Purpose of review Varicella zoster virus (VZV) causes varicella, establishes latency, then reactivates to produce herpes zoster. VZV reactivation can also cause central nervous system (CNS) disease with or without rash. Herein, we review these CNS diseases, pathogenesis, diagnosis, and treatment. Recent findings The most common CNS manifestation of VZV infection is vasculopathy that presents as headache, cognitive decline, and/or focal neurological deficits. VZV vasculopathy has also been associated with cerebral amyloid angiopathy and moyamoya syndrome. Rarely, VZV will produce a meningitis, encephalitis, cerebellitis, and myelopathy. Pathogenic mechanisms include direct VZV infection of affected tissue, persistent inflammation, and/or virus-induced hypercoagulability. Diagnosis is confirmed by the temporal association of rash to disease onset, intrathecal synthesis of anti-VZV antibodies, and/or the presence of VZV DNA in CSF. Most cases respond to intravenous acyclovir with corticosteroids. Summary VZV produces a wide spectrum of CNS disorders that may be missed as some cases do not have an associated rash or a CSF pleocytosis. Clinicians must be vigilant in including VZV in their differential diagnosis of CNS infections as VZV is a ubiquitous pathogen; importantly, VZV CNS infections are treatable with intravenous acyclovir therapy and corticosteroids.

BackgroundUnderstanding viral infection of the olfactory epithelium is essential because smell loss can occur with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), and because the olfactory nerve is an important route of entry for viruses to the central nervous system. Specialized chemosensory epithelial cells that express the transient receptor potential cation channel subfamily M member 5 (TRPM5) are found throughout the airways and intestinal epithelium and are involved in responses to viral infection.ResultsHerein we performed deep transcriptional profiling of olfactory epithelial cells sorted by flow cytometry based on the expression of fluorescent protein markers for olfactory sensory neurons and TRPM5 in the mouse (Mus musculus). We find profuse expression of transcripts involved in inflammation, immunity and viral infection in TRPM5-expressing microvillous cells and olfactory sensory neurons. These cells express the Tmprss2 transcript that encodes for a serine protease that primes the SARS-CoV-2 spike protein before entry into host cells. Intranasal infection with herpes simplex virus type 1 (HSV-1) elicited a decrease in olfactory sensory neurons.ConclusionOur study provides new insights into a potential role for TRPM5-expressing cells in viral infection of the olfactory epithelium. We find that, as found for solitary chemosensory cells (SCCs) and brush cells in the airway epithelium, and for tuft cells in the intestine, the transcriptome of TRPM5-expressing microvillous cells and olfactory sensory neurons indicates that they are likely involved in the inflammatory response elicited by viral infection of the olfactory epithelium.

Background Herpes zoster is linked to amyloid-associated diseases, including dementia, macular degeneration, and diabetes mellitus, in epidemiological studies. Thus, we examined whether varicella-zoster virus (VZV)-infected cells produce amyloid. Methods Production of intracellular amyloidogenic proteins (amylin, amyloid precursor protein [APP], and amyloid-β [Aβ]) and amyloid, as well as extracellular amylin, Aβ, and amyloid, was compared between mock- and VZV-infected quiescent primary human spinal astrocytes (qHA-sps). The ability of supernatant from infected cells to induce amylin or Aβ42 aggregation was quantitated. Finally, the amyloidogenic activity of viral peptides was examined. Results VZV-infected qHA-sps, but not mock-infected qHA-sps, contained intracellular amylin, APP, and/or Aβ, and amyloid. No differences in extracellular amylin, Aβ40, or Aβ42 were detected, yet only supernatant from VZV-infected cells induced amylin aggregation and, to a lesser extent, Aβ42 aggregation into amyloid fibrils. VZV glycoprotein B (gB) peptides assembled into fibrils and catalyzed amylin and Aβ42 aggregation. Conclusions VZV-infected qHA-sps produced intracellular amyloid and their extracellular environment promoted aggregation of cellular peptides into amyloid fibrils that may be due, in part, to VZV gB peptides. These findings suggest that together with host and other environmental factors, VZV infection may increase the toxic amyloid burden and contribute to amyloid-associated disease progression.

Summary Human motor neuron (MN) diseases encompass a spectrum of disorders. A critical barrier to dissecting disease mechanisms is the lack of appropriate human MN models. Here, we describe a scalable, suspension-based differentiation system to generate functional human MN diseases in 3 weeks. Using this model, we translated recent findings that mRNA mis-localization plays a role in disease development to the human context by establishing a membrane-based system that allows efficient fractionation of MN cell soma and neurites. In response to hypoxia, used to mimic diabetic neuropathies, MNs upregulated mitochondrial transcripts in neurites; however, mitochondria were decreased. These data suggest that hypoxia may disrupt translation of mitochondrial mRNA, potentially leading to neurite damage and development of neuropathies. We report the development of a novel human MN model system to investigate mechanisms of disease affecting soma and/or neurites that facilitates the rapid generation and testing of patient-specific MN diseases.

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