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Interferon regulated gene (IRG) expression-signature in a mouse model of chikungunya virus neurovirulence

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Abstract

Interferon regulated genes (IRGs) are critical in controlling virus infections. Here, we analyzed the expression profile of IRGs in the brain tissue in a mouse model of chikungunya virus (CHIKV) neurovirulence. Neurovirulence is one of the newer complications identified in disease caused by re-emerging strains of CHIKV, an alphavirus with positive-strand RNA in the Togaviridae family. In microarray analysis, we identified significant upregulation of 269 genes, out of which a predominant percentage (76%) was IRGs. The highly modulated IRGs included Ifit1, Ifi44, Ddx60, Usp18, Stat1, Rtp4, Mnda, Gbp3, Gbp4, Gbp7, Oasl2, Oas1g, Ly6a, Igtp, and Gbp10, along with many others exhibiting lesser changes in expression levels. We found that these IRG mRNA transcripts are modulated in parallel across CHIKV-infected mouse brain tissues, human neuronal cell line IMR-32 and hepatic cell line Huh-7. The genes identified to be highly modulated both in mouse brain and human neuronal cells were Ifit1, Ifi44, Ddx60, Usp18, and Mnda. In Huh-7 cells, however, only two IRGs (Gbp4 and Gbp7) showed a similar level of upregulation. Concordant modulation of IRGs in both mice and human cells indicates that they might play important roles in regulating CHIKV replication in the central nervous system (CNS). The induction of several IRGs in CNS during infection underscores the robustness of IRG-mediated innate immune response in CHIKV restriction. Further studies on these IRGs would help in evolving possibilities for their targeting in host-directed therapeutic interventions against CHIKV.

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Acknowledgements

The authors are thankful to the Director, RGCB for the infrastructure facilities; Mr. Dinesh R, Genomic Core facility, RGCB Bio-innovation Centre, Thiruvananthapuram and Ms. Anju, Histopathology Core facility, RGCB for technical assistance with microarray and histopathology analyses, respectively. The authors are thankful to Dr. Tessy Thomas Maliekal for helping with microscopic imaging of histopathology sections. SRN is a Research Scholar of University of Kerala.

Funding

Authors acknowledge funding from Department of Biotechnology (DBT), Government of India (No.BT/PR13801/MED/29/952/2015). SRN acknowledges the Kerala Veterinary and Animal Sciences University (KVASU) for financial support through Faculty Improvement Program.

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  1. Molecular Virology Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thycaud P.O., Thiruvananthapuram, Kerala, 695014, India

    Sreeja R. Nair, Rachy Abraham & Easwaran Sreekumar

  2. Department of Pathology, Government Medical College, Kottayam, Kerala, India

    Sankar Sundaram

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  1. Sreeja R. Nair
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Correspondence to Easwaran Sreekumar.

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All virus infection and animal handling expreriments were done as per the approved protocols by Institutional Bio-safety Committee (IBSC) and  Institutional Animal  Ethics Committee (IAEC).

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The authors declare that they have no conflict of interest.

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Nair, S.R., Abraham, R., Sundaram, S. et al. Interferon regulated gene (IRG) expression-signature in a mouse model of chikungunya virus neurovirulence. J. Neurovirol. 23, 886–902 (2017). https://doi.org/10.1007/s13365-017-0583-3

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