Glial Sensing of Replicative DNA Virus Infection by Intracellular Pattern Recognition Receptors
Austin Jeffries1,2, Ian Marriott1,2
1,2University of North Carolina at Charlotte Department of Biological Sciences;
1,2Center for Biomedical Engineering and Science
Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long term neurological deficits in survivors. Astrocytes and microglia are known to produce key inflammatory and antiviral mediators following infection with replicative DNA viruses. However, the mechanisms by which these cell types perceive such threats are poorly understood. By elucidating the mechanisms by which glia sense and respond to neurotropic DNA viruses, we can begin to develop targeted therapeutics to improve clinical outcome, either by decreasing detrimental inflammation or by augmenting protective antiviral responses. Recently, several candidate intracellular DNA sensors have been identified in peripheral leukocytes as having important roles in antiviral mediator production/control of viral propagation and/or inflammatory responses. These sensors include cyclic GMP-AMP synthase (cGAS), interferon inducible protein 16 (IFI16), and DNA dependent activator of interferon regulatory factors (DAI). We have established the functional expression of DAI by isolated murine glia and demonstrated a role for this sensor in their inflammatory responses to herpes simplex virus-1 (HSV-1). Furthermore, we have recently described the expression of cGAS and the critical downstream cGAS/DAI adaptor protein, stimulator of interferon genes (STING), by human astrocytes and microglia. We now report that human glial cells constitutively express IFI16, and demonstrate that HSV-1 infection selectively down-regulates the expression of this viral sensor/regulatory molecule. Furthermore, we have extended our analyses to study the functional importance of DAI in HSV-1 infections of the CNS using genetically deficient mice, and the role of IFI16 and cGAS in human glial cell responses to this pathogen by employing CRISPR/Cas9 technology. Together, our data indicates that cGAS, IFI16, and DAI are important components in the anti-viral and/or inflammatory responses of resident CNS cells to this neurotropic DNA virus and, as such, are likely to play crucial roles during HSV pathogenesis.