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

点击翻译按钮获取中文摘要

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 management skills. My training plan will prepare me to become an academic professor leading a research program investigating virus-host interactions.