Astrocytes evoke a robust IRF7-independent type I interferon response upon neurotropic viral infection

• Published in: Journal of neuroinflammation Vol. 20; no. 1; pp. 1 - 213
• Main Authors: Weichert, Loreen, Düsedau, Henning Peter, Fritzsch, David, Schreier, Sarah, Scharf, Annika, Grashoff, Martina, Cebulski, Kristin, Michaelsen-Preusse, Kristin, Erck, Christian, Lienenklaus, Stefan, Dunay, Ildiko Rita, Kröger, Andrea
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 22-09-2023; BioMed Central; BMC
• Subjects: Analysis; Astrocytes; Bone marrow; Brain; Care and treatment; Central nervous system; Diagnosis; Encephalitis; Flow cytometry; Immune privilege; Immune response; Immunohistochemistry; Infection control; Infections; Infiltration; Innate immunity; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Interferon regulatory factor 7; IRF7; LGTV; Methods; Microglia; Pathogens; Penicillin; TBEV; Tick-borne encephalitis; Type I interferon; Viral infections; Viruses; West Nile virus; Germany
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02892-w

Abstract
Background
Type I interferons (IFN-I) are fundamental in controlling viral infections but fatal interferonopathy is restricted in the immune-privileged central nervous system (CNS). In contrast to the well-established role of Interferon Regulatory Factor 7 (IRF7) in the regulation of IFN-I response in the periphery, little is known about the specific function in the CNS.
Methods
To investigate the role for IRF7 in antiviral response during neurotropic virus infection, mice deficient for IRF3 and IRF7 were infected systemically with Langat virus (LGTV). Viral burden and IFN-I response was analyzed in the periphery and the CNS by focus formation assay, RT-PCR, immunohistochemistry and in vivo imaging. Microglia and infiltration of CNS-infiltration of immune cells were characterized by flow cytometry.
Results
Here, we demonstrate that during infection with the neurotropic Langat virus (LGTV), an attenuated member of the tick-borne encephalitis virus (TBEV) subgroup, neurons do not rely on IRF7 for cell-intrinsic antiviral resistance and IFN-I induction. An increased viral replication in IRF7-deficient mice suggests an indirect antiviral mechanism. Astrocytes rely on IRF7 to establish a cell-autonomous antiviral response. Notably, the loss of IRF7 particularly in astrocytes resulted in a high IFN-I production. Sustained production of IFN-I in astrocytes is independent of an IRF7-mediated positive feedback loop.
Conclusion
IFN-I induction in the CNS is profoundly regulated in a cell type-specific fashion.