RESUMEN
To compare cell adhesion molecules levels in cerebrospinal fluid (CSF) between Zika virus (ZIKV)-exposed neonates with/without microcephaly (cases) and controls, 16 neonates (cases), 8 (50%) with and 8 (50%) without microcephaly, who underwent lumbar puncture (LP) during the ZIKV epidemic (2015-2016) were included. All mothers reported ZIKV clinical symptoms during gestation, all neonates presented with congenital infection findings, and other congenital infections were ruled out. Fourteen control neonates underwent LP in the same laboratory (2017-2018). Five cell adhesion proteins were measured in the CSF using mass spectrometry. Neurexin-1 (3.50 [2.00-4.00] vs. 7.5 [5.00-10.25], P = 0.001), neurexin-3 (0.00 [0.00-0.00] vs. 3.00 [1.50-4.00], P = 0.001) and neural cell adhesion molecule 2 (NCAM2) (0.00 [0.00-0.75] vs. 1.00 [1.00-2.00], P = 0.001) were significantly lower in microcephalic and non-microcephalic cases than in controls. When these two sub-groups of prenatally ZIKA-exposed children were compared to controls separately, the same results were found. When cases with and without microcephaly were compared, no difference was found. Neurexin-3 (18.8% vs. 78.6%, P = 0.001) and NCAM2 (25.0% vs. 85.7%, P = 0.001) were less frequently found among the cases. A positive correlation was found between cephalic perimeter and levels of these two proteins. Neurexin-2 and neurexin-2b presented no significant differences. Levels of three cell adhesion proteins were significantly lower in CSF of neonates exposed to ZIKV before birth than in controls, irrespective of presence of congenital microcephaly. Moreover, the smaller the cephalic perimeter, the lower CSF cell adhesion protein levels. These findings suggest that low CSF levels of neurexin-1, neurexin-3 and NCAM2 may reflect the effects of ZIKV on foetal brain development.
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Microcefalia , Complicaciones Infecciosas del Embarazo , Infección por el Virus Zika , Virus Zika , Recién Nacido , Embarazo , Femenino , Niño , Humanos , Infección por el Virus Zika/diagnóstico , Infección por el Virus Zika/epidemiología , Microcefalia/epidemiología , Estudios de Casos y Controles , Adhesión Celular , Complicaciones Infecciosas del Embarazo/epidemiología , Moléculas de Adhesión Celular , Moléculas de Adhesión de Célula NerviosaRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of severe acute lower respiratory tract infections in infants. Natural killer (NK) cells are important antiviral effector cells that likely encounter RSV in the presence of virus-specific (maternal) antibodies. As NK cells potentially contribute to immunopathology, we investigated whether RSV affects their antiviral effector functions. METHODS: We assessed the phenotype and functionality of primary neonatal and adult NK cells by flow cytometry after stimulation with RSV or RSV-antibody complexes. RESULTS: We demonstrate for the first time that RSV infects neonatal and adult NK cells in vitro. Preincubation of virus with subneutralizing concentrations of RSV-specific antibodies significantly increased the percentage of infected NK cells. Upon infection, NK cells were significantly more prone to produce interferon-γ, while secretion of the cytotoxicity molecule perforin was not enhanced. CONCLUSIONS: Our findings suggest that (antibody-enhanced) RSV infection of NK cells induces a proinflammatory rather than a cytotoxic response, which may contribute to immunopathology. Considering that most RSV vaccines currently being developed aim at inducing (maternal) antibodies, these results highlight the importance of understanding the interactions between innate effector cells and virus-specific antibodies.
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Interacciones Huésped-Patógeno , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Virus Sincitial Respiratorio Humano/crecimiento & desarrollo , Adulto , Anticuerpos Bloqueadores/inmunología , Anticuerpos Antivirales/inmunología , Células Cultivadas , Voluntarios Sanos , Humanos , Recién Nacido , Interferones/metabolismo , Células Asesinas Naturales/metabolismo , Perforina/metabolismo , Infecciones por Virus Sincitial RespiratorioRESUMEN
Background: Different clinical manifestations of invasive pneumococcal disease (IPD) have thus far mainly been explained by patient characteristics. Here we studied the contribution of pneumococcal genetic variation to IPD phenotype. Methods: The index cohort consisted of 349 patients admitted to 2 Dutch hospitals between 2000-2011 with pneumococcal bacteremia. We performed genome-wide association studies to identify pneumococcal lineages, genes, and allelic variants associated with 23 clinical IPD phenotypes. The identified associations were validated in a nationwide (n = 482) and a post-pneumococcal vaccination cohort (n = 121). The contribution of confirmed pneumococcal genotypes to the clinical IPD phenotype, relative to known clinical predictors, was tested by regression analysis. Results: Among IPD patients, the presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (odds ratio [OR], 10.5; P = .001), as was sequence cluster 9 (serotype 7F: OR, 3.68; P = .057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR, 3.4; P = .003). We could detect the pneumococcal variants of concern in these patients' blood samples. Conclusions: In this study, knowledge of pneumococcal genotypic variants improved the clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate, or avert the pathogenic effects related to particular pneumococcal variants, and indicates that information on pneumococcal genotype is important for the diagnostic and treatment strategy in IPD. Ongoing surveillance is warranted to monitor the clinical value of information on pneumococcal variants in dynamic microbial and susceptible host populations.
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Bacteriemia/microbiología , Bacteriemia/patología , Variación Genética , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/patología , Streptococcus pneumoniae/clasificación , Streptococcus pneumoniae/genética , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Serogrupo , Streptococcus pneumoniae/aislamiento & purificación , Adulto JovenRESUMEN
Interferon gamma (IFN-γ) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell-cell interactions between monocytes and T cells regulate IFN-γ production. In this study, micro-array data identified the upregulation of sialic acid-binding immunoglobulin-type lectin 1 (Siglec-1) in human RSV-infected infants. In vitro, RSV increased expression of Siglec-1 on healthy newborn and adult monocytes. RSV-induced Siglec-1 on monocytes inhibited IFN-γ production by adult CD4+ T cells. In contrast, IFN-γ production by RSV in newborns was not affected by Siglec-1. The ligand for Siglec-1, CD43, is highly expressed on adult CD4+ T cells compared to newborns. Our data show that Siglec-1 reduces IFN-γ release by adult T cells possibly by binding to the highly expressed CD43. The Siglec-1-dependent inhibition of IFN-γ in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood.
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Linfocitos T CD4-Positivos/inmunología , Interferón gamma/biosíntesis , Monocitos/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Lectina 1 Similar a Ig de Unión al Ácido Siálico/inmunología , Factores de Edad , Humanos , Recién Nacido , Interferón gamma/inmunología , Leucosialina/metabolismo , Infecciones por Virus Sincitial Respiratorio/virología , Regulación hacia Arriba/inmunologíaRESUMEN
The pneumococcal capsular serotype is an important determinant of complement resistance and invasive disease potential, but other virulence factors have also been found to contribute. Pneumococcal surface protein C (PspC), a highly variable virulence protein that binds complement factor H to evade C3 opsonization, is divided into two subgroups: choline-bound subgroup I and LPxTG-anchored subgroup II. The prevalence of different PspC subgroups in invasive pneumococcal disease (IPD) and functional differences in complement evasion are unknown. The prevalence of PspC subgroups in IPD isolates was determined in a collection of 349 sequenced strains of Streptococcus pneumoniae isolated from adult patients. pspC deletion mutants and isogenic pspC switch mutants were constructed to study differences in factor H binding and complement evasion in relation to capsule thickness. Subgroup I pspC was far more prevalent in IPD isolates than subgroup II pspC The presence of capsule was associated with a greater ability of bound factor H to reduce complement opsonization. Pneumococcal subgroup I PspC bound significantly more factor H and showed more effective complement evasion than subgroup II PspC in isogenic encapsulated pneumococci. We conclude that variation in the PspC subgroups, independent of capsule serotypes, affects pneumococcal factor H binding and its ability to evade complement deposition.
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Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Proteínas del Sistema Complemento/inmunología , Genotipo , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/microbiología , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/inmunología , Anciano , Factor H de Complemento/inmunología , Factor H de Complemento/metabolismo , Proteínas del Sistema Complemento/metabolismo , Femenino , Humanos , Evasión Inmune , Masculino , Persona de Mediana Edad , Tipificación Molecular , Mutación , Infecciones Neumocócicas/epidemiología , Prevalencia , Serogrupo , Virulencia/genética , Factores de Virulencia/genéticaRESUMEN
Respiratory syncytial virus (RSV) is the leading cause of severe respiratory illness in infants. At this young age, infants typically depend on maternally transferred antibodies (matAbs) and their innate immune system for protection against infections. RSV-specific matAbs are thought to protect from severe illness, yet severe RSV disease occurs mainly below 6 months of age, when neutralizing matAb levels are present. To investigate this discrepancy, we asked if disease severity is related to antibody properties other than neutralization. Some antibody effector functions are mediated via their Fc binding region. However, it has been shown that this binding may lead to antibody-dependent enhancement (ADE) of infection or reduction of neutralization, both possibly leading to more disease. In this study, we first showed that high levels of ADE of RSV infection occur in monocytic THP-1 cells in the presence of RSV antibodies and that neutralization by these antibodies was reduced in Vero cells when they were transduced with Fc gamma receptors. We then demonstrated that antibodies from cotton rats with formalin-inactivated (FI)-RSV-induced pulmonary pathology were capable of causing ADE. Human matAbs also caused ADE and were less neutralizing in vitro in cells that carry Fc receptors. However, these effects were unrelated to disease severity because they were seen both in uninfected controls and in infants hospitalized with different levels of RSV disease severity. We conclude that ADE and reduction of neutralization are unlikely to be involved in RSV disease in infants with neutralizing matAbs.IMPORTANCE It is unclear why severity of RSV disease peaks at the age when infants have neutralizing levels of maternal antibodies. Additionally, the exact reason for FI-RSV-induced enhanced disease, as seen in the 1960s vaccine trials, is still unclear. We hypothesized that antibodies present under either of these conditions could contribute to disease severity. Antibodies can have effects that may lead to more disease instead of protection. We investigated two of those effects: antibody-dependent enhancement of infection (ADE) and neutralization reduction. We show that ADE occurs in vitro with antibodies from FI-RSV-immunized RSV-infected cotton rats. Moreover, passively acquired maternal antibodies from infants had the capacity to induce ADE and reduction of neutralization. However, no clear association with disease severity was seen, ruling out that these properties explain disease in the presence of maternal antibodies. Our data contribute to a better understanding of the impact of antibodies on RSV disease in infants.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Receptores de IgG/metabolismo , Infecciones por Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Virus Sincitiales Respiratorios/inmunología , Índice de Severidad de la Enfermedad , Animales , Anticuerpos Antivirales/sangre , Acrecentamiento Dependiente de Anticuerpo , Estudios de Casos y Controles , Chlorocebus aethiops , Femenino , Humanos , Lactante , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Monocitos/inmunología , Monocitos/patología , Monocitos/virología , Pruebas de Neutralización , Ratas , Receptores de IgG/inmunología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Sigmodontinae , Vacunación , Células Vero , Proteínas del Envoltorio Viral/inmunología , Proteínas Virales de Fusión/inmunologíaRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) can cause recurrent and severe respiratory tract infections. Cytoskeletal proteins are often involved during viral infections, either for cell entry or the initiation of the immune response. The importance of actin and clathrin dynamics for cell entry and the initiation of the cellular immune response against RSV in human immune cells is not known yet. The aim of this study was to investigate the role of actin and clathrin on cell entry of RSV and the subsequent effect on T cell activation and interferon gamma release in human immune cells. METHODS: Peripheral blood mononuclear cells and purified monocytes were isolated from healthy adults and stimulated in vitro with RSV. Actin and clathrin dynamics were inhibited with respectively cytochalasin D and chlorpromazine. T cell receptor signaling was inhibited with cyclosporin A. Flow cytometry was used to determine the role of actin and clathrin on cell entry and T cell activation by RSV. Enzyme-linked immunosorbent assays were used to investigate the contribution of actin and clathrin on the release of interferon gamma. RESULTS: Cell entry, virus gene transcription and interferon gamma release are actin-dependent. Post-endocytic processes like the increased expression of major histocompatibility complex II on monocytes , T cell activation and the release of interferon gamma are clathrin-dependent. Finally, T cell receptor signaling affects T cell activation, whereas soluble interleukin 18 is dispensable. CONCLUSION: Analysis of cell entry and interferon gamma release after infection with RSV reveals the importance of actin- and clathrin-dependent signaling in human immune cells. Insights into the cellular biology of the human immune response against respiratory syncytial virus will provide a better understanding of disease pathogenesis and may prove useful in the development of preventive strategies.
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Actinas/metabolismo , Clatrina/metabolismo , Interacciones Huésped-Patógeno , Interferón gamma/metabolismo , Virus Sincitiales Respiratorios/fisiología , Internalización del Virus , Adulto , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virologíaRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infections in infants. A small percentage of the infected infants develops a severe infection, while most of these severely ill patients were previously healthy. It remains unclear why these children develop severe RSV infections. In this study, we investigate whether pneumococcal nasopharyngeal carriage patterns correlate with mucosal inflammation and severity of disease. METHODS: In total, 105 infants hospitalized with RSV infection were included and recovery samples were taken from 42 patients. The presence and density of Streptococcus pneumoniae was determined by RT qPCR to study its relation to viral load, inflammation (MMP-9 and IL-6) and severity of RSV disease. RESULTS: We show that pneumococcal presence or absence in the nasopharynx does not correlate with viral load, inflammation or severity of disease. However, when pneumococcus is present in patients, a higher nasopharyngeal pneumococcal density was correlated with a higher RSV load, higher MMP-9 levels and a less severe course of disease. CONCLUSIONS: Our results show correlations between S. pneumoniae density and viral load, inflammation and disease severity, suggesting that pneumococcal density may be an indicator for severity in paediatric RSV disease.
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Infecciones por Virus Sincitial Respiratorio/epidemiología , Virus Sincitiales Respiratorios/aislamiento & purificación , Infecciones del Sistema Respiratorio/epidemiología , Streptococcus pneumoniae/aislamiento & purificación , Servicios de Salud del Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Nasofaringe/microbiología , Nasofaringe/virología , Países Bajos/epidemiología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/patogenicidad , Infecciones del Sistema Respiratorio/virología , Índice de Severidad de la Enfermedad , Streptococcus pneumoniae/patogenicidad , Carga ViralRESUMEN
There is still uncertainty whether extremely low frequency electromagnetic fields (ELF-EMF) can induce health effects like immunomodulation. Despite evidence obtained in vitro, an unambiguous association has not yet been established in vivo. Here, mice were exposed to ELF-EMF for 1, 4, and 24 h/day in a short-term (1 week) and long-term (15 weeks) set-up to investigate whole body effects on the level of stress regulation and immune response. ELF-EMF signal contained multiple frequencies (20-5000 Hz) and a magnetic flux density of 10 µT. After exposure, blood was analyzed for leukocyte numbers (short-term and long-term) and adrenocorticotropic hormone concentration (short-term only). Furthermore, in the short-term experiment, stress-related parameters, corticotropin-releasing hormone, proopiomelanocortin (POMC) and CYP11A1 gene-expression, respectively, were determined in the hypothalamic paraventricular nucleus, pituitary, and adrenal glands. In the short-term but not long-term experiment, leukocyte counts were significantly higher in the 24 h-exposed group compared with controls, mainly represented by increased neutrophils and CD4 ± lymphocytes. POMC expression and plasma adrenocorticotropic hormone were significantly lower compared with unexposed control mice. In conclusion, short-term ELF-EMF exposure may affect hypothalamic-pituitary-adrenal axis activation in mice. Changes in stress hormone release may explain changes in circulating leukocyte numbers and composition. Bioelectromagnetics. 37:433-443, 2016. © 2016 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.
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Campos Electromagnéticos/efectos adversos , Sistema Hipotálamo-Hipofisario/citología , Sistema Hipotálamo-Hipofisario/efectos de la radiación , Recuento de Leucocitos , Sistema Hipófiso-Suprarrenal/citología , Sistema Hipófiso-Suprarrenal/efectos de la radiación , Transducción de Señal/efectos de la radiación , Animales , Ratones , Factores de TiempoRESUMEN
Respiratory syncytial virus (RSV) causes mild infections in the vast majority of children. However, in some cases, it causes severe disease, such as bronchiolitis and pneumonia. Development of severe RSV infection is determined by the host response. Therefore, the main aim of this study was to identify biomarkers associated with severe RSV infection. To identify biomarkers, nasopharyngeal gene expression was profiled by microarray studies, resulting in the selection of five genes: ubiquitin D, tetraspanin 8, mucin 13, ß-microseminoprotein and chemokine ligand 7. These genes were validated by real-time quantitative PCR in an independent validation cohort, which confirmed significant differences in gene expression between mildly and severely infected and between recovery and acute patients. Nasopharyngeal aspirate samples are regularly taken when a viral respiratory tract infection is suspected. In this article, we describe a method to discriminate between mild and severe RSV infection based on differential host gene expression. The combination of pathogen detection and host gene expression analysis in nasopharyngeal aspirates will significantly improve the diagnosis and prognosis of respiratory tract infections.
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Quimiocina CCL7/genética , Interacciones Huésped-Patógeno/genética , Mucinas/genética , Proteínas de Secreción Prostática/genética , Infecciones por Virus Sincitial Respiratorio , Tetraspaninas/genética , Preescolar , Femenino , Perfilación de la Expresión Génica , Marcadores Genéticos , Humanos , Lactante , Masculino , Análisis por Micromatrices , Nasofaringe/virología , Gravedad del Paciente , Valor Predictivo de las Pruebas , Pronóstico , Recuperación de la Función/genética , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Infecciones por Virus Sincitial Respiratorio/genética , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Infecciones por Virus Sincitial Respiratorio/virologíaRESUMEN
Respiratory syncytial virus (RSV) bronchiolitis is a major burden in infants below three months of age, when the primary immune response is mainly dependent on innate immunity and maternal antibodies. We investigated the influence of antibodies on innate immunity during RSV infection. PBMCs from infants and adults were stimulated with live RSV and inactivated RSV in combination with antibody-containing and antibody-depleted serum. The immune response was determined by transcriptome analysis and chemokine levels were measured using ELISA and flow cytometry. Microarray data showed that CXCL10 gene transcription was RSV dependent, whereas CXCL11 and IFNα were upregulated in an antibody-dependent manner. Although the presence of antibodies reduces RSV infection rate, it enhances the innate immune response. In adult immune cells, antibodies enhance CXCL10, CXCL11, IFNα and IFNγ production in response to RSV infection. Contrary, in infant immune cells only CXCL10 was enhanced in an antibody-dependent manner. Monocytes are the main source of CXCL10 and they produce CXCL10 in both an antibody- and virus-dependent manner. This study shows that antibodies enhance CXCL10 production in infant immune cells. CXCL10 has been implicated in exuberating the inflammatory response during viral infections and antibodies could therefore play a role in the pathogenesis of RSV infections.
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Anticuerpos/inmunología , Quimiocina CXCL10/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Adulto , Quimiocina CXCL10/genética , Citocinas/biosíntesis , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunidad Innata , Lactante , Transcripción GenéticaRESUMEN
Novel viral diagnostic tools need to be affordable, fast, accurate and easy to use with sensitivity and specificity equivalent or superior to current standards. At present, viral diagnostics are based on direct detection of viral components or indirect detection by measuring antibodies generated in response to viral infection. While sensitivity of detection and quantification are still important challenges, we expect major advances from new assay formats and synthetic binding molecules, such as aptamers. Compared to traditional antibody-based detection, aptamers could provide faster adaptation to continuously evolving virus strains and higher discriminating capacity between specific virus serotypes. Aptamers are very stable and easily modifiable, so are ideal molecules for detection and chemical sensing applications. Here, we review the use of aptasensors for detection of viral pathogens and consider the feasibility of aptasensors to become standard devices for point-of-care diagnostics of viruses.
RESUMEN
RSV infections are a major burden in infants less than 3 months of age. Newborns and infants express a distinct immune system that is largely dependent on innate immunity and passive immunity from maternal antibodies. Antibodies can regulate immune responses against viruses through interaction with Fc gamma receptors leading to enhancement or neutralization of viral infections. The mechanisms underlying the immunomodulatory effect of Fc gamma receptors on viral infections have yet to be elucidated in infants. Herein, we will discuss current knowledge of the effects of antibodies and Fc gamma receptors on infant innate immunity to RSV. A better understanding of the pathogenesis of RSV infections in young infants may provide insight into novel therapeutic strategies such as vaccination.
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Anticuerpos Antivirales/inmunología , Inmunidad Innata , Receptores de IgG/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Humanos , Lactante , Recién Nacido , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/patogenicidadRESUMEN
Matrix metallopeptidase 9 (MMP-9) is a protease involved in the degradation of extracellular matrix collagen. Evidence suggests that MMP-9 is involved in pathogenesis during Streptococcus pneumoniae infection. However, not much is known about the induction of MMP-9 and the regulatory processes involved. We show here that the Gram-positive bacteria used in this study induced large amounts of MMP-9, in contrast to the Gram-negative bacteria that were used. An important pathogen-associated molecular pattern (PAMP) for Gram-positive bacteria is muramyl dipeptide (MDP). MDP is a very potent inducer of MMP-9 and showed a dose-dependent MMP-9 induction. Experiments using peripheral blood mononuclear cells (PBMCs) from Crohn's disease patients with nonfunctional NOD2 showed that MMP-9 induction by Streptococcus pneumoniae and MDP is NOD2 dependent. Increasing amounts of lipopolysaccharide (LPS), an important PAMP for Gram-negative bacteria, resulted in decreasing amounts of MMP-9. Moreover, the induction of MMP-9 by MDP could be counteracted by simultaneously adding LPS. The inhibition of MMP-9 expression by LPS was found to be regulated posttranscriptionally, independently of tissue inhibitor of metalloproteinase 1 (TIMP-1), an endogenous inhibitor of MMP-9. Collectively, these data show that Streptococcus pneumoniae is able to induce large amounts of MMP-9. These high MMP-9 levels are potentially involved in Streptococcus pneumoniae pathogenesis.
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Acetilmuramil-Alanil-Isoglutamina/metabolismo , Interacciones Huésped-Patógeno , Lipopolisacáridos/metabolismo , Metaloproteinasa 9 de la Matriz/biosíntesis , Proteína Adaptadora de Señalización NOD2/metabolismo , Streptococcus pneumoniae/fisiología , Células Cultivadas , Enfermedad de Crohn/inmunología , Humanos , Leucocitos Mononucleares/inmunologíaRESUMEN
OBJECTIVES: In blood culture-proven pneumococcal infections, streamlining empirical therapy to monotherapy with a penicillin is preferred in order to reduce the use of broad-spectrum antibiotics. However, adherence to this international recommendation is poor, and curiously it is unclear whether antibiotic streamlining may be harmful to individual patients. We investigated whether streamlining in bacteraemic pneumococcal infections is associated with mortality. METHODS: Adults admitted to two Dutch hospitals between 2001 and 2011 with bacteraemic pneumococcal infections were retrospectively included. Detailed clinical data on patient characteristics, comorbidities and severity and outcome of disease were obtained in addition to data on antibiotic treatment. Those eligible for streamlining were selected for further analyses. RESULTS: In the 45.8% of cases (126 of 275) where antibiotic treatment was streamlined, a lower mortality rate was observed (6.3% versus 15.4%, Pâ=â0.021). The decision to streamline was only marginally explained by the 38 determinants accounted for. After correction for potential confounders, the OR for death while streamlining was 0.45 (95% CI: 0.18-1.11, Pâ=â0.082) in all cases and 0.35 (95% CI: 0.12-0.99, Pâ=â0.048) specifically in pneumonia cases. CONCLUSIONS: Our results suggest that streamlining in eligible pneumococcal bacteraemia cases is safe, irrespective of patient characteristics, severity of disease or empirical treatment regimen.
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Bacteriemia/tratamiento farmacológico , Bacteriemia/mortalidad , Penicilinas/uso terapéutico , Infecciones Neumocócicas/tratamiento farmacológico , Infecciones Neumocócicas/mortalidad , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Bacteriemia/microbiología , Comorbilidad , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Países Bajos , Infecciones Neumocócicas/microbiología , Neumonía Neumocócica/tratamiento farmacológico , Estudios Retrospectivos , Streptococcus pneumoniae/efectos de los fármacos , Resultado del TratamientoRESUMEN
INTRODUCTION: The clinical severity and course of invasive pneumococcal disease (IPD) differs substantially between patients. Streptococcus pneumoniae harbors large genetic variability. Zinc metalloproteinase C (ZmpC), a secreted pneumococcal protein involved in neutrophil extravasation, inflammation and tissue remodeling, is present in a minority of IPD isolates. We investigated whether the presence of zmpC was associated with the clinical manifestation of IPD. MATERIAL AND METHODS: IPD patients admitted to two Dutch hospitals between 2000 and 2013 were included in the study. Detailed clinical data were collected and the serotype and presence of zmpC were determined in the corresponding blood culture isolates. RESULTS: ZmpC was present in 21% of the 542 included IPD cases and was mainly associated with serotypes 8, 4, 33A/F and 11A/D. Infection with S. pneumoniae positive for zmpC was more frequently observed in females (p=0.048) and patients with a history of smoking (p=0.033). Although no relation to clinical syndrome was observed, zmpC positive cases more often presented with cough, dyspnea and sepsis (p-values 0.026, 0.001 and 0.018), and more frequently required ICU admission (p=0.011) compared to zmpC negative cases. CONCLUSION: The presence of zmpC was associated with a more severe clinical manifestation of IPD. This study demonstrates that information on pneumococcal genetic background may be useful to identify vulnerable individuals, to monitor clinical presentation and to predict the course of IPD.
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Metaloendopeptidasas/metabolismo , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/patología , Streptococcus pneumoniae/enzimología , Factores de Virulencia/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Metaloendopeptidasas/clasificación , Metaloendopeptidasas/genética , Persona de Mediana Edad , Países Bajos , Serogrupo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/aislamiento & purificación , Factores de Virulencia/genética , Adulto JovenRESUMEN
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, with remarkable variability in disease severity. An exaggerated proinflammatory response and influx of leukocytes is part of the pathogenesis of severe RSV disease. Here, we show an increase in proinflammatory cytokine production by human immune cells after stimulation with RSV and muramyl dipeptide (MDP), which is recognized by nucleotide-binding oligomerization domain containing 2 (NOD2). PBMCs from Crohn's disease patients homozygous for the 3020insC mutation in the NOD2 gene did not show a synergistic response to stimulation with RSV and MDP, suggesting that NOD2 is essential for the observed synergy. Further experiments aimed at identifying the viral ligand indicated that viral RNA plays an essential role in the recognition of RSV. Stimulation with RSV or Poly(I:C) induced IFN-ß expression, which resulted in an increased expression of the viral receptors TLR3 and RIG-I, as well as an increased NOD2 expression. Our data indicate that IFN-ß induction by viral RNA is an essential first step in the increased proinflammatory response to MDP. We hypothesize that the enhanced proinflammatory response to MDP following RSV infection may be an important factor in determining the outcome of the severity of disease.
Asunto(s)
Enfermedad de Crohn/inmunología , Interferón beta/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , ARN Viral/metabolismo , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/fisiología , Acetilmuramil-Alanil-Isoglutamina/inmunología , Células Cultivadas , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Humanos , Lactante , Recién Nacido , Mediadores de Inflamación/metabolismo , Mutación/genética , Proteína Adaptadora de Señalización NOD2/genética , Cultivo Primario de Células , Receptores Inmunológicos , Transducción de Señal , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Current tools to predict the severity of respiratory syncytial virus (RSV) infection might be improved by including immunological parameters. We hypothesized that a combination of inflammatory markers would differentiate between severe and mild disease in RSV-infected children. METHODS: Blood and nasopharyngeal samples from 52 RSV-infected children were collected during acute infection and after recovery. Retrospectively, patients were categorized into three groups based on disease severity: mild (no supportive treatment), moderate (supplemental oxygen and/or nasogastric feeding), and severe (mechanical ventilation). Clinical data, number of flow-defined leukocyte subsets, and cytokine concentrations were compared. RESULTS: Children with severe RSV infection were characterized by young age; lymphocytopenia; increased interleukin (IL)-8, granulocyte colony-stimulating factor (G-CSF), and IL-6 concentrations; and decreased chemokine (C-C motif) ligand (CCL-5) concentrations in plasma. The combination of plasma levels of IL-8 and CCL-5, and CD4+ T-cell counts, with cutoff values of 67 pg/ml, 13 ng/ml, and 2.3 × 10(6)/ml, respectively, discriminated severe from mild RSV infection with 82% sensitivity and 96% specificity. CONCLUSION: This study demonstrates that the combination of CD4+ T-cell counts and IL-8 and CCL-5 plasma concentrations correlates with disease severity in RSV-infected children. In addition to clinical features, these immunological markers may be used to assess severity of RSV infection and guide clinical management.
Asunto(s)
Bronquiolitis Viral/diagnóstico , Linfocitos T CD4-Positivos/inmunología , Quimiocina CCL5/sangre , Mediadores de Inflamación/sangre , Interleucina-8/sangre , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Virus Sincitial Respiratorio Humano/inmunología , Factores de Edad , Biomarcadores/sangre , Bronquiolitis Viral/sangre , Bronquiolitis Viral/inmunología , Bronquiolitis Viral/terapia , Bronquiolitis Viral/virología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/virología , Distribución de Chi-Cuadrado , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Infecciones por Virus Sincitial Respiratorio/sangre , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/terapia , Infecciones por Virus Sincitial Respiratorio/virología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Carga ViralRESUMEN
Acute respiratory viral infections (ARVI's) are the most common infectious disease in humans. With the appearance of molecular techniques the recovery of viruses has dramatically increased. Nowadays virologists can quickly discriminate virological families and related viruses from emerging viruses and consequently identify novel viruses. Many new respiratory viruses have been identified in children in the past 15 years. In this review we shortly discuss novel respiratory viruses and their pathogenic role in pediatric respiratory disease. Advantages and drawbacks of the technique and our current knowledge will be discussed. We will conclude this review with a general discussion on the future role of molecular diagnostic virology in the clinic.