title: Nucleic acid recognition orchestrates the anti-viral response to retroviruses.
abstract: Intrinsic restriction factors and viral nucleic acid sensors are important for the anti-viral response. Here, we show how upstream sensing of retroviral reverse transcripts integrates with the downstream effector APOBEC3, an IFN-induced cytidine deaminase that introduces lethal mutations during retroviral reverse transcription. Using a murine leukemia virus (MLV) variant with an unstable capsid that induces a strong IFNβ antiviral response, we identify three sensors, IFI203, DDX41, and cGAS, required for MLV nucleic acid recognition. These sensors then signal using the adaptor STING, leading to increased production of IFNβ and other targets downstream of the transcription factor IRF3. Using knockout and mutant mice, we show that APOBEC3 limits the levels of reverse transcripts that trigger cytosolic sensing, and that nucleic acid sensing in vivo increases expression of IFN-regulated restriction factors like APOBEC3 that in turn reduce viral load. These studies underscore the importance of the multiple layers of protection afforded by host factors.
authors: Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Spyridon
authors: S
authors: Stavrou
authors: Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Kristin
authors: K
authors: Blouch
authors: Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Swathi
authors: S
authors: Kotla
authors: Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Antonia
authors: A
authors: Bass
authors: Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rosss@mail.med.upenn.edu.
authors: Susan R
authors: SR
authors: Ross
mesh_terms: D000818:Animals; D002460:Cell Line; D003564:Cytidine Deaminase / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D009052:Leukemia Virus, Murine / Q000276:immunology* / Q000502:physiology; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism; D048348:Reverse Transcription; D015398:Signal Transduction; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D003564:Cytidine Deaminase; D053487:DEAD-box RNA Helicases; D004279:DNA, Viral; D016899:Interferon-beta; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; C109045:Ifi203 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C503504:Apobec3 protein, mouse; C567960:DDX41 protein, mouse