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The Edward Jenner Institute for Vaccine Research, Compton, Berkshire, United Kingdom
Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type 1 IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection.
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 core funding from the Edward Jenner Institute for Vaccine Research. P.B. is a Jenner Institute Investigator.
2 Current address: Immunological Memory Group, Nuffield Department of Clinical Medicine, University of Oxford, Peter Medawar Building, South Parks Road, Oxford, U.K.
3 Current address: Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, Cambridgeshire, U.K.
4 Current address: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
5 Address correspondence and reprint requests to Dr. Persephone Borrow, Nuffield Department of Clinical Medicine, University of Oxford, The Jenner Institute, Compton, Newbury, Berkshire, U.K. E-mail address: persephone.borrow{at}jenner.ac.uk
6 Abbreviations used in this paper: PRR, pattern recognition receptor; RIG-1, retinoic acid inducing gene-1; RLR, RIG-I-like receptor; DC, dendritic cell; pDC, plasmacytoid DC; LCMV, lymphocytic choriomeningitis virus; cDC, conventional DC; qRT-PCR, real-time quantitative RT-PCR; HPRT, hypoxanthine ribosyl transferase; Ct, cycle threshold; P/S, penicillin-streptomycin; BM-DC, bone marrow-derived DC; m.o.i., multiplicity of infection; IRF, interferon regulatory factor; NP, nucleoprotein; polyIC, polyinosinic:polycytidyl acid; FSDC, fetal mouse skin-derived DC line.
7 The online version of this article contains supplementary material.
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