RESUMO
Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/ß, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.
Assuntos
Sistema Nervoso Central/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Microcefalia/imunologia , Células-Tronco Neurais/citologia , Zika virus/imunologia , Brasil , Camboja , Células Cultivadas , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/líquido cefalorraquidiano , Quimiocina CXCL9/imunologia , Citocinas/análise , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Inflamação/imunologia , Inflamação/patologia , Interferon-alfa/líquido cefalorraquidiano , Interferon-alfa/imunologia , Interferon beta/imunologia , Masculino , Microcefalia/patologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Replicação Viral/imunologia , Infecção por Zika virus/imunologiaRESUMO
Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.
Assuntos
Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Quimiocina CCL11 , Quimiocina CCL2 , Quimiocina CCL4 , Quimiocina CCL5 , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/sangue , Quimiocina CXCL9/líquido cefalorraquidiano , Árvores de Decisões , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/líquido cefalorraquidiano , Diagnóstico Precoce , Fator de Crescimento Epidérmico , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/líquido cefalorraquidiano , Fator de Crescimento de Hepatócito , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-7/sangue , Interleucina-7/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Análise Multivariada , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico , Prognóstico , Medição de RiscoRESUMO
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and debilitating disorder marked by cognitive and sensory dysfunction and unexplained physical fatigue. Classically, cases present after a prodrome consistent with infection; however, some cases are atypical and have a different presentation and comorbidities that pose challenges for differential diagnosis. We analyzed cerebrospinal fluid (CSF) from 32 cases with classical ME/CFS and 27 cases with atypical ME/CFS using a 51-plex cytokine assay. Atypical subjects differed in cytokine profiles from classical subjects. In logistic regression models incorporating immune molecules that were identified as potential predictor variables through feature selection, we found strong associations between the atypical ME/CFS phenotype and lower CSF levels of the inflammatory mediators, interleukin 17A and CXCL9. Network analysis revealed an absence of inverse inter-cytokine relationships in CSF from atypical patients, and more sparse positive intercorrelations, than classical subjects. Interleukin 1 receptor antagonist appeared to be a negative regulator in classical ME/CFS, with patterns suggestive of disturbances in interleukin 1 signaling and autoimmunity-type patterns of immune activation. Immune signatures in the central nervous system of ME/CFS patients with atypical features may be distinct from those with more typical clinical presentations.
Assuntos
Líquido Cefalorraquidiano/imunologia , Citocinas/líquido cefalorraquidiano , Síndrome de Fadiga Crônica/líquido cefalorraquidiano , Síndrome de Fadiga Crônica/imunologia , Adulto , Quimiocina CXCL9/líquido cefalorraquidiano , Quimiocina CXCL9/imunologia , Citocinas/imunologia , Diagnóstico Diferencial , Síndrome de Fadiga Crônica/diagnóstico , Feminino , Humanos , Interleucina-17/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Interleukin-6 (IL-6), an inflammatory cytokine, plays important roles in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH). Chemokines are chemoattractant cytokines that regulate trafficking of monocytes/macrophages and lymphocytes to sites of inflammation. However, no studies have been reported regarding the temporal expression of these cytokines in CSF after SAH. FINDINGS: The concentrations of IL-6, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-inducible protein-10 (IP-10), and monokine induced by interferon-γ (MIG) in the CSF of ten patients with SAH were measured using ELISA kits over a period of 14 days. All aneurysms were located in the anterior circulation. CSF samples from patients with unruptured aneurysms were used as controls. The concentration of IL-6 significantly increased during the acute stage of the disease. The concentration of MCP-1 increased from days 1 to 5, peaking on day 3, and decreased thereafter. The concentrations of IP-10 and MIG progressively increased, peaked on day 5, and then gradually decreased. There were strong correlations between the maximum levels of IL-6 and MCP-1 and IP-10 and MIG on day 5. The maximum level of IL-6 was much higher in poor outcome patients than in good outcome patients. CONCLUSIONS: The present investigation demonstrated that increases in IL-6 levels may induce the expression of MCP-1 in CSF after SAH, followed by increases in the expression of IP-10 and MIG. Dynamic changes in the levels of these cytokines may induce inflammation and may be closely associated with the development of delayed ischemic neurological deficits after SAH.
Assuntos
Quimiocina CCL2/líquido cefalorraquidiano , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Hemorragia Subaracnóidea/líquido cefalorraquidiano , Hemorragia Subaracnóidea/diagnóstico , Adulto , Idoso , Biomarcadores/líquido cefalorraquidiano , Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Feminino , Expressão Gênica , Humanos , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Hemorragia Subaracnóidea/genéticaRESUMO
BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined "deteriorating HAM/TSP" as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and "stable HAM/TSP" as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set. CONCLUSIONS/SIGNIFICANCE: As the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.
Assuntos
Biomarcadores/líquido cefalorraquidiano , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/líquido cefalorraquidiano , Infecções por HTLV-I/diagnóstico , Neopterina/líquido cefalorraquidiano , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Adulto JovemAssuntos
Líquido Cefalorraquidiano/citologia , Quimiocina CCL2/líquido cefalorraquidiano , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Síndrome Uveomeningoencefálica/líquido cefalorraquidiano , Adulto , Idoso , Quimiocina CCL5/líquido cefalorraquidiano , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Brainstem encephalitis (BE) is a serious neurological complication of enterovirus 71 (EV71) infection. The present study was designed to determine the characteristics of the chemokine response in the blood and cerebrospinal fluid (CSF) of patients with EV71-associated BE. METHODS: Thirty-one patients with BE were studied. They consisted of 12 with uncomplicated BE, 9 with autonomic nervous system (ANS) dysregulation, and 10 with pulmonary edema (PE); 13 healthy control subjects were also studied. Plasma and CSF concentrations of various chemokines were determined by a particle-based flow cytometry immunoassay. RESULTS: Plasma levels of interferon (IFN)-gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by IFN-gamma (MIG), and interleukin (IL)-8 were significantly higher in patients with PE than in those with uncomplicated BE. CSF levels of MIG were significantly higher in patients with PE than in those with uncomplicated BE and ANS dysregulation. The ratios of mean CSF to plasma levels for MCP-1 and IL-8 were highest in patients with uncomplicated BE and tended to fall with increasing severity of the disease. CONCLUSIONS: Overexpression of the chemokine cascade in the central nervous system compartment appears to play an important role in the elicitation of the immune response to EV71. The chemokine CSF to plasma ratios suggest that IL-8, IP-10, MCP-1, and possibly MIG-but not RANTES-are synthesized in the brain in response to encephalitis.