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Inhibition of the Type I Interferon Antiviral Response During Arenavirus Infection
Nuffield Department of Clinical Medicine, The Jenner Institute, University of Oxford, Compton, Newbury, Berkshire RG20 7NN, UK
Department of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA
Department of Immunology and Microbial Science, IMM-6, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
* Authors to whom correspondence should be addressed.
Received: 8 October 2010; in revised form: 22 October 2010 / Accepted: 22 October 2010 / Published: 5 November 2010
Abstract: Arenaviruses merit interest both as tractable experimental model systems to study acute and persistent viral infections, and as clinically-important human pathogens. Several arenaviruses cause hemorrhagic fever (HF) disease in humans. In addition, evidence indicates that the globally-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a human pathogen of clinical significance in congenital infections, and also poses a great danger to immunosuppressed individuals. Arenavirus persistence and pathogenesis are facilitated by their ability to overcome the host innate immune response. Mammalian hosts have developed both membrane toll-like receptors (TLR) and cytoplasmic pattern recognition receptors (PRRs) that recognize specific pathogen-associated molecular patterns (PAMPs), resulting in activation of the transcription factors IRF3 or IRF7, or both, which together with NF-κB and ATF-2/c-JUN induce production of type I interferon (IFN-I). IFN-I plays a key role in host anti-microbial defense by mediating direct antiviral effects via up-regulation of IFN-I stimulated genes (ISGs), activating dendritic cells (DCs) and natural killer (NK) cells, and promoting the induction of adaptive responses. Accordingly, viruses have developed a plethora of strategies to disrupt the IFN-I mediated antiviral defenses of the host, and the viral gene products responsible for these disruptions are often major virulence determinants.IRF3- and IRF7-dependent induction of host innate immune responses is frequently targeted by viruses. Thus, the arenavirus nucleoprotein (NP) was shown to inhibit the IFN‑I response by interfering with the activation of IRF3. This NP anti-IFN activity, together with alterations in the number and function of DCs observed in mice chronically infected with LCMV, likely play an important role in LCMV persistence in its murine host. In this review we will discuss current knowledge about the cellular and molecular mechanisms by which arenaviruses can subvert the host innate immune response and their implications for understanding HF arenaviral disease as well as arenavirus persistence in their natural hosts.
Keywords: arenavirus; type I interferon; hemorrhagic fever; innate immunity; lymphocytic choriomeningitis virus; nucleoprotein; dendritic cells
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Borrow, P.; Martínez-Sobrido, L.; De la Torre, J.C. Inhibition of the Type I Interferon Antiviral Response During Arenavirus Infection. Viruses 2010, 2, 2443-2480.
Borrow P, Martínez-Sobrido L, De la Torre JC. Inhibition of the Type I Interferon Antiviral Response During Arenavirus Infection. Viruses. 2010; 2(11):2443-2480.
Borrow, Persephone; Martínez-Sobrido, Luis; De la Torre, Juan C. 2010. "Inhibition of the Type I Interferon Antiviral Response During Arenavirus Infection." Viruses 2, no. 11: 2443-2480.