The HIF transcription network exerts innate antiviral activity in neurons and limits brain inflammation
Ensieh Farahani,
Line S. Reinert,
Ryo Narita,
Manutea C. Serrero,
Morten Kelder Skouboe,
Demi van der Horst,
Sonia Assil,
Baocun Zhang,
Marie B. Iversen,
Eugenio Gutierrez,
Hossein Hazrati,
Mogens Johannsen,
David Olagnier,
Reiner Kunze,
Mark Denham,
Trine H. Mogensen,
Michael Lappe,
Søren R. Paludan
Affiliations
Ensieh Farahani
Department of Biomedicine, Aarhus University, Aarhus, Denmark
Line S. Reinert
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Ryo Narita
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Manutea C. Serrero
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Morten Kelder Skouboe
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Demi van der Horst
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Sonia Assil
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Baocun Zhang
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Marie B. Iversen
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Eugenio Gutierrez
Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark
Hossein Hazrati
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark; Department of Forensic Science, Aarhus University, Aarhus, Denmark
Mogens Johannsen
Department of Forensic Science, Aarhus University, Aarhus, Denmark
David Olagnier
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark
Reiner Kunze
Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
Mark Denham
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Danish Research Institute of Translational Neuroscience, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Aarhus, Denmark
Trine H. Mogensen
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Michael Lappe
Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark; CONNECT - Center for Clinical and Genomic Data, Aarhus University Hospital, Aarhus, Denmark
Søren R. Paludan
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Center for Immunology of Viral Infections, Aarhus University, Aarhus, Denmark; Corresponding author
Summary: Pattern recognition receptors (PRRs) induce host defense but can also induce exacerbated inflammatory responses. This raises the question of whether other mechanisms are also involved in early host defense. Using transcriptome analysis of disrupted transcripts in herpes simplex virus (HSV)-infected cells, we find that HSV infection disrupts the hypoxia-inducible factor (HIF) transcription network in neurons and epithelial cells. Importantly, HIF activation leads to control of HSV replication. Mechanistically, HIF activation induces autophagy, which is essential for antiviral activity. HSV-2 infection in vivo leads to hypoxia in CNS neurons, and mice with neuron-specific HIF1/2α deficiency exhibit elevated viral load and augmented PRR signaling and inflammatory gene expression in the CNS after HSV-2 infection. Data from human stem cell-derived neuron and microglia cultures show that HIF also exerts antiviral and inflammation-restricting activity in human CNS cells. Collectively, the HIF transcription factor system senses virus-induced hypoxic stress to induce cell-intrinsic antiviral responses and limit inflammation.
