Herpes Simplex Virus Type 1 Infects Schwann Cells via Exosomal CD81 , Exploits the MVB –Exosomal Pathway, and Induces Demyelination

Herpes simplex virus type 1 (HSV1) is a highly prevalent neurotropic pathogen that causes a wide range of diseases, including cold sores, blinding keratitis, and life-threatening encephalitis. HSV1 first replicates in the epithelial cells of the oronasal mucosa and enters the peripheral nervous system (PNS) to establish latency in sensory neurons. HSV1 persistence in the host has been associated with neurological diseases, including multiple sclerosis. Several in vivo studies reported that HSV1 infection can cause PNS and CNS demyelination; however, the viral pathogenesis remains unclear. Schwann cells (SCs) are the main myelinating cells of the PNS, but it is unknown whether they can be infected by HSV1. Here, we demonstrated that HSV1 productively infects SCs, but the infection efficiency is viral strain-dependent. We showed that HSV1 downregulates the expression of the myelin-related PMP22 gene at late stages of infection. In vivo studies confirmed that HSV1 infection induces PNS demyelination with a clear loss of myelin basic protein (MBP) expression observed in infected tissues together with the presence of demyelinating lesions. Besides, we demonstrated that HSV1 hijacks the multivesicular bodies (MVB)-exosomal pathway in SCs in vitro for efficient infection and spread. TEM confirmed the presence of MVB containing virions and the release of extracellular vesicles with virions near the plasma membrane. By function-blocking antibody and siRNA treatments, we demonstrated that HSV1 uses tetraspanin CD81 as the main entry receptor in SCs. Overall, this study provides new insights into the role of SCs in the pathogenesis of herpesviruses and viral-induced demyelination processes.