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      Distinct gene loci control the host response to influenza H1N1 virus infection in a time-dependent manner

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          There is strong but mostly circumstantial evidence that genetic factors modulate the severity of influenza infection in humans. Using genetically diverse but fully inbred strains of mice it has been shown that host sequence variants have a strong influence on the severity of influenza A disease progression. In particular, C57BL/6J, the most widely used mouse strain in biomedical research, is comparatively resistant. In contrast, DBA/2J is highly susceptible.


          To map regions of the genome responsible for differences in influenza susceptibility, we infected a family of 53 BXD-type lines derived from a cross between C57BL/6J and DBA/2J strains with influenza A virus (PR8, H1N1). We monitored body weight, survival, and mean time to death for 13 days after infection. Qivr5 (quantitative trait for influenza virus resistance on chromosome 5) was the largest and most significant QTL for weight loss. The effect of Qivr5 was detectable on day 2 post infection, but was most pronounced on days 5 and 6. Survival rate mapped to Qivr5, but additionally revealed a second significant locus on chromosome 19 ( Qivr19). Analysis of mean time to death affirmed both Qivr5 and Qivr19. In addition, we observed several regions of the genome with suggestive linkage. There are potentially complex combinatorial interactions of the parental alleles among loci. Analysis of multiple gene expression data sets and sequence variants in these strains highlights about 30 strong candidate genes across all loci that may control influenza A susceptibility and resistance.


          We have mapped influenza susceptibility loci to chromosomes 2, 5, 16, 17, and 19. Body weight and survival loci have a time-dependent profile that presumably reflects the temporal dynamic of the response to infection. We highlight candidate genes in the respective intervals and review their possible biological function during infection.

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          Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.

          The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.
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            IFITM3 restricts the morbidity and mortality associated with influenza

            The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in an unfortunate few. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses 1-7 . Both the magnitude and breadth of the IFITM proteins’ in vitro effects suggest they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model 8 , we now directly test this hypothesis and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza 9, 10 . Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalised with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalised subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and man. IFITM3 was identified in a functional genomic screen as mediating resistance to influenza A virus, dengue virus and West Nile virus infection in vitro 1 . However, the role of the Ifitm proteins in anti-viral immunity in vivo is unknown. Therefore, we infected mice that are homozygous for a disruptive insertion in exon 1 of the Ifitm3 gene that abolishes its expression 8 (Ifitm3 −/−), with a low-pathogenicity (LP) murine-adapted H3N2 influenza A virus (A/X-31). LP strains of influenza do not normally cause extensive viral replication throughout the lungs, or cause the cytokine dysregulation and death typically seen after infection with highly-pathogenic (HP) viral strains 9 , at the doses used (Fig. 1a). However, LP-infected Ifitm3 −/− mice became moribund, losing >25% of their original body weight and exhibiting severe signs of clinical illness (rapid breathing, piloerection) 6 days after infection. In comparison, wild-type (WT) litter mates shed 95% C57BL/6) and Ifitm3 −/− mice 8 8-10 weeks of age were maintained in accordance with UK Home Office regulations, UK Animals Scientific Procedures Act 1986 under the project licence PPL80/2099. This licence was reviewed by The Wellcome Trust Sanger Institute Ethical Review Committee. Groups of >5 isofluorane-anaesthetised mice of both genotype were intranasally inoculated with 104 PFU of A/X-31 influenza in 50μl of sterile PBS. In some experiments A/X-31 was substituted with 200 PFU of A/England/195/09 influenza, or 50-103 PFU of A/PR/8/34 (PR/8) or an otherwise isogenic virus with a deletion of the NS1 gene (delNS1) 19 , made as described 23 . Their weight was recorded daily and they were monitored for signs of illness. Mice exceeding 25% total weight loss were killed in accordance with UK Home Office guidelines. Littermate controls were used in all experiments. Influenza virus quantification Lungs from five mice per genotype were collected on days 1, 2, 3, 4 and 6 post-infection, weighed and homogenised in 5% weight / volume (w/v) of Leibovitz’s L-15 medium (Invitrogen) containing antibiotic-antimycotic (Invitrogen). Samples were quantified for viral load by plaque assay in 10-fold serial dilutions on Madin-Darby canine kidney (MDCK) cell monolayers overlaid with 1% Avicell medium 24 . Lungs were subjected to two freeze-thaw cycles before titration. Virus was also quantified by RT-qPCR, wherein RNA was first extracted from lung, heart, brain and spleen using the RNeasy Mini Plus Kit (Qiagen). Purified RNA was normalised by mass and quantified with SYBR Green (Qiagen) using the manufacturer’s instructions and 0.5μM primers for influenza matrix 1 protein (M1) Fw: 5′-TGAGTCTTCTAACCGAGGTC-3′, Rv: 5′GGTCTTGTCTTTAGCCATTCC-3′ (Sigma-Aldrich) and mouse β-actin (Actb) Fw: 5′CTAAGGCCAACCGTGAAAAG-3′, Rv: 5′-ACCAGAGGCATACAGGGACA-3′. qPCR was performed on a StepOnePlus machine (Applied Biosystems) and analysed with StepOne software v2.1 (Applied Biosystems). Western blotting Lungs were homogenised in 5% w/v of Tissue Protein Extraction Reagent (Thermo Scientific) containing “cOmplete Protease Inhibitor” (Roche). Total protein was quantified by BCA assay (Thermo Scientific) and was normalised before loading into wells. Proteins were visualised with the following indicated primary antibodies: Mouse Ifitm2 rabbit polyclonal was purchased from Santa Cruz Biotechnology (Cat# sc-66828); Anti-fragilis (Ifitm3) rabbit polyclonal antibody was from Abcam (Cat # ab15592). The IFITM3 and NΔ21 western blot using the A549 stable cell lines were probed with the anti-IFITM1 antibody from Prosci (Cat# 5807), which recognises a conserved portion of the IFITM1, 2 and 3 proteins which is still present even in the absence of the first twenty one N-terminal amino acids. The LCL blots (including the A549 cell line lysate controls) were probed with either an antibody which is specific for the N-terminus of IFITM3 (Rabbit anti-IFITM3 (N-term aa 8-38) (Abgent, #AP1153a)), or with anti-IFITM1 antibody from Prosci (Cat# 5807), as well as Rabbit anti-MX1 (Proteintech, #13750-1-AP) and mouse anti-GAPDH (clone GAPDH-71.1) (Sigma, #G8795). For the LCL immunoblots all antibodies were diluted in DPBS (Sigma) containing 0.1% Tween 20 (Sigma) and 5% non-far dried milk (Carnation) and incubated overnight at 4°C. All primary antibodies were consequently bound to the corresponding species-appropriate HRP-conjugated secondary antibodies (Dako). Actin antibody was purchased from either Abcam or Sigma, Mouse monoclonal, Cat# A5316. Pathological examination 5-μm sections of paraffin-embedded tissue were stained with hematoxylin and eosin (Sigma-Aldrich) and were examined and scored twice, once by a pathologist under blinded conditions. The TUNEL assay for apoptosis was conducted using the TACS XL DAB In Situ Apoptosis Detection Kit (R&D Systems). Immunofluorescent tissue staining: protein Lung tissue was embedded in glycol methacrylate (GMA) to visualise the spread of viral protein, as described previously 25 . Briefly, 2-μm sections were blocked with 0.1% sodium azide and 30% hydrogen peroxide followed by a second block of RPMI 1640 (Invitrogen) containing 10% fetal calf serum (Sigma-Aldrich) and 1% bovine serum albumen (Invitrogen). Viral antigen was stained using M149 polyclonal antibody to influenza A, B (Takara) and visualised with a secondary goat anti-rabbit antibody conjugated to AP (Dako). Sections were counterstained with hematoxylin (Sigma-Aldrich). Murine Ifitm1 and Ifitm3 protein expression in lung sections from either uninfected mice, or those two days post-infection with A/X-31, were immunostained with either anti-IFITM1 antibody (Abcam, cat# ab106265) or anti-fragilis (anti-Ifitm3) rabbit polyclonal antisera (Abcam, cat# ab15592). Sections were also stained for DNA with Hoechst 33342 (Sigma). Immunofluorescent staining: RNA Viral RNA was visualised in 5-μm paraffin-embedded sections using the QuantiGene viewRNA kit (Affymetrix). Briefly, sections were rehydrated and incubated with Proteinase K. They were subsequently incubated with a viewRNA probe set designed against the negative stranded vRNA encoding the NP gene of A/X-31 (Affymetrix). The signal was amplified before incubation with labelled probes and visualised. Flow cytometry Single cell suspensions were generated by passing lungs twice through a 100μm filter before lysing red blood cells with RBC lysis buffer (eBioscience) and assessing for cell viability via Trypan blue exclusion. Cells were characterised by flow cytometry as follows: T-lymphocytes CD4+ or CD8+, T-lymphocytes (activated) CD4+CD69+ or CD8+CD69+, neutrophils CD11bhiCD11c−Ly6g+, dendritic cells CD11c+CD11bloLy6glo MHC class II high, macrophages CD11b+CD11c+F4/80hi, natural killer cells NKp46+CD4−CD8−. All antibodies (Supp. Table S3) were from BD Bioscience, except CD69 and F4/80, which were from AbD Serotec. Samples were run on a FACSAria II (BD Bioscience) and visualised using FlowJo 7.2.4. Data were analysed statistically and graphed using Prism 5.0 (GraphPad Software). Peripheral leukocyte analysis Mice (n=3 per genotype per day) were bled on days 0, 1, 2, 3, 4 and 6 by tail vein puncture. Leukocyte counts were determined by haemocytometer, whilst blood cell differential counts were calculated by counting from duplicate blood smears stained with Wright-Giemsa stain (Sigma-Aldrich). At least 100 leukocytes were counted per smear. All blood analyses were conducted in a blinded fashion. Data were analysed statistically and graphed using Prism 5.0 (GraphPad Software). Cytokine/chemokine analysis Lungs were collected and homogenised days 0, 1, 2, 3, 4 and 6 post-infection from four mice of each genotype. G-CSF, GM-CSF, IFNγ, IL-10, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IP-10, KC-like, MCP-1, MIP-1α,. RANTES and TNFα were analysed using a mouse antibody bead kit (Millipore) according to the manufacturer’s instructions on a Luminex FlexMAP3D. Results were analysed and quality control checked using Masterplex QT 2010 and Masterplex Readerfit 2010 (MiraiBio). Data were analysed statistically and graphed using Prism 5.0 (GraphPad Software). Murine embryonic fibroblast generation, transduction, and infectivity assays Adult Ifitm3 −/− mice 8 were intercrossed and fibroblasts (MEFs) were derived from embryos at day 13.5 of gestation, as described previously 1 . MEFs were genotyped by PCR (Thermo-Start Taq DNA Polymerase, ABgene; Epsom, UK) on embryo tail genomic DNA using primers and the cycle profile described previously 8 to detect the presence of the WT allele (450 bp band) and the targeted/knockout allele (650 bp band). MEFs were cultured in DMEM, containing 10% FBS, 1X MEM essential amino acids, 1X 2-Mercapto-ethanol (Gibco). MEFs were transduced with VSV-G pseudotyped retroviruses expressing either the empty vector control (pQXCIP, Clontech), or one expressing Ifitm3, as previous described 1 . After puromycin selection the respective cell lines were challenged with either A/X-31 virus (moi 0.3-0.4) or PR/8 (moi 0.4). For PR/8 infections, after 12h the media was removed and the cells were then fixed with 4% formalin and stained with purified anti-HA monoclonal antibody (Hybridoma HA36-4-5.2, Wistar Institute). For A/X-31 experiments, cells were processed comparably as above, but in addition were permeabilized, followed by immunostaining for NP expression (NP (clone H16-L10-4R5) mouse monoclonal (Millipore MAB8800)). Both sets of experiments were completed using an Alexa Fluor 488 goat anti-mouse secondary at 1:1,000 (A11001, Invitrogen). The cells were imaged on an automated Image Express Micro microscope (Molecular Devices), and images were analysed using the Metamorph Cell Scoring software program (Molecular Devices Inc.). Cytokines: Cells were incubated with cytokines for 24 h prior to viral infection. Murine interferon α (PBL Interferon Source, Cat # 12100-1) and IFN-γ (PBL Interferon Source, Cat # 12500-2) were used at 500-2500 U/ml., and 100-300 ng/ml respectively. A549 transduction and infectivity assays A549 cells (ATCC Cat#CCL-185) were grown in complete media (DMEM (Invitrogen Cat#11965) with 10% FBS (Invitrogen)). A549 stable cell lines were made by gamma-retroviral transduction using either the empty vector control virus (pQXCIP, Clontech), the full-length human IFITM3 cDNA, or a truncated human IFITM3 cDNA which is missing the first 21 amino acids (NΔ21). After puromycin selection, expression of the IFITM3 and NΔ21 proteins were confirmed by Western blotting using an 18% SDS-PAGE gel and an anti-IFITM3 antibody that was raised against the conserved intracellular loop (CIL) of IFITM3 (Proteintech). A549 cell lines were challenged with one of the following strains: A/WSN/33 (a kind gift of Dr. Peter Palese), A/California/7/2009, A/Uruguay/716/2007 and B/Brisbane/60/2008 (kind gift of Dr. Jan Malbry, CDC, Atlanta, GA, USA) for 12h, then fixed with 4% PFA and immunostained with anti-HA antibody (HA (Wistar collection) or anti-NP antibodies (Abcam), or Millipore clone H16-L10-4R5 anti-influenza A virus antibody). Percent infection was calculated from immunofluorescent images as described for the MEF experiments above. Alternatively, cells were transduced with lentiviral vectors to express green fluorescent protein (GFP) or IFITM3 and were stained with anti-NP antibody (Abcam) and analysed by flow cytometry following challenge with B/Bangladesh/3333/2007 virus (NIMR, England). For the immunofluorescence-based viral titering experiments, virus-containing supernatant was collected from the indicated A549 cell line cultures after 12h of infection with WSN/33 (Part One). Next this supernatant was used to infect MDCK cells (ATCC) in a well by well manner (Part Two). Both the A549 and MDCK cells were then processed to detect viral HA expression as described above. LCL infectivity assays LCL TT and LCL CC cells were grown in RPMI-1640 (Sigma-Aldrich) containing 10% FCS, 2mM L-glutamine, 1mM sodium pyruvate, 1× MEM non-essential amino acids solution, and 20mM HEPES (all from Invitrogen). For infectivity assays, LCL cells were either treated with recombinant human IFN-α2 (PBL Interferon Source, #11100) at 100 units/ml or DPBS (Sigma-Aldrich) for 16h. The LCL cells were then counted, resuspended at a concentration of 5 × 105 cells/ml, and plated on a 96-well round-bottom plate (200μl cell suspension/well). The cells were then challenged with WSN/33 influenza A virus (MOI 0.1). After 18h, the cells were washed twice with 250μl MACS buffer (DPBS containing 2% FCS and 2mM EDTA (Sigma-Aldrich)). The cells were fixed and permeabilised using the BD Cytofix/Cytoperm Fixation/Permeabilisation Kit (BD Biosciences), following the manufacturer’s instructions. Briefly, the cells were resuspended in 100μl of Cytofix/Cytoperm Fixation and Permeabilisation solution and incubated at 4°C for 20 minutes. The cells were then washed twice with 250μl 1× Perm/Wash buffer and resuspended in 50ml 1× Perm/Wash buffer containing a 2 μg/ml solution of a fluorescein isothiocyanate (FITC)-conjugated mouse monoclonal antibody against influenza A virus NP (clone 431, Abcam, #ab20921). The cells were incubated in the diluted antibody solution for 1h at 4°C, washed twice with 250μl 1× Perm/Wash buffer, resuspended in 200μl MACS buffer, and analysed by flow cytometry using a BD FACS Calibur (BD Biosciences). Ethics and sampling We recruited patients with confirmed seasonal influenza A or B virus or pandemic influenza A pH1N1/09 infection who required hospitalisation in England and Scotland between November 2009 and February 2011. Patients with significant risk factors for severe disease, and patients whose daily activity was limited by co-morbid illness were excluded. 53 patients, 29 male and 24 female, average age 37 (range 2-62) were selected. 46 (88%) had no concurrent comorbidities. The remaining 6 had the following comorbid conditions: hypertension (3 patients), alcohol dependency and cerebrovascular disease (1 patient), bipolar disorder (1 patient) and kyphoscoliosis (1 patient). Four patients were pregnant. Where assessed, 36 patients had normal body mass (69%), one had a BMI 40. Seasonal influenza A H3N2, influenza B and pandemic influenza A pH1N1/09 were confirmed locally by viral PCR or serological tests according to regional protocols. Consistent with the prevalent influenza viruses circulating in the UK between 2009 and 2011 26 44 (85%) had pH1N1/09, 2 had pH1N1/09 and influenza B co-infection, 4 had influenza B and 2 had non-subtyped influenza A virus infection. Of the adults, 24 required admission to an intensive care unit (ICU) and 1 required admission to a high dependency unit (HDU). The remainder were managed on medical wards and survived their illnesses. The GenISIS study was approved by the Scotland ‘A’ Research Ethics Committee (09/MRE00/77) and the MOSAIC study was approved by the NHS National Research Ethics Service, Outer West London REC (09/H0709/52, 09/MRE00/67). Consent was obtained directly from competent patients, and from relatives/friends/welfare attorneys of incapacitated patients. Anonymised 9ml EDTA blood samples were transported at ambient temperature. DNA was extracted using a Nucleon Kit (GenProbe) with the BACC3 protocol. DNA samples were re-suspended in 1 ml TE buffer pH 7.5 (10mM Tris-Cl pH 7.5, 1mM EDTA pH 8.0). Sequencing and Genetics Human IFITM3 sequences were amplified from DNA obtained from peripheral blood by nested PCR (GenBank accession numbers JQ610570 – 621). The first round utilised primers FW: 5′-TGAGGGTTATGGGAGACGGGGT-3′and Rv: 5′-TGCTCACGGCAGGAGGCC-3′, followed by an additional round using primers FW: 5′-GCTTTGGGGGAACGGTTGTG-3′and RV: 5′-TGCTCACGGCAGGAGGCCCGA-3′. The 1.8kb IFITM3 band was gel extracted and purified using the QiaQuick Gel Extraction Kit (Qiagen). IFITM3 was Sanger sequenced on an Applied Biosystems 3730×l DNA Analyzer (GATC Biotech) using a combination of eight sequencing primers (Supp. Table S4). Single nucleotide polymorphisms were identified by assembly to the human IFITM3 encoding reference sequence (Acc. No.: NC_000011.9) using Lasergene (DNAStar). Homozygotes were called based on high, single base peaks with high Phred quality scores, whilst heterozygotes were identified based on low, overlapping peaks of two bases with lower Phred quality scores relative to surrounding base calls (Supp. Fig. S9). We identified SNP rs12252 in our sequencing and compared the allele and genotype frequencies to allele and genotype frequencies from 1000 Genomes sequencing data from different populations (Supp. Table S3). In addition, we used the most recent release of phased 1000 Genomes data 27 to impute the region surrounding SNP rs12252 to determine allele frequencies in the publicly available genotype dataset of WTCCC1 controls (n=2,938) and four previously published datasets genotyped from the Netherlands (n=8,892) and Germany (n=6,253) 22 . In the imputation, samples genotyped with Illumina 550k, 610k and 670k platforms were imputed against the June 2011 release of 1000 Genotypes phased haplotypes using the Impute software 28 , version 2.1.2. Only individuals with European ethnicities (CEU, FIN, GBR, IBS, TSI) were included from the 1000 Genomes reference panel. Recommended settings were used for imputing the region 200 kb in either direction from the variants of interest, along with 1Mb buffer size. The statistical significance of the allele frequencies was determined by Fisher’s exact test. We assessed for population stratification by principal component analysis. Genotype data from the WTCCC1 1958 Birth Cohort dataset were obtained from the European Genotype Archive with permission, reformatted and merged with genotype data from the GenISIS study to match 113,819 SNPs present in both cohorts. Suspected strand mismatches were removed by identifying SNPs with more than 2 genotypes and using the LD method as implemented in Plink (v1.07) 29 , resulting in 105,362 matched SNPs. Quality control was applied in GenABEL version 1.6-9 to genotype data for these SNPs for the GenISIS cases and 1499 individuals from WTCCC. Thresholds for quality control (deviation from Hardy-Weinberg equilibrium (p<0.05), MAF<0.0005, call rate<98% in all samples) were applied iteratively to identify all markers and subjects passing all quality control criteria, followed by principal component analysis using GenABEL. We tested for positive selection using both a haplotype-based test (∣XP-EHH-max∣) and allele frequency spectrum-based test statistics, namely Tajima’s D, Fay and Wu’s H and Nielsen et al.’s CLR on 10 kb windows across the entire genome as described previously 27, 30 . The three statistics were combined and the combined p value was plotted corresponding to the 10 kb windows. Supplementary Material Supplementary Figures 10 Supplementary Tables
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              Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.

              The cellular protein retinoic acid-inducible gene I (RIG-I) senses intracellular viral infection and triggers a signal for innate antiviral responses including the production of type I IFN. RIG-I contains a domain that belongs to a DExD/H-box helicase family and exhibits an N-terminal caspase recruitment domain (CARD) homology. There are three genes encoding RIG-I-related proteins in human and mouse genomes. Melanoma differentiation associated gene 5 (MDA5), which consists of CARD and a helicase domain, functions as a positive regulator, similarly to RIG-I. Both proteins sense viral RNA with a helicase domain and transmit a signal downstream by CARD; thus, these proteins share overlapping functions. Another protein, LGP2, lacks the CARD homology and functions as a negative regulator by interfering with the recognition of viral RNA by RIG-I and MDA5. The nonstructural protein 3/4A protein of hepatitis C virus blocks the signaling by RIG-I and MDA5; however, the V protein of the Sendai virus selectively abrogates the MDA5 function. These results highlight ingenious mechanisms for initiating antiviral innate immune responses and the action of virus-encoded inhibitors.

                Author and article information

                [1 ]Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, 38124, Braunschweig, Germany
                [2 ]Department of Bioinformatics and Statistics, Helmholtz Centre for Infection Research, Braunschweig, Germany
                [3 ]Department of Computer Science, Ostfalia University of Applied Sciences, Wolfenbüttel, Germany
                [4 ]Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
                [5 ]Department of Molecular and Cellular Neurobiology, Neuroscience Campus Amsterdam, Amsterdam, VU, the Netherlands
                [6 ]Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China
                [7 ]Nycomed GmbH, Institute for Pharmacology and Preclinical Drug Safety, Barsbuettel-Willinghusen, Germany
                BMC Genomics
                BMC Genomics
                BMC Genomics
                BioMed Central
                20 August 2012
                : 13
                : 411
                Copyright ©2012 Nedelko et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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