Induction of MxA Gene Expression by Influenza A Virus Requires Type I or Type III Interferon Signaling

Holzinger, Dirk; Jorns, Carl; Stertz, Silke; Boisson–Dupuis, Stéphanie; Thimme, Robert; Weidmann, Manfred; Casanova, Jean‐Laurent; Haller, Otto; Kochs, Georg

doi:10.1128/jvi.00546-06

Cited by 205 publications

(163 citation statements)

References 84 publications

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“…ISG56/IFIT1 could be induced upon infection of patient cells with virus, consistent with the observation that IRF3 activation was intact ( Fig. 1C) and that IRF3 itself can up-regulate ISG56 expression but not that of MxA (8,9,20). Neither gene was up-regulated by IFN-γ.…”

Section: Resultssupporting

confidence: 68%

STAT2 deficiency and susceptibility to viral illness in humans

Hambleton

Goodbourn

Young

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

221

205

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Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.measles vaccine | viruses | rare diseases

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Section: Resultssupporting

confidence: 68%

STAT2 deficiency and susceptibility to viral illness in humans

Hambleton

Goodbourn

Young

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

221

205

View full text Add to dashboard Cite

show abstract

“…Further, in vivo MxA mRNA expression appears to lack a strong IFN-␣␤ independent response; thus, this mode of gene regulation does not seem to play a significant role in inducing MxA expression (39). In fact, MxA expression and MxA-mediated resistance to influenza virus is associated with IFN-␣␤ -dependent ISRE induction (5). It has recently been shown that, in influenza-infected human cells, type I and type III IFN activity is required for MxA expression (5).…”

Section: Discussionmentioning

confidence: 99%

“…4). MxA expression and MxA-mediated resistance to the influenza virus is associated with IFN-␣␤-dependent, IFN-␣␤-stimulated response element (ISRE) induction (5), and MxA expression during influenza virus infection requires type I and type III IFN activity (5). Despite the clear and critical role of Mx1 in anti-influenza immunity in mice and in human cells in vitro, the role of MxA in controlling influenza in primates, including humans, is unknown.…”

Section: Interferon-induced Expression Of Mxa In the Respiratory Tracmentioning

confidence: 99%

Interferon-Induced Expression of MxA in the Respiratory Tract of Rhesus Macaques Is Suppressed by Influenza Virus Replication

Carroll

Matzinger

Genescà

et al. 2008

The Journal of Immunology

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To determine the relationship between influenza A virus replication and innate antiviral immune responses, rhesus monkeys were given oseltamivir before influenza A/Memphis/7/01 (H1N1) challenge. We found that oseltamivir treatment significantly reduced viral replication in the trachea (p < 0.029). Further, in the trachea of both treated and untreated monkeys the mRNA levels of most innate antiviral molecules in the IFN-αβ pathway were dramatically increased by 24 h postinfection. However, the mRNA level of a single IFN-stimulated gene, MxA (myxovirus resistance A), the IFN-stimulated gene known to be critical in blocking influenza virus replication, was significantly lower in the tracheal lavages of untreated monkeys than in the oseltamivir-treated monkeys (p = 0.05). These results demonstrate for the first time that uncontrolled influenza A virus replication actively suppresses MxA gene expression and emphasize the critical role of innate immunity in controlling influenza virus replication in vivo.

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“…Stimulation of TLR2 and TLR4 with agonists, including lipopolysaccharide, provided the best protection against influenza viruses in animal models compared with other TLR3 and TLR7 agonists [56]. Early control of HPAI H5N1 virus is mediated by the type I IFN response in mice [57].…”

Section: Ifns and Influenza Virusmentioning

confidence: 99%

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

2012

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Interferons (IFNs) comprise type I, II and III families with multiple subtypes. Via transcription of IFNstimulated genes (ISGs), IFNs can exert multiple biological effects on the cell. In infectious and chronic inflammatory diseases, the IFNs and their ISG sets can be potentially utilized as biomarkers of disease outcome. Animal models allow investigations into disease pathogenesis and gene knockout models have proved cause and effect relationships of molecules related to the IFN response. Sets of IFN subtypes and their ISG products provide immunological signature patterns for different viral and other diseases. In this article, we give an overview of IFNs in several virus infection models and autoimmune diseases of medical relevance. Lessons learned from animal models inform us of IFN system parameters as indicators of disease outcome and whether clinical research is warranted. Moreover, validated IFN biomarkers for prognosis enhance our understanding of therapeutic and vaccine development.

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Induction of MxA Gene Expression by Influenza A Virus Requires Type I or Type III Interferon Signaling

Cited by 205 publications

References 84 publications

STAT2 deficiency and susceptibility to viral illness in humans

STAT2 deficiency and susceptibility to viral illness in humans

Interferon-Induced Expression of MxA in the Respiratory Tract of Rhesus Macaques Is Suppressed by Influenza Virus Replication

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

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