Journal Article

Varicella zoster virus differentially alters morphology and suppresses proinflammatory cytokines in primary human spinal cord and hippocampal astrocytes

Nagel, Maria A., Blackmon, Anna M., Como, Christina N., Jones, Dallas, Bubak, Andrew N.

2018

Overview

Background Varicella zoster virus (VZV) is a ubiquitous alphaherpesvirus that produces varicella and zoster. VZV can infect multiple cell types in the spinal cord and brain, including astrocytes, producing myelopathy and encephalopathy. While studies of VZV-astrocyte interactions are sparse, a recent report showed that quiescent primary human spinal cord astrocytes (qHA-sps) did not appear activated morphologically during VZV infection. Since astrocytes play a critical role in host defenses during viral infections of the central nervous system, we examined the cytokine responses of qHA-sps and quiescent primary human hippocampal astrocytes (qHA-hps) to VZV infection in vitro, as well as the ability of conditioned supernatant to recruit immune cells. Methods At 3 days post-infection, mock- and VZV-infected qHA-sps and qHA-hps were examined for morphological changes by immunofluorescence antibody assay using antibodies directed against glial fibrillary acidic protein and VZV. Conditioned supernatants were analyzed for proinflammatory cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma, and tumor necrosis factor-α] using the Meso Scale Discovery multiplex ELISA platform. Finally, the ability of conditioned supernatants to attract peripheral blood mononuclear cells (PBMCs) was determined using a chemotaxis assay. Quiescent primary human perineurial cells (qHPNCs) served as a control for VZV-induced cytokine production and PBMC migration. To confirm that the astrocytes have the ability to increase cytokine secretion, qHA-sps and qHA-hps were treated with IL-1β and examined for morphological changes and IL-6 secretion. Results VZV-infected qHA-sps displayed extensive cellular processes, whereas VZV-infected qHA-hps became swollen and clustered together. Astrocytes had the capacity to secrete IL-6 in response to IL-1β. Compared to mock-infected cells, VZV-infected qHA-sps showed significantly reduced secretion of IL-2, IL-4, IL-6, IL-12p70, and IL-13, while VZV-infected qHA-hps showed significantly reduced IL-8 secretion. In contrast, levels of all 10 cytokines examined were significantly increased in VZV-infected qHPNCs. Consistent with these results, conditioned supernatant from VZV-infected qHPNCs, but not that from VZV-infected qHA-sps and qHA-hps, recruited PBMCs. Conclusions VZV-infected qHA-sps and qHA-hps have distinct morphological alterations and patterns of proinflammatory cytokine suppression that could contribute to ineffective viral clearance in VZV myelopathy and encephalopathy, respectively.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Analysis / Astrocytes / Astrocytes - drug effects / Astrocytes - metabolism / Astrocytes - virology / Biomedical and Life Sciences / Biomedicine / Brain / Cell adhesion & migration / Cell Movement - physiology / Central nervous system / Central nervous system diseases / Chemotaxis / Chicken pox / Cytokines / Cytokines - genetics / Cytokines - metabolism / Cytokines - pharmacology / Encephalitis / Encephalopathy / Enzyme-linked immunosorbent assay / Fibroblasts / Gene Expression Regulation, Viral - drug effects / Gene Expression Regulation, Viral - physiology / Glial fibrillary acidic protein / Glial Fibrillary Acidic Protein - metabolism / Health aspects / Herpesvirus 3, Human - metabolism / Hippocampus / Hippocampus - pathology / Humans / Immune cell migration / Immune clearance / Immunofluorescence / Immunology / Infections / Inflammation / Interleukin 10 / Interleukin 12 / Interleukin 13 / Interleukin 2 / Interleukin 4 / Interleukin 6 / Interleukin 8 / Leukocyte migration / Leukocytes (mononuclear) / Male / Morphology / Myelopathy / Nervous system / Neurobiology / Neurology / Neurosciences / Pathogenesis / Postpositivism / Proteins / RNA polymerase / RNA, Messenger - metabolism / Spinal cord / Spinal Cord - pathology / Varicella / Varicella zoster virus / Varicella Zoster Virus Infection - pathology / Viral infections / Viruses / γ-Interferon