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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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Levels of type I IFN in the serum of DENV-infected mice.Mice were infected i.v. with 1010 GE of S221, and serum collected at 6, 12, 18, or 24 hours post-infection. Levels of (A) IFN-α and (B) IFN-β in the serum were determined by ELISA (n = 4–6 mice per group). Error bars represent the SEM. Results are representative of two independent experiments.
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ppat-1001297-g003: Levels of type I IFN in the serum of DENV-infected mice.Mice were infected i.v. with 1010 GE of S221, and serum collected at 6, 12, 18, or 24 hours post-infection. Levels of (A) IFN-α and (B) IFN-β in the serum were determined by ELISA (n = 4–6 mice per group). Error bars represent the SEM. Results are representative of two independent experiments.

Mentions: Based on the survival data indicating that STAT1-independent protection is mediated via type I IFN signaling, we next examined type I IFN levels in infected mice, as expression of type I IFN is partially dependent upon a positive feedback mechanism [2]. Specifically, type I IFN levels in wild type and single-deficient mice were compared to STAT1−/−/2−/− mice, which are not expected to possess the positive feedback loop. Serum levels of IFN-α and IFN-β in wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice were measured by ELISA between 0 and 24 hours post-infection. High levels of serum IFN-α were present in wild type mice by 12 hours post-infection, and these levels diminished between 18 and 24 hours after infection (Figure 3A), consistent with our previous observations in wild type C57BL/6 mice following DENV infection [28]. However, robust IFN-α production in both STAT1−/− and STAT2−/− mice was delayed until 18 hours following infection, and STAT1−/− mice exhibited decreased expression of IFN-α compared with STAT2−/− mice. Serum IFN-α levels in STAT1−/−/2−/− mice followed the same kinetics as STAT1−/− mice, including increased expression at 18 hours post-infection. However, despite similar levels of viremia detected in both strains at 24 hours post-infection (Figure 2A), IFN-α in STAT1−/− mice remained elevated but in STAT1−/−/2−/− mice it decreased to the level at or below the limit of detection (p<0.0001). Similar trends were observed for IFN-β production following DENV infection (Figure 3B), including delayed induction in the knockout strains relative to wild type mice, and elevated IFN-β levels in STAT1−/− but not STAT1−/−/2−/− mice at 24 hours. Together, these results demonstrate that the combined function of STAT1 and STAT2 is required for maximum early induction of type I IFN in response to DENV infection. The presence of either STAT1 or STAT2 alone is also sufficient to drive type I IFN expression, but with delayed kinetics when compared to an intact IFN signaling pathway. Additionally, the difference in IFN levels between STAT1−/− and the double knockout mice at 24 hours shows that a STAT2-dependent mechanism contributes to type I IFN expression in the absence of STAT1.


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)

Levels of type I IFN in the serum of DENV-infected mice.Mice were infected i.v. with 1010 GE of S221, and serum collected at 6, 12, 18, or 24 hours post-infection. Levels of (A) IFN-α and (B) IFN-β in the serum were determined by ELISA (n = 4–6 mice per group). Error bars represent the SEM. Results are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001297-g003: Levels of type I IFN in the serum of DENV-infected mice.Mice were infected i.v. with 1010 GE of S221, and serum collected at 6, 12, 18, or 24 hours post-infection. Levels of (A) IFN-α and (B) IFN-β in the serum were determined by ELISA (n = 4–6 mice per group). Error bars represent the SEM. Results are representative of two independent experiments.
Mentions: Based on the survival data indicating that STAT1-independent protection is mediated via type I IFN signaling, we next examined type I IFN levels in infected mice, as expression of type I IFN is partially dependent upon a positive feedback mechanism [2]. Specifically, type I IFN levels in wild type and single-deficient mice were compared to STAT1−/−/2−/− mice, which are not expected to possess the positive feedback loop. Serum levels of IFN-α and IFN-β in wild type, STAT1−/−, STAT2−/−, and STAT1−/−/2−/− mice were measured by ELISA between 0 and 24 hours post-infection. High levels of serum IFN-α were present in wild type mice by 12 hours post-infection, and these levels diminished between 18 and 24 hours after infection (Figure 3A), consistent with our previous observations in wild type C57BL/6 mice following DENV infection [28]. However, robust IFN-α production in both STAT1−/− and STAT2−/− mice was delayed until 18 hours following infection, and STAT1−/− mice exhibited decreased expression of IFN-α compared with STAT2−/− mice. Serum IFN-α levels in STAT1−/−/2−/− mice followed the same kinetics as STAT1−/− mice, including increased expression at 18 hours post-infection. However, despite similar levels of viremia detected in both strains at 24 hours post-infection (Figure 2A), IFN-α in STAT1−/− mice remained elevated but in STAT1−/−/2−/− mice it decreased to the level at or below the limit of detection (p<0.0001). Similar trends were observed for IFN-β production following DENV infection (Figure 3B), including delayed induction in the knockout strains relative to wild type mice, and elevated IFN-β levels in STAT1−/− but not STAT1−/−/2−/− mice at 24 hours. Together, these results demonstrate that the combined function of STAT1 and STAT2 is required for maximum early induction of type I IFN in response to DENV infection. The presence of either STAT1 or STAT2 alone is also sufficient to drive type I IFN expression, but with delayed kinetics when compared to an intact IFN signaling pathway. Additionally, the difference in IFN levels between STAT1−/− and the double knockout mice at 24 hours shows that a STAT2-dependent mechanism contributes to type I IFN expression in the absence of STAT1.

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