Measles skin rash: Infection of lymphoid and myeloid cells in the dermis precedes viral dissemination to the epidermis

Author summary Several viral infections are associated with skin rash, including parvovirus B19, human herpesvirus type 6, dengue virus and rubella virus. However, the archetype virus infection that leads to skin rash is measles. Although all of these viral exanthemata often appear similar, their pathogenesis is different. In the case of measles, the appearance of skin rash is a sign that the immune system is clearing MV-infected cells from the skin. How the virus reaches the skin and is locally disseminated remains unknown. Here, we combine observations and expertise from pathologists, dermatologists, virologists and immunologists to delineate the pathogenesis of measles skin rash. We show that MV infection of dermal myeloid and lymphoid cells precedes viral dissemination to the epidermal leukocytes and keratinocytes. We speculate that immune-mediated clearance of these infected cells results in hyperemia and edema, explaining the redness of the skin and the slightly elevated spots of the morbilliform rash.Measles is characterized by fever and a maculopapular skin rash, which is accompanied by immune clearance of measles virus (MV)-infected cells. Histopathological analyses of skin biopsies from humans and non-human primates (NHPs) with measles rash have identified MV-infected keratinocytes and mononuclear cells in the epidermis, around hair follicles and near sebaceous glands. Here, we address the pathogenesis of measles skin rash by combining data from experimentally infected NHPs,ex vivoinfection of human skin sheets andin vitroinfection of primary human keratinocytes. Analysis of NHP skin samples collected at different time points following MV inoculation demonstrated that infection in the skin precedes onset of rash by several days. MV infection was detected in lymphoid and myeloid cells in the dermis before dissemination to the epidermal leukocytes and keratinocytes. These data were in good concordance withex vivoMV infections of human skin sheets, in which dermal cells were more targeted than the epidermal ones. To address viral dissemination to the epidermis and to determine whether the dissemination is receptor-dependent, we performed experimental infections of primary keratinocytes collected from healthy donors. These experiments demonstrated that MV infection of keratinocytes is mainly nectin-4-dependent, and differentiated keratinocytes, which express higher levels of nectin-4, are more susceptible to MV infection than proliferating keratinocytes. Based on these data, we propose a model to explain measles skin rash: migrating MV-infected lymphocytes initiate the infection of dermal skin-resident CD150(+)immune cells. The infection is subsequently disseminated from the dermal papillae to nectin-4(+)keratinocytes in the basal epidermis. Lateral spread of MV infection is observed in the superficial epidermis, most likely due to the higher level of nectin-4 expression on differentiated keratinocytes. Finally, MV-infected cells are cleared by infiltrating immune cells, causing hyperemia and edema, which give the appearance of morbilliform skin rash.