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Deprecated: Implicit conversion from float 276.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Virol 2020 ; 94 (20): ä Nephropedia Template TP
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Neuronal Ablation of Alpha/Beta Interferon (IFN-alpha/beta) Signaling Exacerbates Central Nervous System Viral Dissemination and Impairs IFN-gamma Responsiveness in Microglia/Macrophages #MMPMID32796063
Hwang M; Bergmann CC
J Virol 2020[Sep]; 94 (20): ä PMID32796063show ga
Alpha/beta interferon (IFN-alpha/beta) signaling through the IFN-alpha/beta receptor (IFNAR) is essential to limit virus dissemination throughout the central nervous system (CNS) following many neurotropic virus infections. However, the distinct expression patterns of factors associated with the IFN-alpha/beta pathway in different CNS resident cell populations implicate complex cooperative pathways in IFN-alpha/beta induction and responsiveness. Here we show that mice devoid of IFNAR1 signaling in calcium/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) expressing neurons (CaMKIIcre:IFNAR(fl/fl) mice) infected with a mildly pathogenic neurotropic coronavirus (mouse hepatitis virus A59 strain [MHV-A59]) developed severe encephalomyelitis with hind-limb paralysis and succumbed within 7 days. Increased virus spread in CaMKIIcre:IFNAR(fl/fl) mice compared to IFNAR(fl/fl) mice affected neurons not only in the forebrain but also in the mid-hind brain and spinal cords but excluded the cerebellum. Infection was also increased in glia. The lack of viral control in CaMKIIcre:IFNAR(fl/fl) relative to control mice coincided with sustained Cxcl1 and Ccl2 mRNAs but a decrease in mRNA levels of IFNalpha/beta pathway genes as well as Il6, Tnf, and Il1beta between days 4 and 6 postinfection (p.i.). T cell accumulation and IFN-gamma production, an essential component of virus control, were not altered. However, IFN-gamma responsiveness was impaired in microglia/macrophages irrespective of similar pSTAT1 nuclear translocation as in infected controls. The results reveal how perturbation of IFN-alpha/beta signaling in neurons can worsen disease course and disrupt complex interactions between the IFN-alpha/beta and IFN-gamma pathways in achieving optimal antiviral responses.IMPORTANCE IFN-alpha/beta induction limits CNS viral spread by establishing an antiviral state, but also promotes blood brain barrier integrity, adaptive immunity, and activation of microglia/macrophages. However, the extent to which glial or neuronal signaling contributes to these diverse IFN-alpha/beta functions is poorly understood. Using a neurotropic mouse hepatitis virus encephalomyelitis model, this study demonstrated an essential role of IFN-alpha/beta receptor 1 (IFNAR1) specifically in neurons to control virus spread, regulate IFN-gamma signaling, and prevent acute mortality. The results support the notion that effective neuronal IFNAR1 signaling compensates for their low basal expression of genes in the IFN-alpha/beta pathway compared to glia. The data further highlight the importance of tightly regulated communication between the IFN-alpha/beta and IFN-gamma signaling pathways to optimize antiviral IFN-gamma activity.
|*Signal Transduction[MESH]
|Animals[MESH]
|Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/metabolism[MESH]