IL-17c promotes peripheral nerve growth during human herpes simplex virus type 2 (HSV-2) infection

Abstract

Abstract During human HSV-2 infection, peripheral nerve destruction and sensory anesthesia are rarely developed, despite frequent virus reactivation. The mechanisms underlying this clinical observation are unclear. Here, we describe a novel interaction between HSV infected keratinocytes and the peripheral nerve system via IL-17c that promotes neurite growth and neuron survival during reactivations. Skin biopsies obtained during asymptomatic human HSV-2 reactivation exhibit a higher nerve fiber density in relation to biopsies obtained during the virological and clinical quiescent phase. Keratinocytes, the peripheral targets of HSV reactivation, produce IL-17c both in vivo during HSV-2 reactivation in humans and in vitro in primary cultures. Further characterization indicates that IL17RE, the receptor specific for IL-17c signaling, is expressed on nerve endings in human skin and on nerve fibers, glia cells and sensory neurons in human dorsal root ganglia. The addition of exogenous human IL-17c promotes neurite growth and branching and provides directional guidance in a microfluidic device. Furthermore, pretreatment of IL-17c reduces apoptosis in HSV-2 infected primary neurons. Taken together, these results suggest that IL-17c might function as a neurotrophic factor to induce peripheral nerve ending growth and protect neurons from apoptosis during HSV reactivation. This interaction provides a potential mechanism for the lack of clinical nerve damage from a lifelong recurrent neurotropic viral infection. It also highlights the role of immune cytokines in regulating the functions of the peripheral nervous system.