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Cited by 296interferon and immune responsesImmune Response and InflammationImmunotherapy and Immune Responses

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IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

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Lazear, Helen M., Lancaster, Alissa, Wilkins, Courtney, Suthar, Mehul S., Huang, Albert, Vick, Sarah C., Clepper, Lisa, Thackray, Larissa, Brassil, Margaret M., Virgin, Herbert W., Nikolich-Zugich, Janko, Moses, Ashlee V., Gale, Michael, Früh, Klaus, Diamond, Michael S.·2013·PLoS Pathogens
DOI 10.1371/journal.ppat.1003118PMC PMC3536698
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Abstract

Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3(-/-)×Irf7(-/-) double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3(-/-)×Irf5(-/-)×Irf7(-/-) triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar(-/-)). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar(-/-) mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs(-/-) mDC. The relative equivalence of TKO and Mavs(-/-) responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.

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Figure 1 Lethality and viral burden after virus infection. A–C. WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were infected subcutaneously with 102 PFU of a virulent (WNV-NY) or an attenuated (WNV-MAD) WNV strain or infected orally with 3×107 PFU of MNV and followed for lethality for 21 days (8 to 20 mice per group). DKO and Ifnar−/− survival curves were compared to TKO by the log-rank test; asterisks indicate survival curves that are significantly different (****, P<0.0001; ***, P<0.001; *, P<0.05). D–G. The indicated groups of mice were infected subcutaneously with WNV-NY or WNV-MAD and tissues were harvested for viral burden analysis at 2 (WNV-NY) or 6 (WNV-MAD) days after infection. Viral infection in the draining lymph node and serum was determined by qRT-PCR, and infection in the spleen and brain was determined by plaque assay. Data are expressed as the mean viral titer ± standard error of the mean (SEM) of 5 to 9 mice per group and the dotted line represents the limit of detection of the assay. DKO and Ifnar−/− groups were compared to TKO by the Mann-Whitney test; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05).
Figure 1 Lethality and viral burden after virus infection. A–C. WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were infected subcutaneously with 102 PFU of a virulent (WNV-NY) or an attenuated (WNV-MAD) WNV strain or infected orally with 3×107 PFU of MNV and followed for lethality for 21 days (8 to 20 mice per group). DKO and Ifnar−/− survival curves were compared to TKO by the log-rank test; asterisks indicate survival curves that are significantly different (****, P<0.0001; ***, P<0.001; *, P<0.05). D–G. The indicated groups of mice were infected subcutaneously with WNV-NY or WNV-MAD and tissues were harvested for viral burden analysis at 2 (WNV-NY) or 6 (WNV-MAD) days after infection. Viral infection in the draining lymph node and serum was determined by qRT-PCR, and infection in the spleen and brain was determined by plaque assay. Data are expressed as the mean viral titer ± standard error of the mean (SEM) of 5 to 9 mice per group and the dotted line represents the limit of detection of the assay. DKO and Ifnar−/− groups were compared to TKO by the Mann-Whitney test; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05).CC BY · PubMed Central
Figure 2 Type I IFN activity in serum. WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were infected with 102 PFU of WNV-NY or WNV-MAD and serum levels of type I IFN were measured 2 (WNV-NY) or 6 (WNV-MAD) days after infection using a bioassay. Data represent the mean ± SEM of 5 to 9 mice per group. DKO and Ifnar−/− groups were compared to TKO by a two-way ANOVA; asterisks indicate differences that are statistically significant (****, P<0.0001).
Figure 2 Type I IFN activity in serum. WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were infected with 102 PFU of WNV-NY or WNV-MAD and serum levels of type I IFN were measured 2 (WNV-NY) or 6 (WNV-MAD) days after infection using a bioassay. Data represent the mean ± SEM of 5 to 9 mice per group. DKO and Ifnar−/− groups were compared to TKO by a two-way ANOVA; asterisks indicate differences that are statistically significant (****, P<0.0001).CC BY · PubMed Central
Figure 3 ISG and IFN-β induction in primary myeloid cells in response to WNV infection. Primary myeloid cells from WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were infected with WNV-NY. A and B. Bone marrow-derived mDC (A) and macrophages (B) were infected at an MOI of 0.001 (mDC) or 0.01 (macrophages), and viral replication was measured by focus-forming assay. Data represent the mean ± SEM of two independent experiments performed in triplicate. The dotted line represents the limit of detection of the assay. C and D: WT and TKO mDCs (C) and macrophages (D) were infected at an MOI of 1 or mock-infected (M). At 12, 24, or 48 hours after infection, cells were lysed, separated by SDS-PAGE and analyzed by western blot to detect expression of specific ISGs or viral proteins. One representative experiment of three is shown. E and F: mDCs (E) and macrophages (F) were infected with WNV at an MOI of 0.1, RNA was isolated at 24 hours after infection, and relative expression of the indicated target genes was measured by qRT-PCR. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to uninfected cells on a log2 scale. Data represent the average of three independent experiments and are expressed as the mean ± SEM. A–B and E–F: DKO and Ifnar−/− groups were compared to TKO by two-way ANOVA; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01).
Figure 3 ISG and IFN-β induction in primary myeloid cells in response to WNV infection. Primary myeloid cells from WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were infected with WNV-NY. A and B. Bone marrow-derived mDC (A) and macrophages (B) were infected at an MOI of 0.001 (mDC) or 0.01 (macrophages), and viral replication was measured by focus-forming assay. Data represent the mean ± SEM of two independent experiments performed in triplicate. The dotted line represents the limit of detection of the assay. C and D: WT and TKO mDCs (C) and macrophages (D) were infected at an MOI of 1 or mock-infected (M). At 12, 24, or 48 hours after infection, cells were lysed, separated by SDS-PAGE and analyzed by western blot to detect expression of specific ISGs or viral proteins. One representative experiment of three is shown. E and F: mDCs (E) and macrophages (F) were infected with WNV at an MOI of 0.1, RNA was isolated at 24 hours after infection, and relative expression of the indicated target genes was measured by qRT-PCR. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to uninfected cells on a log2 scale. Data represent the average of three independent experiments and are expressed as the mean ± SEM. A–B and E–F: DKO and Ifnar−/− groups were compared to TKO by two-way ANOVA; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01).CC BY · PubMed Central
Figure 4 ISG induction by IFN-β and TLR agonists in WT and deficient mDC. mDC from WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were treated with IFN-β (500 IU/ml) (A), poly(I∶C) (50 µg/ml) (B), or LPS (5 µg/ml) (C). Total RNA was isolated 24 hours later and relative gene expression was measured by qRT-PCR. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to untreated cells on a log2 scale. Data represent the average of three independent experiments and are expressed as the mean ± SEM. DKO and Ifnar−/− groups were compared to TKO by two-way ANOVA; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05).
Figure 4 ISG induction by IFN-β and TLR agonists in WT and deficient mDC. mDC from WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, and Ifnar−/− mice were treated with IFN-β (500 IU/ml) (A), poly(I∶C) (50 µg/ml) (B), or LPS (5 µg/ml) (C). Total RNA was isolated 24 hours later and relative gene expression was measured by qRT-PCR. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to untreated cells on a log2 scale. Data represent the average of three independent experiments and are expressed as the mean ± SEM. DKO and Ifnar−/− groups were compared to TKO by two-way ANOVA; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05).CC BY · PubMed Central
Figure 5 Microarray analysis of WNV infected mDC. mDC from WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, Mavs−/− and Ifnar−/− mice were infected with WNV-NY at an MOI of 25 and total RNA was harvested 24 hours later. A. WNV infection of mDC from the indicated genotypes as assessed by anti-WNV MAb staining at 24 hours after infection. B. Heatmap showing the 50 genes with the greatest fold change in expression in WNV-infected mDC compared to mock-infected cells, according to the indicated color scale. The gray portion of the color scale, labeled “ns” for non-significant, represents genes that failed to meet the cutoff criteria for induction. Gene expression was assessed by microarray analysis on Illumina chips. Each column represents the mean of three independent samples per genotype. C. Quantitative RT-PCR was performed on the same RNA samples analyzed by microarray to detect expression of the indicated target genes. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to mock-infected cells on a log2 scale. Data represent the average of three independent samples and are expressed as the mean ± SEM. The dotted line indicates a 1.5-fold increase in expression.
Figure 5 Microarray analysis of WNV infected mDC. mDC from WT, Irf3−/−×Irf7−/− DKO, Irf3−/−×Irf5−/−×Irf7−/− TKO, Mavs−/− and Ifnar−/− mice were infected with WNV-NY at an MOI of 25 and total RNA was harvested 24 hours later. A. WNV infection of mDC from the indicated genotypes as assessed by anti-WNV MAb staining at 24 hours after infection. B. Heatmap showing the 50 genes with the greatest fold change in expression in WNV-infected mDC compared to mock-infected cells, according to the indicated color scale. The gray portion of the color scale, labeled “ns” for non-significant, represents genes that failed to meet the cutoff criteria for induction. Gene expression was assessed by microarray analysis on Illumina chips. Each column represents the mean of three independent samples per genotype. C. Quantitative RT-PCR was performed on the same RNA samples analyzed by microarray to detect expression of the indicated target genes. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to mock-infected cells on a log2 scale. Data represent the average of three independent samples and are expressed as the mean ± SEM. The dotted line indicates a 1.5-fold increase in expression.CC BY · PubMed Central
Figure 6 Type I IFN signaling mediates gene induction by IRF-5 and MAVS. A. Heatmap displaying 22 genes induced upon WNV infection in Ifnar−/− mDC (greater than 1.5 fold upregulated compared to mock-infected cells, P<0.05). B. Expression of selected IFN-independent genes was validated by qRT-PCR using the same RNA samples analyzed by microarray. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to mock-infected cells on a log2 scale. Data represent the average of three independent samples and are expressed as the mean ± SEM. The dotted line indicates a 1.5-fold increase in expression. C. Venn diagram of the expression patterns of IFN-independent genes, based on microarray and qRT-PCR analyses. D. DKO mDC were treated with 25 µg/ml of an IFNAR-blocking antibody (MAR1-5A3) or an isotype control antibody (GIR-208) for one hour prior to infection with WNV-NY at an MOI of 0.1. Total RNA was isolated after 24 hours and relative gene expression was measured by qRT-PCR. Expression of the indicated target genes was normalized to Gapdh and is displayed as the fold increase compared to untreated cells on a log2 scale. Data represent the average of four samples from two independent experiments and are expressed as the mean ± SEM. E. mDC from WT, Irf5−/−, and DKO mice were infected with WNV-NY at an MOI of 0.1 and qRT-PCR was performed as in panel D. Data represent the average of 12 samples from four independent experiments, are displayed as the fold increase compared to untreated cells on a log2 scale, and are expressed as the mean ± SEM. F. mDC from WT, Irf5−/−, DKO, and TKO mice were infected with SeV at an MOI of 3 and qRT-PCR was performed as in panel D. Data represent the average of six samples from two independent experiments, are displayed as the fold increase compared to untreated cells on a log2 scale, and are expressed as the mean ± SEM. G. mDC from WT and Irf5−/− mice were infected at an MOI of 0.001 and viral replication was measured by focus-forming assay. Data represent the mean ± SEM of six independent experiments performed in triplicate. WT and Irf5−/− titers were compared by two-way ANOVA and were not significantly different (P>0.05). The dotted line represents the limit of detection of the assay.
Figure 6 Type I IFN signaling mediates gene induction by IRF-5 and MAVS. A. Heatmap displaying 22 genes induced upon WNV infection in Ifnar−/− mDC (greater than 1.5 fold upregulated compared to mock-infected cells, P<0.05). B. Expression of selected IFN-independent genes was validated by qRT-PCR using the same RNA samples analyzed by microarray. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to mock-infected cells on a log2 scale. Data represent the average of three independent samples and are expressed as the mean ± SEM. The dotted line indicates a 1.5-fold increase in expression. C. Venn diagram of the expression patterns of IFN-independent genes, based on microarray and qRT-PCR analyses. D. DKO mDC were treated with 25 µg/ml of an IFNAR-blocking antibody (MAR1-5A3) or an isotype control antibody (GIR-208) for one hour prior to infection with WNV-NY at an MOI of 0.1. Total RNA was isolated after 24 hours and relative gene expression was measured by qRT-PCR. Expression of the indicated target genes was normalized to Gapdh and is displayed as the fold increase compared to untreated cells on a log2 scale. Data represent the average of four samples from two independent experiments and are expressed as the mean ± SEM. E. mDC from WT, Irf5−/−, and DKO mice were infected with WNV-NY at an MOI of 0.1 and qRT-PCR was performed as in panel D. Data represent the average of 12 samples from four independent experiments, are displayed as the fold increase compared to untreated cells on a log2 scale, and are expressed as the mean ± SEM. F. mDC from WT, Irf5−/−, DKO, and TKO mice were infected with SeV at an MOI of 3 and qRT-PCR was performed as in panel D. Data represent the average of six samples from two independent experiments, are displayed as the fold increase compared to untreated cells on a log2 scale, and are expressed as the mean ± SEM. G. mDC from WT and Irf5−/− mice were infected at an MOI of 0.001 and viral replication was measured by focus-forming assay. Data represent the mean ± SEM of six independent experiments performed in triplicate. WT and Irf5−/− titers were compared by two-way ANOVA and were not significantly different (P>0.05). The dotted line represents the limit of detection of the assay.CC BY · PubMed Central
Figure 7 WT, Irf3−/−×Irf7−/− DKO, and Irf3−/−×Irf5−/−×Irf7−/− TKO immortalized MEFs were transfected with plasmids expressing myc-tagged IRF-5 or residues 1–229 of RIG-I (N-RIG) and analyzed at 24 hours after transfection by western blot (A) or qRT-PCR (B–D). A. Transfected cell lysates were separated by SDS-PAGE and N-RIG or IRF-5 were detected with an anti-myc-tag antibody. Un: no transfection. Expression of N-RIG and IRF-5 was decreased slightly upon co-transfection, likely secondary to promoter competition. B–D. Expression of the indicated ISGs was measured from total RNA by qRT-PCR. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to untransfected cells on a log2 scale. Data represent the average of four samples from two independent experiments and are expressed as the mean ± SEM. The co-transfection group was compared to transfection with the individual plasmids by two-way ANOVA for DKO and TKO groups; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05).
Figure 7 WT, Irf3−/−×Irf7−/− DKO, and Irf3−/−×Irf5−/−×Irf7−/− TKO immortalized MEFs were transfected with plasmids expressing myc-tagged IRF-5 or residues 1–229 of RIG-I (N-RIG) and analyzed at 24 hours after transfection by western blot (A) or qRT-PCR (B–D). A. Transfected cell lysates were separated by SDS-PAGE and N-RIG or IRF-5 were detected with an anti-myc-tag antibody. Un: no transfection. Expression of N-RIG and IRF-5 was decreased slightly upon co-transfection, likely secondary to promoter competition. B–D. Expression of the indicated ISGs was measured from total RNA by qRT-PCR. Gene expression was normalized to Gapdh and is displayed as the fold increase compared to untransfected cells on a log2 scale. Data represent the average of four samples from two independent experiments and are expressed as the mean ± SEM. The co-transfection group was compared to transfection with the individual plasmids by two-way ANOVA for DKO and TKO groups; asterisks indicate differences that are statistically significant (****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05).CC BY · PubMed Central
Figure 8 Model of Type I IFN and ISG induction in mDC. WNV infection is sensed by PRR from the RLR family (RIG-I and MDA5, green) or TLR family (TLR3 and TLR7, yellow and orange). PRR signal through their respective adaptor molecules (MAVS, TRIF, MyD88), which activates cellular kinases (TBK1, IKKε, TRAF6, IRAK1). Phosphorylation of IRF-3, IRF-5, and IRF-7 (blue) induces nuclear localization, and in concert with other transcription factors (e.g., NF-κB), results in induced expression of Ifnb and ISGs. IRF-3, IRF-5, and IRF-7 are each sufficient to induce expression of IFN-β (red), which can signal through IFNAR to activate expression of hundreds of ISGs (pink). Some ISGs, including Ifna, Oas1a, and Pkr, are dependent strictly upon IFN signaling for their induction. Others, including Ifit1, Ifit2, Rsad2, and Cxcl10, can be induced directly by IRF-3, although IRF-5 apparently is not sufficient to induce these genes independently of IFN signaling. In addition to being activated by TLR7 signaling through MyD88, IRF-5 is activated by MAVS through an uncharacterized pathway.
Figure 8 Model of Type I IFN and ISG induction in mDC. WNV infection is sensed by PRR from the RLR family (RIG-I and MDA5, green) or TLR family (TLR3 and TLR7, yellow and orange). PRR signal through their respective adaptor molecules (MAVS, TRIF, MyD88), which activates cellular kinases (TBK1, IKKε, TRAF6, IRAK1). Phosphorylation of IRF-3, IRF-5, and IRF-7 (blue) induces nuclear localization, and in concert with other transcription factors (e.g., NF-κB), results in induced expression of Ifnb and ISGs. IRF-3, IRF-5, and IRF-7 are each sufficient to induce expression of IFN-β (red), which can signal through IFNAR to activate expression of hundreds of ISGs (pink). Some ISGs, including Ifna, Oas1a, and Pkr, are dependent strictly upon IFN signaling for their induction. Others, including Ifit1, Ifit2, Rsad2, and Cxcl10, can be induced directly by IRF-3, although IRF-5 apparently is not sufficient to induce these genes independently of IFN signaling. In addition to being activated by TLR7 signaling through MyD88, IRF-5 is activated by MAVS through an uncharacterized pathway.CC BY · PubMed Central

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Authors
Lazear, H. M., Lancaster, A., Wilkins, C., Suthar, M. S., Huang, A., Vick, S. C., Clepper, L., Thackray, L., Brassil, M. M., Virgin, H. W., Nikolich-Zugich, J., Moses, A. V., Gale, M., Früh, K., & Diamond, M. S.
Affiliations
  • Washington University in St. Louis (US)
  • Oregon Health & Science University (US)
  • University of Washington (US)
  • Emory University (US)
  • Vaccine and Gene Therapy Institute (US)
Corresponding author
Diamond, Michael S.
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2013-01-03
Volume
9
Issue
1
Pages
e1003118
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1003118
PMC
PMC3536698
OpenAlex
W2036679352
Cited by
296
References
85
Citations by year
2026: 7 · 2025: 11 · 2024: 12 · 2023: 11 · 2022: 21 · 2021: 25 · 2020: 27 · 2019: 22 · 2018: 30 · 2017: 25 · 2016: 28 · 2015: 20 · 2014: 33 · 2013: 23
FWCI
19.19
Type
journal article
Language
en
Update notices
correction (2013-05-03)
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • National Institutes of Health (n01ai50027-8-0-1, AI083019, AI057160)
  • National Institute of Allergy and Infectious Diseases (N01 AI50027, U19AI083019, U54AI081680, N01 AI050027, R01AI074973, U54AI057160)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
IRF3, IRF5, IRF7, type I interferon, myeloid dendritic cells, MAVS, interferon-stimulated genes, West Nile virus, murine norovirus, positive-strand RNA viruses, interferon-beta, Toll-like receptor signaling, RIG-I-like receptor signaling, transcription factors, macrophages, viral pathogenesis
MeSH terms
Animals, Dendritic Cells, Macrophages, Mice, Inbred C57BL, West Nile Fever, West Nile virus, Signal Transduction, Interferon-beta, Mice, Knockout, Viral Load, Myeloid Cells, Adaptor Proteins, Signal Transducing, Interferon Regulatory Factors, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Toll-Like Receptors, Mice, Receptor, Interferon alpha-beta

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