Mechanisms of neuronal infection by varicella-zoster virus (VZV) have been challenging to study due to the relatively strict human tropism of the virus and the paucity of tractable experimental models. Cellular mitogen-activated protein kinases (MAPKs) have been shown to play a role in VZV infection of nonneuronal cells, with distinct consequences for infectivity in different cell types. Here, we utilize several human neuronal culture systems to investigate the role of one such MAPK, the c-Jun N-terminal kinase (JNK), in VZV lytic infection and reactivation. We find that the JNK pathway is specifically activated following infection of human embryonic stem cell-derived neurons and that this activation of JNK is essential for efficient viral protein expression and replication. Inhibition of the JNK pathway blocked viral replication in a manner distinct from that of acyclovir, and an acyclovir-resistant VZV isolate was as sensitive to the effects of JNK inhibition as an acyclovir-sensitive VZV isolate in neurons. Moreover, in a microfluidic-based human neuronal model of viral latency and reactivation, we found that inhibition of the JNK pathway resulted in a marked reduction in reactivation of VZV. Finally, we utilized a novel technique to efficiently generate cells expressing markers of human sensory neurons from neural crest cells and established a critical role for the JNK pathway in infection of these cells. In summary, the JNK pathway plays an important role in lytic infection and reactivation of VZV in physiologically relevant cell types and may provide an alternative target for antiviral therapy. Varicella-zoster virus (VZV) has infected over 90% of people worldwide. While primary infection leads to the typically self-limiting condition of chickenpox, the virus can remain dormant in the nervous system and may reactivate later in life, leading to shingles or inflammatory diseases of the nervous system and eye with potentially severe consequences. Here, we take advantage of newer stem cell-based technologies to study the mechanisms by which VZV infects human neurons. We find that the c-Jun N-terminal kinase (JNK) pathway is activated by VZV infection and that blockade of this pathway limits lytic replication (as occurs during primary infection). In addition, JNK inhibition limits viral reactivation, exhibiting parallels with herpes simplex virus reactivation. The identification of the role of the JNK pathway in VZV infection of neurons reveals potential avenues for the development of alternate antiviral drugs.
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.
The neuropathogenesis of varicella-zoster virus (VZV) has been challenging to study due to the strict human tropism of the virus and the resultant difficulties in establishing tractable experimental models. In vivo, sensory neurons of the dorsal root ganglia and trigeminal ganglia serve as cellular niches that support viral latency, and VZV can subsequently reactivate from these cells to cause disease. Whether sensory neurons possess intrinsic properties that position them to serve as a reservoir of viral latency remains unknown. Here, we utilize a robust human sensory neuron system to investigate lytic infection and viral latency. We find that sensory neurons exhibit resistance to lytic infection by VZV. On the other hand, latent infection in sensory neurons is associated with an episomal-like configuration of viral DNA and expression of the VZV latency-associated transcript (VLT), thus closely mirroring the in vivo state. Moreover, despite the relative restriction in lytic infection, we demonstrate that viral reactivation is possible from latently infected sensory neurons. Taken together, our data suggest that human sensory neurons possess intrinsic properties that serve to facilitate their role as a latent reservoir of VZV.IMPORTANCEVaricella-zoster virus (VZV) has infected over 90% of people worldwide. Following primary infection, the virus can remain dormant in the nervous system and may reactivate later in life, with potentially severe consequences. Here, we develop a model of VZV infection in human sensory neurons in order to determine whether these cells are intrinsically positioned to support latency and reactivation. We find that human sensory neurons are relatively resistant to lytic infection, but can support latency and reactivation. Moreover, during in vitro latency human sensory neurons, but not other neurons, express the newly discovered VZV latency-associated transcript (VLT), thus closely mirroring the in vivo latent state. Taken together, these data indicate that human sensory neurons are uniquely positioned to support latency. We anticipate that this human sensory neuron model will serve to facilitate further understanding of the mechanisms of VZV latency and reactivation.
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