Interferon-stimulated genes and their antiviral effector functions

Schoggins, John W.; Rice, Charles M.

doi:10.1016/j.coviro.2011.10.008

Cited by 1,113 publications

(1,053 citation statements)

References 68 publications

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“…This is extremely surprising given the critical role of IFN in the induction of an antiviral state in uninfected cells, thereby slowing the spread of virus from the initial focus of infection. Although many ISGs may be activated by other transcription factors [including IRF1 (39)], such ISGF3-independent activation usually occurs only within virally infected cells. Thus, recognition of this unusual PID phenotype challenges understanding of the concerted antiviral immune response and provides an important model in which to define the role of innate IFN and its interaction with viral pathogenesis in humans.…”

Section: Resultsmentioning

confidence: 99%

STAT2 deficiency and susceptibility to viral illness in humans

Hambleton

Goodbourn

Young

et al. 2013

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

225

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: Resultsmentioning

confidence: 99%

STAT2 deficiency and susceptibility to viral illness in humans

Hambleton

Goodbourn

Young

et al. 2013

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

225

205

View full text Add to dashboard Cite

show abstract

“…For example, triggering the type I IFN response leads to expression of hundreds of proteins with antiviral effector functions (1). To persist in nature, viruses evolved a variety of subterfuges to hide from their hosts or actively counter defense mechanisms.…”

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confidence: 99%

Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants

Panda

Fernández

Lal

et al. 2017

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

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Viruses and their hosts can reach balanced states of evolution ensuring mutual survival, which makes it difficult to appreciate the underlying dynamics. To uncover hidden interactions, virus mutants that have lost defense genes may be used. Deletion of the gene that encodes serine protease inhibitor 1 (SPI-1) of rabbitpox virus and vaccinia virus, two closely related orthopoxviruses, prevents their efficient replication in human cells, whereas certain other mammalian cells remain fully permissive. Our highthroughput genome-wide siRNA screen identified host factors that prevent reproduction and spread of the mutant viruses in human cells. More than 20,000 genes were interrogated with individual siRNAs and those that prominently increased replication of the SPI-1 deletion mutant were subjected to a secondary screen. The top hits based on the combined data-replication factor C3 (RFC3), FAM111A, and interferon regulatory factor 2 (IRF2)-were confirmed by custom assays. The siRNAs to RFC1, RFC2, RFC4, and RFC5 mRNAs also enhanced spread of the mutant virus, strengthening the biological significance of the RFC complex as a host restriction factor for poxviruses. Whereas association with proliferating cell nuclear antigen and participation in processive genome replication are common features of FAM111A and RFC, IRF2 is a transcriptional regulator. Microarray analysis, quantitative RT-PCR, and immunoblotting revealed that IRF2 regulated the basal level expression of FAM111A, suggesting that the enhancing effect of depleting IRF2 on replication of the SPI-1 mutant was indirect. Thus, the viral SPI-1 protein and the host IRF2, FAM111A, and RFC complex likely form an interaction network that influences the ability of poxviruses to replicate in human cells.poxviruses | host range | DNA replication factors | interferon regulatory factor | RNAi screen

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“…The receptor IFNAR1 mediates the type I IFN response to induce the transcription of a large number of IFN-stimulated genes [30]. MX1 was one of the most highly up-regulated genes studied, with expression increasing over 7-fold.…”

Section: Discussionmentioning

confidence: 99%

Bovine Endometrial Cells Mount Innate Immune Response to the Intracellular Ligands CL097 and Poly(dA:dT) Indicating Roles against Uterine Viruses

Oguejiofor¹,

Cheng²,

Fouladi-Nashta³

et al. 2017

OJAS

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Uterine infection and endometritis cause infertility and economic losses in the cattle industry. The innate immune response of the endometrium is critical in the elimination of pathogenic organisms that invade the uterus in postpartum cows. This study investigated the response of bovine endometrium to synthetic intracellular ligands which activate innate immunity by stimulating similar receptors to those used to recognise the presence of some viruses. Mixed primary epithelial and stromal cell cultures were treated with 5 μg/ml of CL097 (a TLR7/8 ligand) or 2 μg/ml of poly(dA:dT) (a DNA analogue) for either 6 h or 24 h. Cellular responses were assessed by the mRNA expression of 18 immune-related genes and 3 endogenous reference genes by conventional PCR followed by qRT-PCR from four replicate experiments. Bovine endometrial cells expressed the cytosolic pattern recognition receptors (PRRs) DDX58 (RIG-I), IFIH1 (MDA5) and LRRFIP1 which act as intracellular nucleic acid sensors. Neither ligand altered the expression of the extra-cytosolic pattern recognition receptors (PRRs) TLR3, TLR4, TLR7 or TLR8 whereas poly(dA:dT) treatment increased the expression of IFIH1 and DDX58.

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Interferon-stimulated genes and their antiviral effector functions

Cited by 1,113 publications

References 68 publications

STAT2 deficiency and susceptibility to viral illness in humans

STAT2 deficiency and susceptibility to viral illness in humans

Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants

Bovine Endometrial Cells Mount Innate Immune Response to the Intracellular Ligands CL097 and Poly(dA:dT) Indicating Roles against Uterine Viruses

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