Pellino1 Restricts Herpes Simplex Virus Infections in the Epidermis and Dissemination to Sebaceous Glands

Nearly all adults are infected with one or more herpes viruses. The most common are herpes simplex virus (HSV)-1 and HSV-2, which upon reactivation can cause painful skin and mucosal erosions. Patients who are immune compromised often experience frequent, atypical, or chronic lesions and thus a greatly diminished QOL. Pellino1 is a ubiquitin ligase involved in IL-1 and toll-like receptor signaling; however, the role of Pellino1 in skin immunity against HSV is unknown. In this study, using the mouse-flank HSV-1 skin infection model, we show that Pellino1 has several critical functions during active viral replication. Peli1^‒/‒ mice succumb more than wild-type mice to systemic disease and develop larger zosteriform skin lesions along affected dermatomes. In Pellino1-deficient mice, the virus spread extensively through the epidermis and follicular infundibulum into sebaceous glands where sebocytes were found positive for the virus. The latter did not appear to involve a shift in how the virus migrated through the nervous system. Immunohistochemistry revealed delayed recruitment of myeloid and T cells to the infected epidermis in Peli1^‒/‒ mice. This was associated with decreased expression of the cytokine mRNAs Il1a, Il36b and 2610528A11Rik; the latter also known as Gpr15l. In conclusion, Pellino1 plays important roles in restricting viral dissemination, and the involved pathways may represent novel therapeutic targets in patients with frequent or chronic HSV infections.