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Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses

Nature Medicine volume 19, pages 458–464 (2013)Cite this article

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Abstract

Although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. Here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded RNA viruses. Granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptibility to viral infection ex vivo and in vivo. By transducing cortical neurons with genes that were expressed more highly in granule cell neurons, we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses. Moreover, we found that the epigenetic state and microRNA (miRNA)-mediated regulation of ISGs correlates with enhanced antiviral response in granule cell neurons. Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, which probably contribute to their relative permissiveness to infection.

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Figure 1: Granule cell neurons are less susceptible to virus infection and more sensitive to the antiviral effects of IFN-β than cortical neurons.
Figure 2: Microarray analysis revealing differential regulation of antiviral genes in granule cell neurons and cortical neurons.
Figure 3: Key ISGs reach peak expression sooner and at higher levels in granule cell neurons.
Figure 4: ISGs with antiviral activity identified in neurons using a lentivirus transduction system.
Figure 5: Epigenetic and miRNA-mediated control mechanism of ISGs.
Figure 6: Differential WNV infection of neurons in the brains of mice and humans.

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Acknowledgements

We thank O. Koues and E. Oltz for the experimental discussions and suggestions, J. Patel and R. Klein for their contribution to the initial phase of the study, B. Bradel-Tretheway for help with initial study design and microarray analysis, Y. Sasaki (Washington University) for the lentiviral plasmids, A. Barrett (University of Texas Medical Branch) for the SLEV, I. Frolov (University of Alabama, Birmingham) for the VEEV, H.W. Virgin (Washington University) for the Stat1−/− mice and B.K. Kleinschmidt-DeMasters (University of Colorado) and C.A. Wiley (University of Pittsburgh) for the human brain autopsy samples. US National Institutes of Health grants U54 AI081680 (Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research), U19 AI083019 (M.G. and M.S.D.) and R01 AI074973 (M.G. and M.S.D.) supported this work. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA

    Hyelim Cho & Michael S Diamond

  2. Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA

    Sean C Proll & Michael G Katze

  3. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Kristy J Szretter & Michael S Diamond

  4. Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA

    Michael Gale Jr

  5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Michael S Diamond

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  1. Hyelim Cho
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Contributions

H.C. and K.J.S. performed the experiments. H.C. and S.C.P. analyzed the microarray data. H.C. and M.S.D. designed the experiments and wrote the initial draft of the manuscript. M.G.K. and M.G. contributed to the study design and preparation of the manuscript.

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Correspondence to Michael S Diamond.

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Cho, H., Proll, S., Szretter, K. et al. Differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded RNA viruses. Nat Med 19, 458–464 (2013). https://doi.org/10.1038/nm.3108

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