Antiviral and immunomodulatory effects of interferon lambda in the skin

ABSTRACT Type III interferons (IFN-λ) play a key role eliciting antiviral immunity at epithelial surfaces, controlling infections locally without the inflammatory immune pathology triggered by the more potent systemic type I IFN (IFN-αβ) response. However, the effects of IFN-λ in the skin have not been extensively investigated. Herpes simplex virus type 1 (HSV-1) infects epithelial cells and establishes a life-long infection in sensory neurons. Using a mouse skin infection model, we found that multiple lines of mice lacking IFN-λ signaling developed more severe HSV-1 skin lesions compared to wild-type mice. However, disease severity was uncoupled from viral loads in the skin, suggesting a role for IFN-λ in suppressing inflammatory immune pathology. We found that IFN-λ signaling in both keratinocytes and leukocytes was necessary for protection from severe skin disease and that Ifnlr1-/- mice exhibited greater neutrophil infiltration into HSV-1 skin lesions compared to WT mice. We hypothesize that IFN- λ protects against inflammatory pathology during HSV-1 infection by suppressing neutrophil recruitment and activation. The greatest burden of HSV-1 disease in humans results from reactivation of lifelong latent infections, rather than new infections. We have developed a simple and tractable mouse model to induce reactivation of latent HSV-1 from dorsal root ganglia which produces recurrent HSV-1 skin lesions. Using this model, we found that Ifnlr1-/- mice develop more severe reactivation disease compared to WT mice. Flaviviruses and other arboviruses are inoculated into the skin by blood-feeding mosquito or tick vectors. We found that IFN-λ signaling reduced viremia caused by Zika virus and Langat virus only when the viruses were inoculated in the skin, not when the skin barrier was bypassed by subcutaneous inoculation. Vector saliva is known to enhance arbovirus pathogenesis in part by recruiting neutrophils, a key IFN-λ responsive cell type. We hypothesize that IFN-λ signaling in the skin restricts flavivirus dissemination and that this effect is greater in the context of vector feeding. Aim 1: Define the mechanism by which IFN-λ restricts acute HSV-1 skin disease. 1A: define the IFN-λ responsive leukocyte populations that limit skin lesion severity. 1B: define the pathogenic immune responses suppressed by IFN-λ in the skin. 1C: investigate how IFN-λ signaling in keratinocytes limits HSV-1 skin disease. Aim 2: Define the mechanism by which IFN-λ restricts recurrent HSV-1 skin disease. 2A: define the role of IFN-λ specifically during HSV-1 recurrent disease. 2B: assess the kinetics of viral replication and skin lesion formation using live animal luminescence imaging. Aim 3: Define skin-specific effects of IFN-λ against mosquito-borne and tick-borne flaviviruses. 3A: define the IFN-λ responsive cell types that restrict replication of mosquito-borne flaviviruses and tick-borne flaviviruses in the skin. 3B: investigate the effect of vector saliva on IFN-λ mediated antiviral immunity in the skin.