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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 03 November 2015, Vol.112(44), pp.13615-20
    Description: The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.
    Keywords: Gene Prioritization ; Gene-Level ; Mutational Damage ; Next Generation Sequencing ; Variant Prioritization ; Exome ; Genetic Diseases, Inborn -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2012, Vol.491(7426), p.769
    Description: In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE) (1-3). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-[beta] (IFN-[beta]) and/or IFN-[lambda]1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-[beta] and IFN-[lambda]1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-a or IFN-[beta] (IFN-[alpha]/[beta]) but not IFN-[lambda]1. Thus, impaired TLR3- and UNC-93B-dependent IFN-[alpha]/[beta] intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.
    Keywords: Herpes Simplex Virus -- Physiological Aspects ; Herpes Simplex Virus -- Health Aspects ; Toll-Like Receptors -- Physiological Aspects ; Toll-Like Receptors -- Health Aspects ; Stem Cells -- Physiological Aspects ; Stem Cells -- Health Aspects ; Neurons -- Physiological Aspects ; Neurons -- Health Aspects ; Virulence (Microbiology) -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Science (New York, N.Y.), 24 April 2015, Vol.348(6233), pp.448-53
    Description: Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.
    Keywords: Heterozygote ; Influenza A Virus, H1n1 Subtype ; Influenza, Human -- Immunology ; Interferon Regulatory Factor-7 -- Genetics ; Interferon Type I -- Biosynthesis ; Respiratory Distress Syndrome, Adult -- Immunology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 4
    Language: English
    In: Science, April 24, 2015, Vol.348(6233), p.448(6)
    Description: Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication.These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from singlegene inborn errors of immunity. 10.1126/science.aaa1578
    Keywords: Influenza -- Case Studies ; Influenza -- Physiological Aspects ; Interferon -- Health Aspects ; Transcription Factors -- Health Aspects
    ISSN: 0036-8075
    Source: Cengage Learning, Inc.
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  • 5
    In: The Journal of Virology, 2006, Vol. 80(24), p.12070
    Description: Matrix (M) proteins reportedly direct the budding of paramyxoviruses from infected cells. In order to begin to characterize the assembly process for the highly lethal, emerging paramyxovirus Nipah virus (NiV), we have examined the budding of NiV M. We demonstrated that expression of the NiV M protein is sufficient to produce budding virus-like particles (VLPs) that are physically and morphologically similar to NiV. We identified in NiV M a sequence, YMYL, with similarity to the YPDL late domain found in the equine infectious anemia virus Gag protein. When the YMYL within NiV M was mutated, VLP release was abolished and M was relocalized to the nucleus, but the mutant M proteins retained oligomerization activity. When YMYL was fused to a late-domain mutant of the Ebola virus VP40 matrix protein, VP40 budding was restored. These results suggest that the YMYL sequence may act as a trafficking signal and a late domain for NiV M.
    Keywords: Biology;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 6
    Language: English
    In: Current Opinion in Immunology, February 2016, Vol.38, pp.109-120
    Description: Influenza viruses cause mild to moderate respiratory illness in most people, and only rarely devastating or fatal infections. The virulence factors encoded by viral genes can explain seasonal or geographic differences at the population level but are unlikely to account for inter-individual clinical variability. Inherited or acquired immunodeficiencies may thus underlie severe cases of influenza. The crucial role of host genes was first demonstrated by forward genetics in inbred mice, with the identification of interferon (IFN)-α/β-inducible as a canonical influenza susceptibility gene. Reverse genetics has subsequently characterized the role of other mouse genes involved in IFN-α/β and -λ immunity. A series of studies with mouse and human cells have also refined the cell-intrinsic mechanisms of protection against influenza viruses. Population-based human genetic studies have not yet uncovered variants with a significant impact. Interestingly, human primary immunodeficiencies affecting T and B cells were also not found to predispose to severe influenza. Recently however, human IRF7 was shown to be essential for IFN-α/β- and IFN-λ-dependent protective immunity against primary influenza , as inferred from a patient with life-threatening influenza revealed to be IRF7-deficient by whole exome sequencing. Next generation sequencing of human exomes and genomes will facilitate the analysis of the human genetic determinism of severe influenza.
    Keywords: Medicine ; Biology
    ISSN: 0952-7915
    E-ISSN: 1879-0372
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  • 7
    Language: English
    In: Current Opinion in Immunology, February 2013, Vol.25(1), pp.19-33
    Description: ► Upon stimulation by dsRNA, TLR3 dimerizes and recruits TRIF, and the subsequent activation of IRF3 and NF-κB leads to induction of target genes. ► TLR3-deficient mice and their wild-type (WT) littermates have been experimentally infected with 16 different viruses. ► Consequences of TLR3 deficiency in mice range from enhanced susceptibility to normal or even greater resistance to certain viruses than WT mice. ► Some human patients with inborn errors of the TLR3 pathway develop herpes simplex virus 1 encephalitis during primary infection. ► Human patients with inborn errors of the TLR3 pathway are apparently normally resistant to most other infections, including viral infections. TLR3 is a receptor for dsRNA, which is generated during most viral infections. However, other cellular processes may also produce dsRNA and there are other receptors for dsRNA. The role of TLR3 in protective immunity to viruses has been investigated in mice and humans with genetically impaired TLR3 responses. TLR3-deficient mice responded to experimental challenge with 16 different viruses in various ways. They were susceptible to eight viruses, normally resistant to three other viruses, and their survival rates were higher than those of wild-type mice following infection with four other viruses. Conflicting results were obtained for the other virus tested. These data are difficult to understand in terms of a simple pattern based on virus structure or tissue tropism. Surprisingly, the known human patients with inborn errors of the TLR3 pathway have remained healthy or developed encephalitis in the course of natural primary infection with HSV-1. These patients display no clear susceptibility to other infections, including viral infections, such as other forms of viral encephalitis and other HSV-1 diseases in particular. This restricted susceptibility to viruses seems to result from impaired TLR3-dependent IFN-α/β production by central nervous system (CNS)-resident non-hematopoietic cells infected with HSV-1. These studies neatly illustrate the value of combining genetic studies of experimental infections in mice and natural infections in humans, to elucidate the biological function of host molecules in protective immunity.
    Keywords: Medicine ; Biology
    ISSN: 0952-7915
    E-ISSN: 1879-0372
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  • 8
    Language: English
    In: Lafaille, Fabien G., Michael J. Ciancanelli, Lorenz Studer, Gregory Smith, Luigi Notarangelo, Jean-Laurent Casanova, and Shen-Ying Zhang. 2015. “Deciphering Human Cell-Autonomous Anti-HSV-1 Immunity in the Central Nervous System.” Frontiers in Immunology 6 (1): 208. doi:10.3389/fimmu.2015.00208. http://dx.doi.org/10.3389/fimmu.2015.00208.
    Description: Herpes simplex virus 1 (HSV-1) is a common virus that can rarely invade the human central nervous system (CNS), causing devastating encephalitis. The permissiveness to HSV-1 of the various relevant cell types of the CNS, neurons, astrocytes, oligodendrocytes, and microglia cells, as well as their response to viral infection, has been extensively studied in humans and other animals. Nevertheless, human CNS cell-based models of anti-HSV-1 immunity are of particular importance, as responses to any given neurotropic virus may differ between humans and other animals. Human CNS neuron cell lines as well as primary human CNS neurons, astrocytes, and microglia cells cultured/isolated from embryos or cadavers, have enabled the study of cell-autonomous anti-HSV-1 immunity in vitro. However, the paucity of biological samples and their lack of purity have hindered progress in the field, which furthermore suffers from the absence of testable primary human oligodendrocytes. Recently, the authors have established a human induced pluripotent stem cells (hiPSCs)-based model of anti-HSV-1 immunity in neurons, oligodendrocyte precursor cells, astrocytes, and neural stem cells, which has widened the scope of possible in vitro studies while permitting in-depth explorations. This mini-review summarizes the available data on human primary and iPSC-derived CNS cells for anti-HSV-1 immunity. The hiPSC-mediated study of anti-viral immunity in both healthy individuals and patients with viral encephalitis will be a powerful tool in dissecting the disease pathogenesis of CNS infections with HSV-1 and other neurotropic viruses.
    Keywords: Review ; Hsv-1 ; Cns ; Disease Modeling ; Antiviral Immunity ; Hipscs ; Hse ; Interferons ; Tlr3
    ISSN: 1664-3224
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  • 9
    In: The Journal of Virology, 2009, Vol. 83(16), p.7828
    Description: The Nipah virus (NiV) phosphoprotein (P) gene encodes the C, P, V, and W proteins. P, V, and W, have in common an amino-terminal domain sufficient to bind STAT1, inhibiting its interferon (IFN)-induced tyrosine phosphorylation. P is also essential for RNA-dependent RNA polymerase function. C is encoded by an alternate open reading frame (ORF) within the common amino-terminal domain. Mutations within residues 81 to 113 of P impaired its polymerase cofactor function, as assessed by a minireplicon assay, but these mutants retained STAT1 inhibitory function. Mutations within the residue 114 to 140 region were identified that abrogated interaction with and inhibition of STAT1 by P, V, and W without disrupting P polymerase cofactor function. Recombinant NiVs were then generated. A G121E mutation, which abrogated inhibition of STAT1, was introduced into a C protein knockout background (C(ko)) because the mutation would otherwise also alter the overlapping C ORF. In cell culture, relative to the wild-type virus, the C(ko) mutation proved attenuating but the G121E mutant virus replicated identically to the C(ko) virus. In cells infected with the wild-type and C(ko) viruses, STAT1 was nuclear despite the absence of tyrosine phosphorylation. This latter observation mirrors what has been seen in cells expressing NiV W. In the G121E mutant virus-infected cells, STAT1 was not phosphorylated and was cytoplasmic in the absence of IFN stimulation but became tyrosine phosphorylated and nuclear following IFN addition. These data demonstrate that the gene for NiV P encodes functions that sequester inactive STAT1 in the nucleus, preventing its activation and suggest that the W protein is the dominant inhibitor of STAT1 in NiV-infected cells.
    Keywords: Cell Nucleus -- Metabolism ; Henipavirus Infections -- Metabolism ; Nipah Virus -- Metabolism ; Phosphoproteins -- Metabolism ; Stat1 Transcription Factor -- Metabolism ; Viral Proteins -- Metabolism ; Viral Structural Proteins -- Metabolism;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 10
    Language: English
    In: Cell, 22 February 2018, Vol.172(5), pp.952-965.e18
    Description: Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. encodes the only known RNA lariat debranching enzyme. We show that expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of -mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients’ fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type . Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses. Autosomal recessive deficiency underlies a cellular accumulation of RNA lariats, resulting in patient susceptibility to severe viral infections of the brainstem.
    Keywords: Dbr1 ; RNA Lariat Debranching ; Viral Encephalitis ; Brainstem ; Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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