Human neural stem cell-derived neuron/astrocyte co-cultures respond to la Crosse virus infection with proinflammatory cytokines and chemokines 11 Medical and Health Sciences 1108 Medical Microbiology 11 Medical and Health Sciences 1109 Neurosciences

Brian E. Dawes, Junling Gao, Colm Atkins, Jacob T. Nelson, Kendra Johnson, Ping Wu, Alexander N. Freiberg

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: La Crosse virus (LACV) causes pediatric encephalitis in the USA. LACV induces severe inflammation in the central nervous system, but the recruitment of inflammatory cells is poorly understood. A deeper understanding of LACV-induced neural pathology is needed in order to develop treatment options. However, there is a severe limitation of relevant human neuronal cell models of LACV infection. Methods: We utilized human neural stem cell (hNSC)-derived neuron/astrocyte co-cultures to study LACV infection in disease-relevant primary cells. hNSCs were differentiated into neurons and astrocytes and infected with LACV. To characterize susceptibility and responses to infection, we measured viral titers and levels of viral RNA, performed immunofluorescence analysis to determine the cell types infected, performed apoptosis and cytotoxicity assays, and evaluated cellular responses to infection using qRT-PCR and Bioplex assays. Results: hNSC-derived neuron/astrocyte co-cultures were susceptible to LACV infection and displayed apoptotic responses as reported in previous in vitro and in vivo studies. Neurons and astrocytes are both targets of LACV infection, with neurons becoming the predominant target later in infection possibly due to astrocytic responses to IFN. Additionally, neuron/astrocyte co-cultures responded to LACV infection with strong proinflammatory cytokine, chemokine, as well as MMP-2, MMP-7, and TIMP-1 responses. Conclusions: hNSC-derived neuron/astrocyte co-cultures reproduce key aspects of LACV infection in humans and mice and are useful models to study encephalitic viruses. Specifically, we show astrocytes to be susceptible to LACV infection and that neurons and astrocytes are important drivers of the inflammatory responses seen in LACV infection through the production of proinflammatory cytokines and chemokines.

Original languageEnglish (US)
Article number315
JournalJournal of neuroinflammation
Volume15
Issue number1
DOIs
StatePublished - Nov 15 2018

Keywords

  • Astrocytes
  • Central nervous system
  • Encephalitis
  • Inflammation
  • La Crosse virus
  • Neural stem cells
  • Neurons

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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