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STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor.

Perry ST, Buck MD, Lada SM, Schindler C, Shresta S - PLoS Pathog. (2011)

Bottom Line: High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication.Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression.Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1.

View Article: PubMed Central - PubMed

Affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

ABSTRACT
Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.

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Comparison of ISG Induction in DENV-infected mice.Gene induction evaluated using the RT2 Profiler PCR Array (Mouse IFN-α/β Response Array; SABioscience). (A,B) Annotated gene expression of transcripts with a difference in expression of 3-fold or more over naïve (upregulation-black; downregulation-white) at 12 and 24 hours post-infection of (A) spleens isolated from wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice infected with S221, and (B) BMMs isolated from wild type, STAT1−/−, and STAT1−/−/2−/− mice infected with S221 (MOI = 5). (C, D) Gene induction in the spleen expressed as fold-increase over naïve for each strain at (C) 12 hours and (D) 24 hours post-infection. Data represent mean fold-induction of three animals per strain at each timepoint.
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ppat-1001297-g004: Comparison of ISG Induction in DENV-infected mice.Gene induction evaluated using the RT2 Profiler PCR Array (Mouse IFN-α/β Response Array; SABioscience). (A,B) Annotated gene expression of transcripts with a difference in expression of 3-fold or more over naïve (upregulation-black; downregulation-white) at 12 and 24 hours post-infection of (A) spleens isolated from wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice infected with S221, and (B) BMMs isolated from wild type, STAT1−/−, and STAT1−/−/2−/− mice infected with S221 (MOI = 5). (C, D) Gene induction in the spleen expressed as fold-increase over naïve for each strain at (C) 12 hours and (D) 24 hours post-infection. Data represent mean fold-induction of three animals per strain at each timepoint.

Mentions: To further define the mechanisms by which type I IFN receptor-STAT2 signaling protects against DENV infection in vivo, we next examined gene expression in the spleens of S221-infected mice using the Type I IFN-related RT2 Profiler PCR Array (SABiosciences/QIAGEN). RNA from whole spleens was analyzed and fold-induction calculated by comparing infected mice to naïve mice of the corresponding strain. Of the 84 genes in the array, 31 (36.9%), 16 (19.0%), 22 (26.2%), and 7 (8.3%) genes, respectively, were induced 3-fold over naïve in wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice at 12 hours post-infection (Figure 4A), and the number of genes upregulated was similar at 24 hours post-infection for each mouse strain. Genes that were induced in STAT1−/−/2−/− mice identified ISGs that were upregulated independently of either STAT1 or STAT2. These ISGs included Ifna2, Ifna4, and Ifnb1, which were induced to high levels in all four strains at 12 hours (>1000-fold) and 24 hours (>100-fold) post-infection (Table S1), and likely represent early IRF3-mediated gene expression [36].


STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor.

Perry ST, Buck MD, Lada SM, Schindler C, Shresta S - PLoS Pathog. (2011)

Comparison of ISG Induction in DENV-infected mice.Gene induction evaluated using the RT2 Profiler PCR Array (Mouse IFN-α/β Response Array; SABioscience). (A,B) Annotated gene expression of transcripts with a difference in expression of 3-fold or more over naïve (upregulation-black; downregulation-white) at 12 and 24 hours post-infection of (A) spleens isolated from wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice infected with S221, and (B) BMMs isolated from wild type, STAT1−/−, and STAT1−/−/2−/− mice infected with S221 (MOI = 5). (C, D) Gene induction in the spleen expressed as fold-increase over naïve for each strain at (C) 12 hours and (D) 24 hours post-infection. Data represent mean fold-induction of three animals per strain at each timepoint.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040673&req=5

ppat-1001297-g004: Comparison of ISG Induction in DENV-infected mice.Gene induction evaluated using the RT2 Profiler PCR Array (Mouse IFN-α/β Response Array; SABioscience). (A,B) Annotated gene expression of transcripts with a difference in expression of 3-fold or more over naïve (upregulation-black; downregulation-white) at 12 and 24 hours post-infection of (A) spleens isolated from wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice infected with S221, and (B) BMMs isolated from wild type, STAT1−/−, and STAT1−/−/2−/− mice infected with S221 (MOI = 5). (C, D) Gene induction in the spleen expressed as fold-increase over naïve for each strain at (C) 12 hours and (D) 24 hours post-infection. Data represent mean fold-induction of three animals per strain at each timepoint.
Mentions: To further define the mechanisms by which type I IFN receptor-STAT2 signaling protects against DENV infection in vivo, we next examined gene expression in the spleens of S221-infected mice using the Type I IFN-related RT2 Profiler PCR Array (SABiosciences/QIAGEN). RNA from whole spleens was analyzed and fold-induction calculated by comparing infected mice to naïve mice of the corresponding strain. Of the 84 genes in the array, 31 (36.9%), 16 (19.0%), 22 (26.2%), and 7 (8.3%) genes, respectively, were induced 3-fold over naïve in wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice at 12 hours post-infection (Figure 4A), and the number of genes upregulated was similar at 24 hours post-infection for each mouse strain. Genes that were induced in STAT1−/−/2−/− mice identified ISGs that were upregulated independently of either STAT1 or STAT2. These ISGs included Ifna2, Ifna4, and Ifnb1, which were induced to high levels in all four strains at 12 hours (>1000-fold) and 24 hours (>100-fold) post-infection (Table S1), and likely represent early IRF3-mediated gene expression [36].

Bottom Line: High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication.Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression.Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1.

View Article: PubMed Central - PubMed

Affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

ABSTRACT
Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.

Show MeSH
Related in: MedlinePlus