RNase L Mediated Protection from Virus Induced Demyelination

PLoS Pathogens

Robert H. Silverman¹  Roscoe A. Atkinson²  Derek D. C. Ireland³  Parul Kapil³  Stephen A. Stohlman³  David R. Hinton⁴  Cornelia C. Bergmann⁴ 

[1]Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, United States of America

[2]Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, United States of America

[3]Department of Neuroscience, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, United States of America

[4]Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America

关键词: Ribonucleases;    Central nervous system;    Spinal cord;    Microglial cells;    Apoptosis;    Brainstem;    Viral replication;    RNA viruses;   

DOI  :  10.1371/journal.ppat.1000602

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

IFN-α/β plays a critical role in limiting viral spread, restricting viral tropism and protecting mice from neurotropic coronavirus infection. However, the IFN-α/β dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood. The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation, inducing apoptosis, and propagating the IFN-α/β pathway through RNA degradation intermediates. Infection of RNase L deficient (RL−/−) mice with a sub-lethal, demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However, RNase L deficiency did not affect overall control of infectious virus, or diminish IFN-α/β expression in the CNS. Furthermore, increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS. The unique phenotype of infected RL−/− mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection. Increased tissue damage coincided with sustained brain stem infection, foci of microglia infection in grey matter, and increased apoptotic cells. These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis, which is not reflected in overall viral control or propagation of IFN-α/β mediated signals. Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination.

【 授权许可】

CC BY