Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23.101
Filtrar
1.
Ther Adv Respir Dis ; 14: 1753466620942129, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32684101

RESUMEN

BACKGROUND: In December of 2019, coronavirus disease 2019 (Covid-19) was reported in Wuhan, China, and has now rapidly swept around the world. Much research has been carried out since the outbreak, but few studies have focused on the dysfunction of the adaptive immunity. METHODS: In this retrospective and multi-center study, 373 patients with laboratory-confirmed COVID-19 from Shanghai Public Health Clinical Center and Affiliated Hospital of Putian University were recruited. Demographic, clinical, radiological features, and laboratory data were recorded and analyzed at admission and at discharge. Results of immunological tests were followed up until the patients were discharged. RESULTS: Of the 373 patients with COVID-19 pneumonia, 322 were in the non-severe group and 51 were in the severe group. Number of T cells, CD4+ and CD8+ T cells, and total lymphocytes declined remarkably upon admission and elevated when the patients were discharged. At admission, counts of total lymphocytes, T cells, CD4+ and CD8+ T cells, and levels of C3 and C4 in the severe group were lower than those in the non-severe group, whereas the neutrophil to lymphocyte ratio (NLR) was higher in the severe group. Counts of T cells, CD4+ and CD8+ T cells, and total lymphocytes were negatively correlated with lactate dehydrogenase and C-reactive protein. CONCLUSION: COVID-19 might target adaptive immunity and cause a decrease in lymphocytes, especially T cells and subsets. Physicians should pay close attention to the adaptive immunity of patients upon admission. Monitoring NLR, T lymphocytes, and subsets would help physicians with the proper diagnosis and treatment of COVID-19.The reviews of this paper are available via the supplemental material section.


Asunto(s)
Inmunidad Adaptativa/inmunología , Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , China/epidemiología , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/fisiopatología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad
2.
Artículo en Inglés | MEDLINE | ID: mdl-32667390

RESUMEN

Capnocytophaga is a group of facultative anaerobic gram-negative bacteria present in the oral cavity of humans, dogs and cats, as part of their normal oral flora. Here, we described two cases of bloodstream infections (BSI) caused by Capnocytophaga in neutropenic autologous hematopoietic stem cell transplantation (auto-HSCT) patients with mucositis (Grade I and Grade III) identified by Maldi-Tof. They were successfully treated with ß-lactam (meropenem and piperacillin-tazobactam). The species C. sputigena was confirmed by 16S rRNA gene sequencing in one patient. The review of literature showed that C. ochraceae was the most frequent species causing BSI in auto-HSCT patients and that the patients usually presented mucositis and were neutropenic at the onset of the infection.


Asunto(s)
Antibacterianos/uso terapéutico , Bacteriemia/diagnóstico , Capnocytophaga/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/diagnóstico , Trasplante de Células Madre Hematopoyéticas/métodos , Neutrófilos/inmunología , Adulto , Bacteriemia/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/inmunología , Humanos , Meropenem/uso terapéutico , Persona de Mediana Edad , Mucositis , Piperacilina/uso terapéutico , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Tazobactam/uso terapéutico , Trasplante Autólogo
3.
Sci Immunol ; 5(49)2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32669287

RESUMEN

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Neutrófilos/inmunología , Neumonía Viral/inmunología , Linfocitos T/inmunología , Anciano , Selección Clonal Mediada por Antígenos/inmunología , Infecciones por Coronavirus/patología , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología
4.
Front Immunol ; 11: 1580, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32670297

RESUMEN

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Proteína HMGB1/metabolismo , Inflamasomas/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/patología , Citocinas/metabolismo , Humanos , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Pandemias , Neumonía Viral/patología
5.
Front Immunol ; 11: 1636, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32670298

RESUMEN

The current pandemic of coronavirus disease 19 (COVID-19) has affected millions of individuals and caused thousands of deaths worldwide. The pathophysiology of the disease is complex and mostly unknown. Therefore, identifying the molecular mechanisms that promote progression of the disease is critical to overcome this pandemic. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. Here, we provide novel perspectives on the pathophysiology of COVID-19 using robust functional approaches to analyze public transcriptome datasets. In addition, we compared the transcriptional signature of COVID-19 patients with individuals infected with SARS-CoV-1 and Influenza A (IAV) viruses. We identified a core transcriptional signature induced by the respiratory viruses in peripheral leukocytes, whereas the absence of significant type I interferon/antiviral responses characterized SARS-CoV-2 infection. We also identified the higher expression of genes involved in metabolic pathways including heme biosynthesis, oxidative phosphorylation and tryptophan metabolism. A BTM-driven meta-analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients showed significant enrichment for neutrophils and chemokines, which were also significant in data from lung tissue of one deceased COVID-19 patient. Importantly, our results indicate higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and BALF, suggesting a critical role for mitochondrial activity during SARS-CoV-2 infection. Collectively, these data point for immunopathological features and targets that can be therapeutically exploited to control COVID-19.


Asunto(s)
Betacoronavirus/inmunología , Quimiocinas/sangre , Infecciones por Coronavirus/inmunología , Interferón Tipo I/sangre , Neutrófilos/inmunología , Neumonía Viral/inmunología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Infecciones por Coronavirus/patología , Perfilación de la Expresión Génica , Humanos , Inflamación/virología , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Neutrófilos/citología , Fosforilación Oxidativa , Pandemias , Neumonía Viral/patología , Transcriptoma/genética
6.
JAMA Netw Open ; 3(6): e2010895, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32492165

RESUMEN

Importance: The epidemiologic and clinical characteristics of pediatric patients with coronavirus disease 2019 (COVID-19) have been reported, but information on immune features associated with disease severity is scarce. Objective: To delineate and compare the immunologic features of mild and moderate COVID-19 in pediatric patients. Design, Setting, and Participants: This single-center case series included 157 pediatric patients admitted to Wuhan Children's Hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data were collected from January 25 to April 18, 2020. Exposures: Documented SARS-CoV-2 infection. Main Outcomes and Measures: Clinical and immunologic characteristics were collected and analyzed. Outcomes were observed until April 18, 2020. Results: Of the 157 pediatric patients with COVID-19, 60 (38.2%) had mild clinical type with pneumonia, 88 (56.1%) had moderate cases, 6 (3.8%) had severe cases, and 3 (1.9%) were critically ill. The 148 children with mild or moderate disease had a median (interquartile range [IQR]) age of 84 (18-123) months, and 88 (59.5%) were girls. The most common laboratory abnormalities were increased levels of alanine aminotransferase (ALT) (median [IQR], 16.0 [12.0-26.0] U/L), aspartate aminotransferase (AST) (median [IQR], 30.0 [23.0-41.8] U/L), creatine kinase MB (CK-MB) activity (median [IQR], 24.0 [18.0-34.0] U/L), and lactate dehydrogenase (LDH) (median [IQR], 243.0 [203.0-297.0] U/L), which are associated with liver and myocardial injury. Compared with mild cases, levels of inflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ were unchanged, whereas the level of immune suppressive interleukin 10 was markedly increased in moderate cases compared with mild cases (median [IQR], 3.96 [3.34-5.29] pg/mL vs 3.58 [3.10-4.36] pg/mL; P = .048). There was no statistically significant difference in absolute number of lymphocytes (including T cells and B cells) between mild and moderate cases, but moderate cases were associated with a decrease in neutrophil levels compared with mild cases (median [IQR], 2310/µL [1680/µL-3510/µL] vs 3120/µL [2040/µL-4170/µL]; P = .01). Immunoglobin G and the neutrophil to lymphocyte ratio were negatively associated with biochemical indices related to liver and myocardial injury (immunoglobulin G, ALT: r, -0.3579; AST: r, -0.5280; CK-MB activity: r, -0.4786; LDH: r, -0.4984; and neutrophil to lymphocyte ratio, ALT: r, -0.1893; AST: r, -0.3912; CK-MB activity: r, -0.3428; LDH: r, -0.3234), while counts of lymphocytes, CD4+ T cells, and interleukin 10 showed positive associations (lymphocytes, ALT: r, 0.2055; AST: r, 0.3615; CK-MB activity: r, 0.338; LDH: r, 0.3309; CD4+ T cells, AST: r, 0.4701; CK-MB activity: r, 0.4151; LDH: r, 0.4418; interleukin 10, ALT: r, 0.2595; AST: r, 0.3386; CK-MB activity: r, 0.3948; LDH: r, 0.3794). Conclusions and Relevance: In this case series, systemic inflammation rarely occurred in pediatric patients with COVID-19, in contrast with the lymphopenia and aggravated inflammatory responses frequently observed in adults with COVID-19. Gaining a deeper understanding of the role of neutrophils, CD4+ T cells, and B cells in the pathogenesis of SARS-CoV-2 infection could be important for the clinical management of COVID-19.


Asunto(s)
Infecciones por Coronavirus/inmunología , Citocinas/inmunología , Neutrófilos/inmunología , Neumonía Viral/inmunología , Distribución por Edad , Alanina Transaminasa/metabolismo , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Aspartato Aminotransferasas/metabolismo , Linfocitos B/inmunología , Proteína C-Reactiva/inmunología , Linfocitos T CD4-Positivos/inmunología , Niño , Preescolar , China/epidemiología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/terapia , Forma MB de la Creatina-Quinasa/metabolismo , Enfermedad Crítica , Femenino , Hospitales Pediátricos , Humanos , Lactante , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-2/inmunología , Interleucina-4/inmunología , Interleucina-6/inmunología , Células Asesinas Naturales/inmunología , L-Lactato Deshidrogenasa/metabolismo , Recuento de Leucocitos , Recuento de Linfocitos , Masculino , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/metabolismo , Neumonía Viral/terapia , Índice de Severidad de la Enfermedad , Distribución por Sexo , Factor de Necrosis Tumoral alfa/inmunología
7.
Signal Transduct Target Ther ; 5(1): 100, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32561706
8.
mSphere ; 5(3)2020 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-32581077

RESUMEN

COVID-19 is often related to hyperinflammation that drives lung or multiorgan injury. The immunopathological mechanisms that cause excessive inflammation are under investigation and constantly updated. Here, a gene network approach was used on recently published data sets to identify possible COVID-19 inflammatory mechanisms and bioactive genes. First, network analysis of putative SARS-CoV-2 cellular receptors led to the mining of a neutrophil-response signature and relevant inflammatory genes. Second, analysis of RNA-seq data sets of lung cells infected with SARS-CoV-2 revealed that infected cells expressed neutrophil-attracting chemokines. Third, analysis of RNA-seq data sets of bronchoalveolar lavage fluid cells from COVID-19 patients identified upregulation of neutrophil genes and chemokines. Different inflammatory genes mined here, including TNFR, IL-8, CXCR1, CXCR2, ADAM10, GPR84, MME, ANPEP, and LAP3, might be druggable targets in efforts to limit SARS-CoV-2 inflammation in severe clinical cases. The possible role of neutrophils in COVID-19 inflammation needs to be studied further.


Asunto(s)
Betacoronavirus/inmunología , Quimiocinas/inmunología , Infecciones por Coronavirus/inmunología , Inflamación/patología , Neutrófilos/inmunología , Neumonía Viral/inmunología , Líquido del Lavado Bronquioalveolar/citología , Quimiocinas/genética , Infecciones por Coronavirus/patología , Humanos , Inflamación/inmunología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Infiltración Neutrófila/inmunología , Pandemias , Neumonía Viral/patología , Receptores Virales/genética
9.
Artículo en Inglés | MEDLINE | ID: mdl-32582575

RESUMEN

Background: A novel enveloped RNA beta coronavirus, Corona Virus Disease 2019 (COVID-19) caused severe and even fetal pneumonia in China and other countries from December 2019. Early detection of severe patients with COVID-19 is of great significance to shorten the disease course and reduce mortality. Methods: We assembled a retrospective cohort of 80 patients (including 56 mild and 24 severe) with COVID-19 infection treated at Beijing You'an Hospital. We used univariable and multivariable logistic regression analyses to select the risk factors of severe and even fetal pneumonia and build scoring system for prediction, which was validated later on in a group of 22 COVID-19 patients. Results: Age, white blood cell count, neutrophil, glomerular filtration rate, and myoglobin were selected by multivariate analysis as candidates of scoring system for prediction of disease severity in COVID-19. The scoring system was applied to calculate the predictive value and found that the percentage of ICU admission (20%, 6/30) and ventilation (16.7%, 5/30) in patients with high risk was much higher than those (2%, 1/50; 2%, 1/50) in patients with low risk (p = 0.009; p = 0.026). The AUC of scoring system was 0.906, sensitivity of prediction is 70.8%, and the specificity is 89.3%. According to scoring system, the probability of patients in high risk group developing severe disease was 20.24 times than that in low risk group. Conclusions: The possibility of severity in COVID-19 infection predicted by scoring system could help patients to receiving different therapy strategies at a very early stage. Topic: COVID-19, severe and fetal pneumonia, logistic regression, scoring system, prediction.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/patología , Neumonía Viral/epidemiología , Neumonía Viral/patología , Índice de Severidad de la Enfermedad , Anciano , Anciano de 80 o más Años , Betacoronavirus/patogenicidad , China , Comorbilidad , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Mioglobina/análisis , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Pandemias , Pronóstico , Estudios Retrospectivos
10.
Clin Immunol ; 217: 108486, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32479985

RESUMEN

The lymphopenia exhibited in patients with COVID-19 has been associated with a worse prognosis in the development of the disease. To understand the factors associated with a worse evolution of COVID-19, we analyzed comorbidities, indicators of inflammation such as CRP and the ratio of neutrophils/lymphocytes, as well as the count of blood cells with T-lymphocyte subtypes in 172 hospitalized patients with COVID-19 pneumonia. Patients were grouped according to their needs for mechanical ventilation (ICU care) or not. Within the comorbidities studied, obesity was the only associated with greater severity and ICU admission. Both the percentage and the absolute number of neutrophils were higher in patients needing ICU care than non-ICU patients, whereas absolute lymphocyte count, and especially the percentage of lymphocytes, presented a deep decline in critical patients. There was no difference between the two groups of patients for CD4 T-lymphocytes, neither in percentage of lymphocyte nor in absolute number, however for CD8 T-cells the differences were significant for both parameters which were in decline in ICU patients. There was a firm correlation between the highest values of inflammation indicators with the decrease in percentage of CD8 T-lymphocytes. This effect was not seen with CD4 cells. Obesity together with lymphopenia, especially whether preferentially affects to CD8 T- lymphocytes, are factors that can predict a poor prognosis in patients with COVID-19.


Asunto(s)
Betacoronavirus/patogenicidad , Linfocitos T CD8-positivos/patología , Infecciones por Coronavirus/inmunología , Linfopenia/inmunología , Neutrófilos/patología , Obesidad/inmunología , Neumonía Viral/inmunología , Anciano , Anciano de 80 o más Años , Betacoronavirus/inmunología , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Estudios de Casos y Controles , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/terapia , Femenino , Humanos , Unidades de Cuidados Intensivos , Recuento de Linfocitos , Linfopenia/complicaciones , Linfopenia/mortalidad , Linfopenia/terapia , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/virología , Obesidad/complicaciones , Obesidad/mortalidad , Obesidad/terapia , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/mortalidad , Neumonía Viral/terapia , Pronóstico , Respiración Artificial , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia
11.
Cells ; 9(6)2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32498376

RESUMEN

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19.


Asunto(s)
Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Trampas Extracelulares/inmunología , Neutrófilos/inmunología , Neumonía Viral/inmunología , Neumonía Viral/patología , Animales , Betacoronavirus/fisiología , Enfermedades Cardiovasculares/complicaciones , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Complicaciones de la Diabetes/virología , Humanos , Inflamación/inmunología , Inflamación/patología , Necrosis/inmunología , Necrosis/patología , Neutrófilos/metabolismo , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico
12.
BMC Infect Dis ; 20(1): 403, 2020 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-32517725

RESUMEN

BACKGROUND: Current tools for diagnosing latent TB infection (LTBI) detect immunological memory of past exposure but are unable to determine whether exposure is recent. We sought to identify a whole-blood transcriptome signature of recent TB exposure. METHODS: We studied household contacts of TB patients; healthy volunteers without recent history of TB exposure; and patients with active TB. We performed whole-blood RNA sequencing (in all), an interferon gamma release assay (IGRA; in contacts and healthy controls) and PET/MRI lung scans (in contacts only). We evaluated differentially-expressed genes in household contacts (log2 fold change ≥1 versus healthy controls; false-discovery rate < 0.05); compared these to differentially-expressed genes seen in the active TB group; and assessed the association of a composite gene expression score to independent exposure/treatment/immunological variables. RESULTS: There were 186 differentially-expressed genes in household contacts (n = 26, age 22-66, 46% male) compared with healthy controls (n = 5, age 29-38, 100% male). Of these genes, 141 (76%) were also differentially expressed in active TB (n = 14, age 27-69, 71% male). The exposure signature included genes from inflammatory response, type I interferon signalling and neutrophil-mediated immunity pathways; and genes such as BATF2 and SCARF1 known to be associated with incipient TB. The composite gene-expression score was higher in IGRA-positive contacts (P = 0.04) but not related to time from exposure, isoniazid prophylaxis, or abnormalities on PET/MRI (all P > 0.19). CONCLUSIONS: Transcriptomics can detect TB exposure and, with further development, may be an approach of value for epidemiological research and targeting public health interventions.


Asunto(s)
Tuberculosis Latente/diagnóstico , ARN/sangre , Adulto , Anciano , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Estudios de Casos y Controles , Trazado de Contacto , Femenino , Humanos , Interferón Tipo I/metabolismo , Tuberculosis Latente/microbiología , Tuberculosis Latente/transmisión , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Mapas de Interacción de Proteínas/genética , ARN/química , ARN/metabolismo , Receptores Depuradores de Clase F/genética , Proteínas Supresoras de Tumor/genética , Adulto Joven
13.
Nature ; 582(7810): 109-114, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32494068

RESUMEN

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.


Asunto(s)
Modelos Animales de Enfermedad , Células Precursoras de Granulocitos/patología , Mutación , Neutropenia/genética , Neutropenia/patología , Neutrófilos/patología , Animales , Candida albicans/inmunología , Candida albicans/patogenicidad , Linaje de la Célula , Proteínas de Unión al ADN/genética , Femenino , Humanos , Inmunidad Innata , Masculino , Ratones , Ratones Transgénicos , Neutropenia/congénito , Neutropenia/inmunología , Neutrófilos/inmunología , Factores de Transcripción/genética
14.
PLoS Pathog ; 16(5): e1008497, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32453780

RESUMEN

Heparan sulfate proteoglycans (HSPGs) are at the forefront of host-microbe interactions. Molecular and cell-based studies suggest that HSPG-pathogen interactions promote pathogenesis by facilitating microbial attachment and invasion of host cells. However, the specific identity of HSPGs, precise mechanisms by which HSPGs promote pathogenesis, and the in vivo relevance of HSPG-pathogen interactions remain to be determined. HSPGs also modulate host responses to tissue injury and inflammation, but functions of HSPGs other than facilitating microbial attachment and internalization are understudied in infectious disease. Here we examined the role of syndecan-1 (Sdc1), a major cell surface HSPG of epithelial cells, in mouse models of Listeria monocytogenes (Lm) infection. We show that Sdc1-/- mice are significantly less susceptible to both intragastric and intravenous Lm infection compared to wild type (Wt) mice. This phenotype is not seen in Sdc3-/- or Sdc4-/- mice, indicating that ablation of Sdc1 causes a specific gain of function that enables mice to resist listeriosis. However, Sdc1 does not support Lm attachment or invasion of host cells, indicating that Sdc1 does not promote pathogenesis as a cell surface Lm receptor. Instead, Sdc1 inhibits the clearance of Lm before the bacterium gains access to its intracellular niche. Large intravascular aggregates of neutrophils and neutrophil extracellular traps (NETs) embedded with antimicrobial compounds are formed in Sdc1-/- livers, which trap and kill Lm. Lm infection induces Sdc1 shedding from the surface of hepatocytes in Wt livers, which is directly associated with the decrease in size of intravascular aggregated NETs. Furthermore, administration of purified Sdc1 ectodomains or DNase inhibits the formation of intravascular aggregated neutrophils and NETs and significantly increases the liver bacterial burden in Sdc1-/- mice. These data indicate that Lm induces Sdc1 shedding to subvert the activity of Sdc1 ectodomains to inhibit its clearance by intravascular aggregated NETs.


Asunto(s)
Trampas Extracelulares/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Neutrófilos/inmunología , Sindecano-1/inmunología , Animales , Trampas Extracelulares/genética , Hepatocitos/inmunología , Hepatocitos/patología , Listeria monocytogenes/patogenicidad , Listeriosis/genética , Listeriosis/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neutrófilos/patología , Dominios Proteicos , Sindecano-1/genética
15.
PLoS Pathog ; 16(5): e1008576, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32392230

RESUMEN

Yersinia suppress neutrophil responses by using a type 3 secretion system (T3SS) to inject 6-7 Yersinia effector proteins (Yops) effectors into their cytoplasm. YopH is a tyrosine phosphatase that causes dephosphorylation of the adaptor protein SKAP2, among other targets in neutrophils. SKAP2 functions in reactive oxygen species (ROS) production, phagocytosis, and integrin-mediated migration by neutrophils. Here we identify essential neutrophil functions targeted by YopH, and investigate how the interaction between YopH and SKAP2 influence Yersinia pseudotuberculosis (Yptb) survival in tissues. The growth defect of a ΔyopH mutant was restored in mice defective in the NADPH oxidase complex, demonstrating that YopH is critical for protecting Yptb from ROS during infection. The growth of a ΔyopH mutant was partially restored in Skap2-deficient (Skap2KO) mice compared to wild-type (WT) mice, while induction of neutropenia further enhanced the growth of the ΔyopH mutant in both WT and Skap2KO mice. YopH inhibited both ROS production and degranulation triggered via integrin receptor, G-protein coupled receptor (GPCR), and Fcγ receptor (FcγR) stimulation. SKAP2 was required for integrin receptor and GPCR-mediated ROS production, but dispensable for degranulation under all conditions tested. YopH blocked SKAP2-independent FcγR-stimulated phosphorylation of the proximal signaling proteins Syk, SLP-76, and PLCγ2, and the more distal signaling protein ERK1/2, while only ERK1/2 phosphorylation was dependent on SKAP2 following integrin receptor activation. These findings reveal that YopH prevents activation of both SKAP2-dependent and -independent neutrophilic defenses, uncouple integrin- and GPCR-dependent ROS production from FcγR responses based on their SKAP2 dependency, and show that SKAP2 is not required for degranulation.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Neutrófilos/inmunología , Proteínas Tirosina Fosfatasas/inmunología , Transducción de Señal/inmunología , Infecciones por Yersinia pseudotuberculosis/inmunología , Yersinia pseudotuberculosis/inmunología , Animales , Péptidos y Proteínas de Señalización Intracelular/genética , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neutrófilos/patología , Especies Reactivas de Oxígeno/inmunología , Transducción de Señal/genética , Yersinia pseudotuberculosis/patogenicidad , Infecciones por Yersinia pseudotuberculosis/genética , Infecciones por Yersinia pseudotuberculosis/patología
16.
Clin Exp Immunol ; 201(1): 76-84, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32365221

RESUMEN

Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Subunidad alfa del Receptor de Interleucina-2/sangre , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Linfocitos T/virología , Anciano , Anciano de 80 o más Años , Betacoronavirus/inmunología , Biomarcadores/sangre , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , China/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Progresión de la Enfermedad , Femenino , Ferritinas/sangre , Ferritinas/inmunología , Humanos , Interleucina-10/sangre , Interleucina-10/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Interleucina-8/sangre , Interleucina-8/inmunología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/virología , Neumonía Viral/inmunología , Neumonía Viral/patología , Polipéptido alfa Relacionado con Calcitonina/sangre , Polipéptido alfa Relacionado con Calcitonina/inmunología , Pronóstico , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología
17.
Anticancer Res ; 40(5): 2871-2880, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366437

RESUMEN

BACKGROUND/AIM: This study aimed to improve the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs). PATIENTS AND METHODS: In this retrospective study, NLR and TIL data from 677 operated breast cancer patients were analysed. The cut-off value of NLR was set at 2.72, and TIL levels were classified as low (<10%), intermediate (≥10 to <50%), and high (≥50%). RESULTS: Recurrence-free survival (RFS) was significantly longer in patients with low NLR (n=459) than in those with high NLR (n=218) (p=0.0383). In ER-positive/HER2-negative and TIL-low breast cancers, there were significant associations between NLR levels and RFS (p=0.0129) or overall survival (OS) (p=0.0046). On multivariate analysis, NLR was a significant and independent factor for OS (hazard ratio=3.78; 95% confidence interval=1.21-14.17; p=0.022). CONCLUSION: These data may be useful for predicting patient prognosis and understanding the clinical significance of immune status in breast cancers.


Asunto(s)
Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos/inmunología , Neutrófilos/inmunología , Neoplasias de la Mama Triple Negativas/inmunología , Femenino , Humanos , Pronóstico , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/patología
18.
Anticancer Res ; 40(5): 2881-2887, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366438

RESUMEN

BACKGROUND/AIM: This study evaluated the prognostic significance of preoperative neutrophil-to-lymphocyte ratio (NLR) and CD8+ tumor-infiltrating lymphocytes (TILs), and whether preoperative NLR was associated with CD8+ TILs in biliary tract cancers (BTCs). PATIENTS AND METHODS: A total of 154 patients with BTCs who underwent surgery were enrolled in this study. We obtained neutrophil and lymphocyte counts, and calculated NLR from preoperative peripheral blood samples. CD8+ TILs were identified by immunohistochemical staining. RESULTS: The overall survival (OS) and recurrence-free survival (RFS) of patients with high NLR were shorter than those with low NLR. The OS and RFS of patients with high CD8+ TILs were longer than those with low CD8+ TILs. Preoperative NLR and CD8+ TILs were negatively correlated. CONCLUSION: NLR and CD8+ TILs were associated with OS and RFS in BTCs. NLR can predict CD8+ TILs infiltrating the cancer microenvironment.


Asunto(s)
Neoplasias del Sistema Biliar/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos/inmunología , Neutrófilos/inmunología , Anciano , Femenino , Humanos , Masculino
19.
EBioMedicine ; 55: 102763, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32361250

RESUMEN

BACKGROUND: The dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. METHODS: Peripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays. FINDINGS: Of the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts [0·6 (0·6-0·8)] but increases in neutrophil counts [4·7 (3·6-5·8)] than 27 mild cases [1.1 (0·8-1·4); 2·0 (1·5-2·9)]. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-lymphocyte ratio (NLR) (AUC=0·93) and neutrophil-to-CD8+ T cell ratio (N8R) (AUC =0·94) were identified as powerful prognostic factors affecting the prognosis for severe COVID-19. INTERPRETATION: The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R and NLR may serve as a useful prognostic factor for early identification of severe COVID-19 cases. FUNDING: The National Natural Science Foundation of China, the National Science and Technology Major Project, the Health Commission of Hubei Province, Huazhong University of Science and Technology, and the Medical Faculty of the University of Duisburg-Essen and Stiftung Universitaetsmedizin, Hospital Essen, Germany.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Citocinas/sangre , Recuento de Leucocitos , Subgrupos Linfocitarios/inmunología , Neumonía Viral/inmunología , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , China/epidemiología , Comorbilidad , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/epidemiología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Femenino , Citometría de Flujo , Humanos , Recuento de Linfocitos , Linfopenia/etiología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/complicaciones , Neumonía Viral/epidemiología , Pronóstico , Factores de Tiempo
20.
Nat Commun ; 11(1): 1613, 2020 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-32235862

RESUMEN

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Testosterona/metabolismo , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Animales , Antineoplásicos/farmacología , Médula Ósea/patología , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Femenino , Terapia de Reemplazo de Hormonas/métodos , Pulmón/patología , Masculino , Melanoma/inmunología , Melanoma/patología , Melanoma/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Testosterona/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA