Sunday, May 18, 2025
5/18/2025
Pellino1 as a regulator of antiviral immunity in the epidermis - SUMMARY Most adults are latently infected with at least one of the two herpes simplex viruses HSV-1 or HSV-2. Upon reactivation these viruses can cause painful skin and mucosal lesions. Numerous patient populations with compromised immune systems or skin barrier function are at risk of frequent or severe disease and thus greatly diminished quality of life. Atopic dermatitis is the most common chronic inflammatory skin condition and is associated with diminish antiviral immunity in the skin through mechanisms that are poorly understood. Drug resistant HSV strains can develop especially in transplant patients. Thus, there continue to be a need for improved treatment strategies that encompass the host immune status. IL-1 and IL-36 are pleotropic cytokines that can promote innate and adaptive immune responses. We recently demonstrated that both IL-1 and IL-36 play important roles in limiting disease severity in a mouse model of reactivation-like disease caused by HSV-1. Pellino1 (Peli1) is a ubiquitin ligase involved in IL-1/IL-36 and TLR signaling. Studies of RNA viruses in vivo have generated diverging conclusions regarding beneficial and detrimental functions of Pellino1. Using our previously established infection model, we find that HSV-1, a DNA virus, causes greater mortality and larger lesions in Pellino1 knockout mice than wild type. In Peli1-/- mice, the virus disseminates rapidly through the skin epidermis and hair follicles; thus, Pellino1 clearly has one or more protective immune functions in keratinocytes and the epidermis. RNA-seq analyses revealed surprising mechanistic insight. Our newly developed hypotheses will be tested in keratinocyte specific conditional knockout mice using the established mouse infection model. Further validation of concepts will be obtained through use of human and mouse conventional and organoid-like cell cultures. We will define how the studied mechanisms may limit viral replication in keratinocytes by preventing, for example, cellular entry and exit of mature viral particles. Improved insight into these antiviral mechanisms may underpin future research into immune dysfunction and drug development aimed at alleviating severe and/or persistent disease in at risk patient populations.
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