Single-cell RNA-sequencing of herpes simplex virus 1-infected cells connects NRF2 activation to an antiviral program

Emanuel Wyler, Vedran Franke, Jennifer Menegatti, Christine Kocks, Anastasiya Boltengagen, Samantha Praktiknjo, Barbara Walch-Rückheim, Jens Bosse, Nikolaus Rajewsky, Friedrich Grässer, Altuna Akalin () and Markus Landthaler ()
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Emanuel Wyler: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Vedran Franke: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Jennifer Menegatti: Saarland University Medical School
Christine Kocks: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Anastasiya Boltengagen: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Samantha Praktiknjo: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Barbara Walch-Rückheim: Saarland University
Jens Bosse: Leibniz Institute for Experimental Virology
Nikolaus Rajewsky: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Friedrich Grässer: Saarland University Medical School
Altuna Akalin: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Markus Landthaler: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Herpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantify the transcriptome of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we define a precise temporal order of early viral gene expression and propose a set-wise emergence of viral genes. We identify host cell genes and pathways relevant for infection by combining three different computational approaches: gene and pathway overdispersion analysis, prediction of cell-state transition probabilities, as well as future cell states. One transcriptional program, which correlates with increased resistance to infection, implicates the transcription factor NRF2. Consequently, Bardoxolone methyl and Sulforaphane, two known NRF2 agonists, impair virus production, suggesting that NRF2 activation restricts viral infection. Our study provides insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogeneous cell states in virus infection.

Date: 2019
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DOI: 10.1038/s41467-019-12894-z

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