Ifit2 deficiency restricts microglial activation and leukocyte migration following murine coronavirus (m-CoV) CNS infection.

Jayasri Das Sarma,Soumya Kundu,Cornelia Bergmann,Mi-Hyun Hwang,Amy Burrows,Ganes C Sen,Nikhil Sharma,Patricia Rayman,Matthias Johannes Schnell

doi:10.1371/journal.ppat.1009034

Abstract

The interferon-induced tetratricopeptide repeat protein (Ifit2) protects mice from lethal neurotropic viruses. Neurotropic coronavirus MHV-RSA59 infection of Ifit2-/- mice caused pronounced morbidity and mortality accompanied by rampant virus replication and spread throughout the brain. In spite of the higher virus load, induction of many cytokines and chemokines in the brains of infected Ifit2-/- mice were similar to that in wild-type mice. In contrast, infected Ifit2-/- mice revealed significantly impaired microglial activation as well as reduced recruitment of NK1.1 T cells and CD4 T cells to the brain, possibly contributing to the lack of viral clearance. These two deficiencies were associated with a lower level of microglial expression of CX3CR1, the receptor of the CX3CL1 (Fractalkine) chemokine, which plays a critical role in both microglial activation and leukocyte recruitment. The above results uncovered a new potential role of an interferon-induced protein in immune protection.

Highlights

Viral infection in the CNS initiates activation of cellular sensors like Toll like receptor (TLRs)/ Rig-I- like receptor (RLRs)/ synthase for the second messenger cyclic GMP–AMP and the cyclic GMP–AMP receptor stimulator of interferon genes [1,2,3], which in turn activate transcription factors such as Interferon regulatory factors (IRFs), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and downstream type I interferon (IFN) genes
To provide better cellular insights into the protective mechanisms of Ifit2 functions, using a neurotropic coronavirus infection in Ifit2 depleted mice we report that in the absence of Ifit2, viral replication is dramatically increased and mice develop severe clinical signs and symptoms of neurological deficit
Despite the enormous viral load, Ifit2 deficient mice are impaired in microglial activation and recruitment of peripheral leukocytes into the CNS

Summary

Introduction

Viral infection in the CNS initiates activation of cellular sensors like Toll like receptor (TLRs)/ Rig-I- like receptor (RLRs)/ synthase for the second messenger cyclic GMP–AMP and the cyclic GMP–AMP receptor stimulator of interferon genes (cGAS-STING) [1,2,3], which in turn activate transcription factors such as Interferon regulatory factors (IRFs), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and downstream type I interferon (IFN) genes. Secreted IFNβ and members of the IFNα family bind to Interferon-α/β receptor (IFNAR), which induces the expression of more than 200 IFN stimulated genes (ISG)[4,5,6,7]. Among these ISGs are the interferon-induced proteins with tetratricopeptide repeats (IFITs) [2,8,9]. Adult 6–7 week old Ifit2-/- mice intracranially infected with a dual hepatotropic and neurotropic strain of mouse hepatitis virus (vMHV-GFP), a coronavirus, exhibited pronounced disease severity and a mortality rate up to 60% compared to benign disease in wildtype (WT) mice. Elevated infectious viral load in the brains of Ifit2-/mice coincided with impaired IFNα/β production and ISG upregulation with no deficits in IFNγ production [16]. vMHV-GFP was derived from a MHV-A59 cDNA clone (vMHV-inf-1) in which the accessory gene 4 was replaced by a gene encoding a fusion protein of EGFP and a lymphocytic choriomeningitis virus-derived cytotoxic T lymphocyte epitope described previously [17]

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Discussion

Conclusion