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

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. Although 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 the 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.

Clinical Manifestations and Pathogenesis of Acute Necrotizing Encephalopathy: The Interface Between Systemic Infection and Neurologic Injury.

Acute necrotizing encephalopathy (ANE) is a devastating neurologic condition that can arise following a variety of systemic infections, including influenza and SARS-CoV-2. Affected individuals typically present with rapid changes in consciousness, focal neurological deficits, and seizures. Neuroimaging reveals symmetric, bilateral deep gray matter lesions, often involving the thalami, with evidence of necrosis and/or hemorrhage. The clinical and radiologic picture must be distinguished from direct infection of the central nervous system by some viruses, and from metabolic and mitochondrial disorders. Outcomes following ANE are poor overall and worse in those with brainstem involvement. Specific management is often directed toward modulating immune responses given the potential role of systemic inflammation and cytokine storm in potentiating neurologic injury in ANE, though benefits of such approaches remain unclear. The finding that many patients have mutations in the nucleoporin gene RANBP2, which encodes a multifunctional protein that plays a key role in nucleocytoplasmic transport, may allow for the development of disease models that provide insights into pathogenic mechanisms and novel therapeutic approaches.