RT Journal Article SR Electronic T1 Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program JF bioRxiv FD Cold Spring Harbor Laboratory SP 566992 DO 10.1101/566992 A1 Emanuel Wyler A1 Vedran Franke A1 Jennifer Menegatti A1 Kocks Christine A1 Anastasiya Boltengagen A1 Samantha Praktiknjo A1 Barbara Walch-Rückheim A1 Nikolaus Rajewsky A1 Friedrich Grässer A1 Altuna Akalin A1 Landthaler Markus YR 2019 UL http://biorxiv.org/content/early/2019/03/04/566992.abstract AB Herpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantified the transcrips of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we defined a precise temporal order of early viral gene expression and found unexpected bifurcations and bottlenecks. We identified individual host cell genes and pathways relevant in early 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 was turned on in infected cells and correlated with increased resistance to infection, implicated the transcription factor NRF2. Consequently, Bardoxolone methyl, a known NRF2 agonist, impaired virus production, suggesting that NRF2 activation restricts the progression of viral infection. Our study provides novel insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogenous cell states in virus infection.