simplex Virus Type 1 Skin Infection (1F31AI167502-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10536270. Licensed CC0.

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