Nectin-1 Is an Entry Mediator for Varicella-Zoster Virus Infection of Human Neurons

Abstract

Varicella zoster virus (VZV) maintains lifelong latency in neurons following initial infection and can subsequently be reactivated to result in herpes zoster or severe neurological manifestations such as encephalitis. Mechanisms of VZV neuropathogenesis have been challenging to study due to the strict human tropism of the virus. While neuronal entry mediators of other herpesviruses, including herpes simplex virus, have been identified, little is known regarding how VZV enters neurons. Here, we utilize a human stem cell based neuronal model to characterize cellular factors that mediate entry. Through transcriptional profiling of infected cells, we identify the cell adhesion molecule nectin-1 as a candidate mediator of VZV entry. Nectin-1 is highly expressed in the cell bodies and axons of neurons. Either knockdown of endogenous nectin-1 or incubation with soluble forms of nectin-1 produced in mammalian cells results in a marked decrease in infectivity of neurons. Notably, while addition of soluble nectin-1 during viral infection inhibits infectivity, addition after infection has no effect on infectivity. Ectopic expression of human nectin-1 in a cell line resistant to productive VZV infection confers susceptibility to infection. In summary, we have identified nectin-1 as a neuronal entry mediator of VZV. IMPORTANCE Varicella zoster virus (VZV) causes chickenpox, gains access to neurons during primary infection where it resides lifelong, and can later be reactivated. Reactivation is associated with shingles and postherpetic neuralgia, as well as with severe neurologic complications including vasculitis and encephalitis. Although the varicella vaccine substantially decreases morbidity and mortality associated with primary infection, the vaccine cannot prevent development of neuronal latency and vaccinated populations are still at risk for reactivation. Furthermore, immunocompromised individuals are at higher risk for VZV reactivation and associated complications. Little is known regarding how VZV enters neurons. Here, we identify nectin-1 as an entry mediator of VZV in human neurons. Identification of nectin-1 as a neuronal VZV entry mediator could lead to improved treatments and preventative measures to reduce VZV related morbidity and mortality.

Herpes zoster: A Review of Clinical Manifestations and Management

“…VZV has been detected in dorsal root ganglia, cranial nerve ganglia, and various autonomic ganglia in the enteric nervous system, and in astrocytes. Nectin-1, which is highly expressed in neurons, seems to be involved in viral entry of axons and cell bodies [7].…”

Single amino acid mutation of nectin-1 provides remarkable resistance against lethal pseudorabies virus infection in mice

“…There is no significant difference between F129A and 135 KO in the resistances against intranasal infection with higher dose of PRV (50 LD 50 ) ( P =0.789). Phenylalanine 129 of nectin-1 V-domain is most important as interfacing to the gD of alphaherpesvirus including PRV in vitro [ 8 , 17 , 27 ]. In particular, it has been indicated that mutation of F129A inhibits nectin-1 binding to gD and viral entry [ 8 , 17 , 27 ].…”

“…Phenylalanine 129 of nectin-1 V-domain is most important as interfacing to the gD of alphaherpesvirus including PRV in vitro [ 8 , 17 , 27 ]. In particular, it has been indicated that mutation of F129A inhibits nectin-1 binding to gD and viral entry [ 8 , 17 , 27 ]. Our present results seen with F129A nectin-1 mouse strongly support the results provided by these in vitro experiments.…”

“…Recent studies have shown that phenylalanine 129, located at the tip of extracellular loop structure of the nectin-1, protrudes to bind viral gD and is key to alphaherpesvirus-cell binding [ 8 , 17 , 27 ]. Furthermore, the phenylalanine 129 to alanine (F129A) mutation was reported to almost completely inhibit gD/nectin-1 binding and to affect cell fusion.…”

“…(50 LD50) (P = 0.789). Phenylalanine 129 of nectin-1 V-domain is most important as interfacing to the gD of alphaherpesvirus including PRV in vitro [8,17,27]. In particular, it has been indicated that mutation of F129A inhibits nectin-1 binding to gD and viral entry [8,17,27].…”