RESUMO
Although IKK-ß has previously been shown as a negative regulator of IL-1ß secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1ß expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1ß secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1ß correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1ß release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1ß secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.
Assuntos
Genes Dominantes , Transplante de Células-Tronco Hematopoéticas , Interleucina-1beta , Hepatopatias , Mutação , Inibidor de NF-kappaB alfa , Imunodeficiência Combinada Severa , Aloenxertos , Animais , Feminino , Células HEK293 , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Hepatopatias/genética , Hepatopatias/imunologia , Hepatopatias/terapia , Masculino , Camundongos , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , Neutropenia/genética , Neutropenia/imunologia , Neutropenia/terapia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: A number of serious human adenovirus (HAdV) outbreaks have been recently reported: HAdV-B7 (Israel, Singapore, and USA), HAdV-B7d (USA and China), HAdV-D8, -D54, and -C2 (Japan), HAdV-B14p1 (USA, Europe, and China), and HAdV-B55 (China, Singapore, and France). METHODS: To understand the epidemiology of HAdV infections in Singapore, we studied 533 HAdV-positive clinical samples collected from 396 pediatric and 137 adult patients in Singapore from 2012 to 2018. Genome sequencing and phylogenetic analyses were performed to identify HAdV genotypes, clonal clusters, and recombinant or novel HAdVs. RESULTS: The most prevalent genotypes identified were HAdV-B3 (35.6%), HAdV-B7 (15.4%), and HAdV-E4 (15.2%). We detected 4 new HAdV-C strains and detected incursions with HAdV-B7 (odds ratio [OR], 14.6; 95% confidence interval [CI], 4.1-52.0) and HAdV-E4 (OR, 13.6; 95% CI, 3.9-46.7) among pediatric patients over time. In addition, immunocompromised patients (adjusted OR [aOR], 11.4; 95% CI, 3.8-34.8) and patients infected with HAdV-C2 (aOR, 8.5; 95% CI, 1.5-48.0), HAdV-B7 (aOR, 3.7; 95% CI, 1.2-10.9), or HAdV-E4 (aOR, 3.2; 95% CI, 1.1-8.9) were at increased risk for severe disease. CONCLUSIONS: Singapore would benefit from more frequent studies of clinical HAdV genotypes to identify patients at risk for severe disease and help guide the use of new antiviral therapies, such as brincidofovir, and potential administration of HAdV 4 and 7 vaccine.
Assuntos
Infecções por Adenovirus Humanos/diagnóstico , Infecções por Adenovirus Humanos/epidemiologia , Adenovírus Humanos/genética , Testes Diagnósticos de Rotina/métodos , Surtos de Doenças/prevenção & controle , Genótipo , Infecções Respiratórias/epidemiologia , Infecções por Adenovirus Humanos/tratamento farmacológico , Infecções por Adenovirus Humanos/prevenção & controle , Vacinas contra Adenovirus/imunologia , Vacinas contra Adenovirus/uso terapêutico , Adenovírus Humanos/imunologia , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Pré-Escolar , DNA Viral/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Filogenia , Estudos Prospectivos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/virologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Singapura/epidemiologia , Sequenciamento Completo do GenomaRESUMO
Background: Although WU polyomavirus (WU) and KI polyomavirus (KI) have been demonstrated to infect the human respiratory tract, it remains unclear if WU or KI cause human disease. We sought to further investigate the relationship between WU and KI infection and respiratory disease in a pediatric population with respiratory symptoms in Singapore. Methods: We conducted a cross-sectional study of pediatric patients with respiratory symptoms in a Singaporean pediatrics hospital. Upon consent, residual respiratory samples from pediatric inpatients, previously screened for common respiratory viruses, were collected and further screened for WU and KI using qPCR. The amplicons of positive samples were sequenced for confirmation. The severity of a patient's illness was assessed by chart review post-discharge looking for clinical markers of respiratory status such as presenting symptoms, diagnoses, and interventions. Results: From December 2016 to April 2017, 201 patients with residual respiratory samples were enrolled in the study. The average age of all participants recruited was 45 months. WU and KI were detected in 13% (26/201) and 3% (6/201) of patients, respectively. Conducting bivariate and multivariate modeling, patients with WU or KI positivity were not at increased risk of SARI, need for additional oxygen, intravenous fluids, and did not receive additional oral antibiotics or bronchodilators during admission. In contrast, patients with RSV detections were at increased risk of requiring supplemental oxygen during hospital admission. Conclusion: While limited in sample size, our pilot study data do not support the hypothesis that molecular evidence of WU or KI was associated with increased morbidity among a sample of general, pediatric patients with respiratory illness in Singapore.
RESUMO
BACKGROUND: Seeking a noninvasive method to conduct surveillance for respiratory pathogens, we sought to examine the usefulness of 2 types of off-the-shelf aerosol samplers to detect respiratory viruses in Singapore. METHODS: In this pilot study, we ran the aerosol samplers several times each week with patients present in the patient waiting areas at 3 primary health clinics during the months of April and May 2016. We used a SKC BioSampler with a BioLite Air Sampling Pump (run for 60 min at 8 L/min) and SKC AirChek TOUCH personal air samplers with polytetrafluoroethylene Teflon filter cassettes (run for 180 min at 5 L/min). The aerosol specimens and controls were studied with molecular assays for influenza A virus, influenza B virus, adenoviruses, and coronaviruses. RESULTS: Overall, 16 (33.3%) of the 48 specimens indicated evidence of at least 1 respiratory pathogen, with 1 (2%) positive for influenza A virus, 3 (6%) positive for influenza B virus, and 12 (25%) positive for adenovirus. CONCLUSIONS: Although we were not able to correlate molecular detection with individual patient illness, patients with common acute respiratory illnesses were present during the samplings. Combined with molecular assays, it would suggest that aerosol sampling has potential as a noninvasive method for novel respiratory virus detection in clinical settings.