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

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 vivo infection of human skin sheets and in vitro infection 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 with ex vivo MV infections of human skin sheets, in which dermal cells were more targeted than the epidermal cells. 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

Interferon-induced Transmembrane Protein 1 restricts replication of virus that enter cells via the plasma membrane

The acute anti-viral response is mediated by a family of interferon stimulated genes (ISG), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with increased susceptibility to viral infections. One family of ISGs with anti-viral function are the interferon-inducible transmembrane proteins (IFITM) of which IFITM3 has been studied extensively. By contrast, IFITM1 has not been studied in detail. Since IFITM1 can localise to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of Paramyxoviridae and Pneumoviridae, including Respiratory Syncytial Virus (RSV), mumps virus and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localisation for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localisation of the protein and reduced anti-viral activity. Screening published datasets, twelve rare non-synonymous SNPs were identified in human IFITM1, some of which are in the CIL domain. Using an Ifitm1-/- knock-out mouse we show that RSV infection was more severe, thereby extending the range of viruses restricted in vivo by IFITM proteins and suggesting overall that IFITM1 is broadly anti-viral and this anti-viral function is associated with cell surface localisation.IMPORTANCE Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane is Interferon inducible transmembrane protein 1 (IFITM1). Here we demonstrate that IFITM1 can restrict a range of viruses that enter via the plasma membrane. Mutant IFITM1 proteins that were unable to localise to the plasma membrane did not restrict viral infection. We also observed for the first time that IFITM1 plays a role in vivo, Ifitm1-/- knock-out mice were more susceptible to viral lung infection. This data contributes to our understanding of how ISG prevent viral infections

Interferon-induced transmembrane protein 1 restricts replication of virus that enter cells via the plasma membrane

The acute anti-viral response is mediated by a family of interferon stimulated genes (ISG), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with increased susceptibility to viral infections. One family of ISGs with anti-viral function are the interferon-inducible transmembrane proteins (IFITM) of which IFITM3 has been studied extensively. By contrast, IFITM1 has not been studied in detail. Since IFITM1 can localise to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of Paramyxoviridae and Pneumoviridae, including Respiratory Syncytial Virus (RSV), mumps virus and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localisation for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localisation of the protein and reduced anti-viral activity. Screening published datasets, twelve rare non-synonymous SNPs were identified in human IFITM1, some of which are in the CIL domain. Using an Ifitm1-/- knock-out mouse we show that RSV infection was more severe, thereby extending the range of viruses restricted in vivo by IFITM proteins and suggesting overall that IFITM1 is broadly anti-viral and this anti-viral function is associated with cell surface localisation.IMPORTANCE Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane is Interferon inducible transmembrane protein 1 (IFITM1). Here we demonstrate that IFITM1 can restrict a range of viruses that enter via the plasma membrane. Mutant IFITM1 proteins that were unable to localise to the plasma membrane did not restrict viral infection. We also observed for the first time that IFITM1 plays a role in vivo, Ifitm1-/- knock-out mice were more susceptible to viral lung infection. This data contributes to our understanding of how ISG prevent viral infections