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Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.
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Encéfalo , Encefalite por Herpes Simples , Herpesvirus Humano 1 , Proteínas de Membrana , Internalização do Vírus , Animais , Feminino , Humanos , Masculino , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/virologia , Encefalite por Herpes Simples/virologia , Encefalite por Herpes Simples/metabolismo , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/fisiologia , Homozigoto , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nectinas/genética , Nectinas/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/virologia , Células-Tronco Pluripotentes/citologia , Replicação Viral , Pré-Escolar , Adulto Jovem , LinhagemRESUMO
Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-ß and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.
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Encefalite por Herpes Simples , Herpes Simples , Herpesvirus Humano 1 , Humanos , Morte Celular , Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismoRESUMO
Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/ß-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/ß-dependent antiviral immunity.
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COVID-19 , Mycobacterium , Criança , Humanos , Interferon gama , SARS-CoV-2 , Interferon-alfa , Fator Regulador 1 de InterferonRESUMO
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.
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Hepatite Viral Humana , Interleucina-10 , Humanos , Interleucina-10/genética , Irmãos , Interferon gama/genéticaRESUMO
The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.
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Toxinas Bacterianas , Síndrome de Cri-du-Chat , Endopeptidases , Haploinsuficiência , Proteínas Hemolisinas , Infecções Estafilocócicas , Staphylococcus aureus , Toxinas Bacterianas/imunologia , Síndrome de Cri-du-Chat/genética , Síndrome de Cri-du-Chat/imunologia , Endopeptidases/genética , Haploinsuficiência/genética , Haploinsuficiência/imunologia , Proteínas Hemolisinas/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Celular/genética , Necrose , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologiaRESUMO
Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-ß). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
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Receptor de Interferon alfa e beta , Viroses , Alelos , Criança , Homozigoto , Humanos , PolinésiaRESUMO
Polarizers are ubiquitous components in current optoelectronic devices as displays or photographic cameras. Yet, control over light polarization is an unsolved challenge, since the main drawback of the existing display technologies is the significant optical losses. In such a context, organometal halide perovskites (OMHP) can play a decisive role given their flexible synthesis with tunable optical properties such as bandgap and photoluminescence, and excellent light emission with a low non-radiative recombination rate. Therefore, along with their outstanding electrical properties have elevated hybrid perovskites as the material of choice in photovoltaics and optoelectronics. Among the different OMHP nanostructures, nanowires and nanorods have lately arisen as key players in the control of light polarization for lighting or detector applications. Herein, the fabrication of highly aligned and anisotropic methylammonium lead iodide perovskite nanowalls by glancing-angle deposition, which is compatible with most substrates, is presented. Their high alignment degree provides the samples with anisotropic optical properties such as light absorption and photoluminescence. Furthermore, their implementation in photovoltaic devices provides them with a polarization-sensitive response. This facile vacuum-based approach embodies a milestone in the development of last-generation polarization-sensitive perovskite-based optoelectronic devices such as lighting appliances or self-powered photodetectors.
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The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.
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Proteína 10 de Linfoma CCL de Células B/deficiência , Linfócitos/imunologia , Doenças da Imunodeficiência Primária/diagnóstico , Proteína 10 de Linfoma CCL de Células B/genética , Criança , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfócitos/metabolismo , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Doenças da Imunodeficiência Primária/terapiaRESUMO
Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-ß in the patients' fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.
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Encefalite Viral/imunologia , Infecções por Enterovirus/imunologia , Helicase IFIH1 Induzida por Interferon/genética , Receptor 3 Toll-Like/genética , Células Cultivadas , Pré-Escolar , Encefalite Viral/genética , Enterovirus/efeitos dos fármacos , Enterovirus/fisiologia , Infecções por Enterovirus/genética , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/virologia , Humanos , Lactente , Interferon alfa-2/farmacologia , Helicase IFIH1 Induzida por Interferon/imunologia , Interferon beta/imunologia , Interferon beta/metabolismo , Mutação com Perda de Função , Masculino , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/imunologia , Poli I-C/farmacologia , Rombencéfalo/virologia , Receptor 3 Toll-Like/imunologia , Replicação Viral/efeitos dos fármacosRESUMO
RESUMEN Introducción: en las prácticas docentes de Enfermería de la educación en el trabajo, que se realizan en centros hospitalarios, los estudiantes y enfermeros están expuestos al contagio por covid-19. De ahí que se haga necesaria la preparación de este personal para ejercer su labor de un modo exitoso en medio de un escenario complejo. Objetivo: evaluar el enfrentamiento a la covid-19 por parte de educandos y personal de enfermería en las prácticas de la educación en el trabajo. Materiales y métodos: se realizó una investigación de intervención y desarrollo en el Servicio de Neurocirugía del Hospital Universitario Clínico Quirúrgico Comandante Faustino Pérez Hernández, de Matanzas, entre septiembre y octubre de 2020, período de rebrote de la covid. Para ello se trabajó con el universo constituido por 12 pacientes, 12 cuidadores y 6 educandos de 5to año de la carrera de Licenciatura en Enfermería. El estudio se dividió en tres etapas: diagnóstica, entrenamiento y evaluación. Se utilizó la entrevista. Resultados: predominó en los pacientes el grupo etario de 40 a 49 años, con 41,66 % del género masculino. En los cuidadores predominó el femenino, y la edad de 50 a 59 años. El entrenamiento resultó efectivo en un 58,33 %. Conclusiones: la prevención y el autocuidado fueron respuestas estratégicas positivas como formas de actuación en los educandos y el resto del personal que participó en la investigación. La labor asistencial educativa minimizó el riesgo epidemiológico en los pacientes y cuidadores, y logró un incremento en la percepción de riesgo de contraer la enfermedad (AU).
ABSTRACT Introduction: students and nurses are exposed to contagion by COVID-19 during the Nursing teaching practices of on-the-job training carried out in hospitals. Therefore, it is necessary train these staff to carry out their work successfully in the middle of a difficult scenario. Objective: to evaluate COVID-19 facing by students and nursing staff in the practices of on-the-job training. Materials and methods: an intervention and development research was conducted in the Neurosurgery Service of the University Hospital Comandante Faustino Pérez Hernández, of Matanzas, between September and October 2020, period of COVID-19 resurgence. For that we worked with a universe of 12 patients, 12 caregivers and 6 5th-year students of Nursing degree. The study was divided into three stages: diagnosis, training and evaluation. The interview was used. Results: the 40-49 age group predominated among patients, with 41.66 % of the male gender. Among caregivers, female gender predominated and 50-59 age group. The training was effective at 58.33 %. Conclusions: prevention and self-care were positive strategic answers as forms of action in students and the rest of the staff involved in the research. The educational aid work minimized the epidemiological risk in patients and caregivers, and achieved an increase in risk perception of contracting the disease (AU).
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Humanos , Masculino , Feminino , Estudantes de Enfermagem/classificação , COVID-19/enfermagem , Cuidadores/educação , Educação em Enfermagem/classificação , Prevenção de Doenças , AprendizagemRESUMO
RESUMEN Introducción: El asma es una enfermedad psicosomática que reduce la calidad de vida de quien la padece, y tiene el riesgo de progresar en intensidad hasta producir daño e incapacidad permanente. Este texto recoge las experiencias de un estudio cuyo objetivo estuvo orientado a identificar las necesidades de aprendizaje de los licenciados en Enfermería del Policlínico Docente Reinol García, del consejo popular Versalles, perteneciente al municipio Matanzas, de la provincia cubana de igual nombre; acerca del manejo del paciente con asma bronquial. Método: El estudio mencionado tuvo carácter exploratorio descriptivo, desplegado como parte del Programa Nacional de Prevención del asma bronquial durante el período 2019-2020, acerca de las necesidades de aprendizaje de este personal para el manejo de tal situación de salud. El universo fue constituido por 31 licenciados, que laboran en los consultorios médicos y en el policlínico implicado en la investigación. Se aplicó un instrumento diseñado por un grupo de expertos y aplicado a la manera de un examen o prueba escrita por personal calificado, con carácter anónimo y previo consentimiento informado, sobre aspectos epidemiológicos, epistemológicos y teóricos prácticos. Resultados: Se constataron carencias y vacíos de conocimientos relacionados con el tema, de lo cual derivaronestrategias de superación profesional. Discusión: Los hallazgos constatados en la etapa experimental se corroboran con los resultados y criterios emitidos por especialistas y académicos que han profundizado en el tratamiento del tema.
ABSTRACT Introduction: Asthma is a psychosomatic disease that reduces the quality of life of those who suffer from it, and has the risk of progressing in intensity until it produces damage and permanent disability. This text collects the experiences of a study whose objective was aimed at identifying the learning needs of the Nursing graduates of the Educational Polyclinic Reinol García, of the Versalles popular council, belonging to the Matanzas municipality, of the Cuban province of the same name; about the management of the patient with bronchial asthma. Method: The aforementioned study had a descriptive exploratory nature, deployed as part of the National Program for the Prevention of bronchial asthma during the 2019-2020 period, about the learning needs of these personnel for the management of such health situation. The universe was made up of 31 graduates, who work in the medical offices and in the polyclinic involved in the research. An instrument designed by a group of experts was applied in the manner of an exam or written test by qualified personnel, with an anonymous character and with prior informed consent, on epidemiological, epistemological and practical theoretical aspects. Results: There were deficiencies and gaps in knowledge related to the subject, from which professional improvement strategies were derived. Discussion: The findings found in the experimental stage are corroborated with the results and criteria issued by specialists and academics who have delved into the treatment of the subject.
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The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-α/ß immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity.
Assuntos
Biologia Computacional/métodos , Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/patologia , Fibroblastos/imunologia , Redes Reguladoras de Genes , Heterogeneidade Genética , Predisposição Genética para Doença , Estudos de Casos e Controles , Encefalite por Herpes Simples/imunologia , Fibroblastos/metabolismo , Humanos , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismo , Sequenciamento do ExomaRESUMO
Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.
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Anticorpos Neutralizantes/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes , COVID-19 , Doenças Genéticas Inatas , Interferon-alfa , Receptor de Interferon alfa e beta , SARS-CoV-2 , Vacina contra Febre Amarela , Vírus da Febre Amarela , Adolescente , Adulto , Idoso , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , COVID-19/genética , COVID-19/imunologia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Células HEK293 , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacina contra Febre Amarela/efeitos adversos , Vacina contra Febre Amarela/genética , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/genética , Vírus da Febre Amarela/imunologiaRESUMO
Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/ß induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-ß protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-ß secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-ß immunity.
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Córtex Cerebral/imunologia , Fibroblastos/imunologia , Herpesvirus Humano 1/imunologia , Interferon beta/imunologia , Neurônios/imunologia , Receptor 3 Toll-Like/imunologia , Vesiculovirus/imunologia , Animais , Linhagem Celular , Córtex Cerebral/patologia , Córtex Cerebral/virologia , Fibroblastos/patologia , Fibroblastos/virologia , Humanos , Interferon beta/genética , Camundongos , Camundongos Knockout , Neurônios/patologia , Neurônios/virologia , Receptor 3 Toll-Like/genéticaRESUMO
Inborn errors of TLR3-dependent IFN-α/ß- and IFN-λ-mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/ß and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient's fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-ß, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient's fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-ß. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/ß are essential for anti-HSV-1 immunity in the CNS.
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Encefalite por Herpes Simples , Herpesvirus Humano 1/metabolismo , Receptor de Interferon alfa e beta/deficiência , Adolescente , Pré-Escolar , Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/metabolismo , Encefalite por Herpes Simples/patologia , Células HEK293 , Herpesvirus Humano 1/genética , Humanos , Interferons/genética , Interferons/metabolismo , Masculino , Receptor de Interferon alfa e beta/metabolismoRESUMO
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
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Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Mutação com Perda de Função , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Infecções Assintomáticas , Betacoronavirus , COVID-19 , Criança , Pré-Escolar , Feminino , Loci Gênicos , Predisposição Genética para Doença , Humanos , Lactente , Fator Regulador 7 de Interferon/deficiência , Fator Regulador 7 de Interferon/genética , Masculino , Pessoa de Meia-Idade , Pandemias , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , SARS-CoV-2 , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética , Adulto JovemRESUMO
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
Assuntos
Autoanticorpos/sangue , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Interferon alfa-2/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Infecções Assintomáticas , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , Estado Terminal , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2RESUMO
Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
Assuntos
Encefalite Viral/etiologia , Infecções por Hantavirus/etiologia , Heterozigoto , Mutação , Orthohantavírus , Receptor 3 Toll-Like/genética , Alelos , Linhagem Celular , Células Cultivadas , Suscetibilidade a Doenças , Encefalite Viral/diagnóstico , Fibroblastos/imunologia , Fibroblastos/metabolismo , Predisposição Genética para Doença , Orthohantavírus/imunologia , Infecções por Hantavirus/diagnóstico , HumanosRESUMO
Buruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a sample of 1524 well characterized patients and controls from rural Benin. Two-stage analyses identify two variants located within LncRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85 × 10-7; odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85 × 10-8; hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest LncRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer.