Early innate immune responses to Sin Nombre hantavirus occur independently of IFN regulatory factor 3, characterized pattern recognition receptors, and viral entry.
Sin Nombre virus (SNV) is a highly pathogenic New World virus and etiologic agent of hantavirus cardiopulmonary syndrome. We have previously shown that replication-defective virus particles are able to induce a strong IFN-stimulated gene (ISG) response in human primary cells. RNA viruses often stimulate the innate immune response by interactions between viral nucleic acids, acting as a pathogen-associated molecular pattern, and cellular pattern-recognition receptors (PRRs). Ligand binding to PRRs activates transcription factors which regulate the expression of antiviral genes, and in all systems examined thus far, IFN regulatory factor 3 (IRF3) has been described as an essential intermediate for induction of ISG expression. However, we now describe a model in which IRF3 is dispensable for the induction of ISG transcription in response to viral particles. IRF3-independent ISG transcription in human hepatoma cell lines is initiated early after exposure to SNV virus particles in an entry- and replication-independent fashion. Furthermore, using gene knockdown, we discovered that this activation is independent of the best-characterized RNA- and protein-sensing PRRs including the cytoplasmic caspase recruitment domain-containing RNA helicases and the TLRs. SNV particles engage a heretofore unrecognized PRR, likely located at the cell surface, and engage a novel IRF3-independent pathway that activates the innate immune response.
Prescott
Joseph B
JB
Department of Pathology, Center for Infectious Diseases and Immunity, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
Hall
Pamela R
PR
Bondu-Hawkins
Virginie S
VS
Ye
Chunyan
C
Hjelle
Brian
B
D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000821:virology; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000276:immunology / Q000528:radiation effects; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000502:physiology; D007372:Interferons / Q000502:physiology; D011971:Receptors, Immunologic; D011991:Receptors, Virus / Q000502:physiology; D029261:Sin Nombre virus / Q000276:immunology* / Q000378:metabolism* / Q000472:pathogenicity / Q000528:radiation effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*; D014466:Ultraviolet Rays; D014771:Virion / Q000276:immunology; D053586:Virus Internalization; D014779:Virus Replication / Q000276:immunology
C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D007372:Interferons; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases