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Early Innate Immune Responses to Sin Nombre Hantavirus Occur Independently of IFN Regulatory Factor 3, Characterized Pattern Recognition Receptors, and Viral Entry¹

Joseph B. Prescott^*, Pamela R. Hall^*, Virginie S. Bondu-Hawkins^*, Chunyan Ye^* and Brian Hjelle^2,*,,

^* Department of Pathology, Department of Biology, and Department of Molecular Genetics and Microbiology, Center for Infectious Diseases and Immunity, School of Medicine, University of New Mexico, Albuquerque, NM 87131

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Services Grants U01 AI56618 and U01 AI054779. J.B.P. was supported by National Institute of Allergy and Infectious Disease Grant 1 T32 AI07583.

² Address correspondence and reprint requests to Dr. Brian L. Hjelle, Department of Pathology, University of New Mexico, 329CRF (MSC08 4640), 1 University of New Mexico, Albuquerque, NM 87131-0001. E-mail address: bhjelle{at}salud.unm.edu

³ Abbreviations used in this paper: PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; ISG, IFN-stimulated gene; RIG-I, retinoic acid-inducible gene I; MDA5, myeloid differentiation-associated factor 5; IRF, IFN regulatory factor; vRNA, viral RNA; SNV, Sin Nombre virus; HCPS, hantavirus cardiopulmonary syndrome; TRIF, Toll/IL-1R domain-containing adaptor protein inducing IFN-; siRNA, small-interfering RNA; qRT-PCR, quantitative RT-PCR; MxA, myxovirus resistance A; poly I:C, polyinosinic/polycytidylic acid; IPS-1, IFN promoter stimulator-1; SeV, Sendai virus; CT, cycle threshold; SEAP, secreted alkaline phosphatase; CARD, caspase recruitment domain.

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