RESUMEN
Dengue is a significant health problem due to the high burden of critical infections during outbreaks. In 1997, the World Health Organization (WHO) classified dengue as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). It was revised in 2009 (updated in 2015), and the new guidelines recommended classifying patients as dengue without warning signs (DNS), dengue with warning signs (DWS), and severe dengue (SD). Although the utility of the revised 2009 classification for clinical studies is accepted, for immunological studies it needs to be clarified. We determined the usefulness of the 2009 classification for pediatric studies that analyze the circulating interleukin (IL)-6 and IL-8, two inflammatory cytokines. Plasma levels of IL-6 and IL-8 were evaluated in the acute and convalescent phases by flow cytometry in children with dengue classified using the 1997 and 2009 WHO guidelines. The plasma levels of IL-6 and IL-8 were elevated during the acute and decreased during convalescence, and both cytokines served as a good marker of acute dengue illness compared to convalescence. There were no differences in the plasma level of the evaluated cytokines among children with different clinical severity with any classification, except for the IL-8, which was higher in DWS than DNS. Based on the levels of IL-8, the 2009 classification identified DWS plus SD (hospital-treated children) compared to the DNS group [area under the curve (AUC): 0.7, p = 0.028]. These results support the utility of the revised 2009 (updated in 2015) classification in studies of immune markers in pediatric dengue.
Asunto(s)
Dengue , Interleucina-6 , Interleucina-8 , Organización Mundial de la Salud , Humanos , Dengue/inmunología , Dengue/diagnóstico , Niño , Masculino , Femenino , Interleucina-6/sangre , Preescolar , Interleucina-8/sangre , Dengue Grave/diagnóstico , Dengue Grave/inmunología , Dengue Grave/sangre , Adolescente , Índice de Severidad de la Enfermedad , Biomarcadores/sangre , Virus del Dengue/inmunología , Guías de Práctica Clínica como Asunto , Citometría de Flujo , Lactante , Citocinas/sangreRESUMEN
BACKGROUND: The intensity of dengue virus (DV) replication and circulating non-structural protein 1 (NS1) levels may promote changes in the human immune response and favor severe forms of infection. We investigated the correlations between NS1 with CXCL-8, CXCL-10, IFN-γ, and IL-12p40 serum levels, and IFN-γ receptor α chain (CD119) expression, and CXCL10 production by peripheral blood mononuclear cells (PBMCs) stimulated with recombinant IFN-γ in DV-infected patients with different clinical forms. METHODS: Dengue virus NS1, CXCL-8, CXCL-10, IFN-γ, and IL-12p40 serum levels were measured in 152 DV-infected patients with different clinical forms and 20 non-infected individuals (NI) using enzyme-linked immunosorbent assay (ELISA). In addition, we investigated the CXCL-10 production after in vitro IFN-γ stimulation of PBMCs from 48 DV-infected individuals (with different clinical forms of dengue fever) and 20 NI individuals using ELISA, and CD119 expression on CD14+ cells with flow cytometry. RESULTS: Patients with dengue hemorrhagic fever (DHF) had significantly higher NS1, CXCL-8, and CXCL-10 serum levels than those with classic dengue fever (DF). The response of PBMCs to IFN-γ stimulation was lower in patients with DHF than in those with DF or dengue with complications (DWC), with lower CD119 expression and reduced CXCL-10 synthesis. In addition, these alterations are associated with high NS1 serum levels. CONCLUSIONS: Patients with DHF reported high NS1 levels, low CD119 expression, and low CXCL-10 synthesis in PBMCs, which may be associated with infection progression and severity.
Asunto(s)
Quimiocina CXCL10 , Ensayo de Inmunoadsorción Enzimática , Dengue Grave , Proteínas no Estructurales Virales , Humanos , Quimiocina CXCL10/sangre , Masculino , Dengue Grave/sangre , Dengue Grave/inmunología , Femenino , Adulto , Persona de Mediana Edad , Leucocitos Mononucleares/metabolismo , Estudios de Casos y Controles , Adulto Joven , Interferón gamma/sangre , Adolescente , Citometría de FlujoRESUMEN
Dengue fever, a neglected tropical arboviral disease, has emerged as a global health concern in the past decade. Necessitating a nuanced comprehension of the intricate dynamics of host-virus interactions influencing disease severity, we analysed transcriptomic patterns using bulk RNA-seq from 112 age- and gender-matched NS1 antigen-confirmed hospital-admitted dengue patients with varying severity. Severe cases exhibited reduced platelet count, increased lymphocytosis, and neutropenia, indicating a dysregulated immune response. Using bulk RNA-seq, our analysis revealed a minimal overlap between the differentially expressed gene and transcript isoform, with a distinct expression pattern across the disease severity. Severe patients showed enrichment in retained intron and nonsense-mediated decay transcript biotypes, suggesting altered splicing efficiency. Furthermore, an up-regulated programmed cell death, a haemolytic response, and an impaired interferon and antiviral response at the transcript level were observed. We also identified the potential involvement of the RBM39 gene among others in the innate immune response during dengue viral pathogenesis, warranting further investigation. These findings provide valuable insights into potential therapeutic targets, underscoring the importance of exploring transcriptomic landscapes between different disease sub-phenotypes in infectious diseases.
Asunto(s)
Empalme Alternativo , Virus del Dengue , Dengue Grave , Humanos , Empalme Alternativo/genética , Femenino , Masculino , Virus del Dengue/genética , Adulto , Dengue Grave/genética , Dengue Grave/inmunología , Dengue Grave/virología , Persona de Mediana Edad , Transcriptoma/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Perfilación de la Expresión Génica/métodos , Inmunidad Innata/genética , Dengue/genética , Dengue/inmunología , Dengue/virología , Adulto Joven , Índice de Severidad de la Enfermedad , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunologíaRESUMEN
Recent studies have demonstrated that cytokine dysregulation has a critical role in the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The aim of this study was to investigate the association between tumor necrosis factor (TNF- α), interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 17 (IL-17) with infection status, and severity of dengue. A prospective cross-sectional study was conducted at three hospitals in Gianyar regency and Denpasar municipality, Bali, Indonesia, from June to December 2022. Sixty-four dengue infected patients were involved. Patients' serum was tested for dengue infection using NS1 antigen rapid test, dengue virus immunoglobulin M (IgM) and immunoglobulin G (IgG) test, and reverse transcription polymerase chain reaction (RT-PCR). Cytokine levels (TNF-α, IL-6, IL-10, and IL-17) were measured using enzyme-linked immunosorbent assay (ELISA). Infection status was determined by combining serological and RT-PCR results, categorizing patients into primary and secondary infections. The present study found that DF patients had lower TNF-α, IL-6, and IL-17 but higher IL-10 levels compared to DHF patients (p<0.001). Elevated TNF-α, IL-6, and IL-17 levels were higher in secondary infection, while IL-10 level was higher in primary infection (p<0.001). In conclusion, cytokines play a crucial role in the interplay between cytokine dysregulation and dengue infection dynamics.
Asunto(s)
Citocinas , Dengue , Dengue Grave , Humanos , Indonesia/epidemiología , Dengue Grave/sangre , Dengue Grave/inmunología , Dengue Grave/epidemiología , Masculino , Femenino , Citocinas/sangre , Estudios Transversales , Estudios Prospectivos , Adulto , Dengue/sangre , Dengue/inmunología , Dengue/epidemiología , Persona de Mediana Edad , Interleucina-6/sangre , Ensayo de Inmunoadsorción Enzimática , Adolescente , Interleucina-10/sangre , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
C-type lectins play a crucial role as pathogen-recognition receptors for the dengue virus, which is responsible for causing both dengue fever (DF) and dengue hemorrhagic fever (DHF). DHF is a serious illness caused by the dengue virus, which exists in four different serotypes: DEN-1, DEN-2, DEN-3, and DEN-4. We conducted a genetic association study, during a significant DEN-2 outbreak in southern Taiwan, to explore how variations in the neck-region length of L-SIGN (also known as CD209L, CD299, or CLEC4M) impact the severity of dengue infection. PCR genotyping was utilized to identify polymorphisms in variable-number tandem repeats. We constructed L-SIGN variants containing either 7- or 9-tandem repeats and transfected these constructs into K562 and U937 cells, and cytokine and chemokine levels were evaluated using enzyme-linked immunosorbent assays (ELISAs) following DEN-2 virus infection. The L-SIGN allele 9 was observed to correlate with a heightened risk of developing DHF. Subsequent results revealed that the 9-tandem repeat was linked to elevated viral load alongside predominant T-helper 2 (Th2) cell responses (IL-4 and IL-10) in K562 and U937 cells. Transfecting K562 cells in vitro with L-SIGN variants containing 7- and 9-tandem repeats confirmed that the 9-tandem repeat transfectants facilitated a higher dengue viral load accompanied by increased cytokine production (MCP-1, IL-6, and IL-8). Considering the higher prevalence of DHF and an increased frequency of the L-SIGN neck's 9-tandem repeat in the Taiwanese population, individuals with the 9-tandem repeat may necessitate more stringent protection against mosquito bites during dengue outbreaks in Taiwan.
Asunto(s)
Virus del Dengue , Lectinas Tipo C , Receptores de Superficie Celular , Dengue Grave , Replicación Viral , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Citocinas/metabolismo , Citocinas/genética , Virus del Dengue/genética , Virus del Dengue/inmunología , Células K562 , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Repeticiones de Minisatélite/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Dengue Grave/inmunología , Dengue Grave/virología , Dengue Grave/genética , Taiwán , Células U937 , Carga Viral , Replicación Viral/genéticaRESUMEN
Natural killer cells (NK cells) are the front line of immune cells to combat pathogens and able to influence the subsequent adaptive immune responses. One of the factors contributing to pathogenesis in dengue hemorrhagic fever (DHF) disease is aberrant immune activation during early phase of infection. This study explored the profile of NK cells in dengue infected pediatric patients with different degrees of disease severity. DHF patients contained higher frequency of activated NK cells but lower ratio of CD56dim:CD56bright NK subsets. Activated NK cells exhibited alterations in several NK receptors. Interestingly, the frequencies of NKp30 expressing activated NK cells were more pronounced in dengue fever (DF) than in DHF pediatric patients. In vitro functional analysis indicated that degranulation of NK cells in responding to dengue infected dendritic cells (DCs) required cell-cell contact and type I IFNs. Meanwhile, Interferon gamma (IFN-γ) production initially required cell-cell contact and type I IFNs followed by Interleukin-12 (IL-12), Interleukin-15 (IL-15) and Interleukin-18 (IL-18) resulting in the amplification of IFN-γ producing NK cells over time. This study highlighted the complexity and the factors influencing NK cells responses to dengue virus. Degree of activation, phenotypes of activated cells and the crosstalk between NK cells and other immune cells, could modulate the outcome of NK cells function in the dengue disease.
Asunto(s)
Células Dendríticas , Virus del Dengue , Interferón gamma , Interleucina-12 , Células Asesinas Naturales , Fenotipo , Células Asesinas Naturales/inmunología , Humanos , Niño , Interleucina-12/inmunología , Masculino , Femenino , Células Dendríticas/inmunología , Virus del Dengue/inmunología , Interferón gamma/inmunología , Interleucina-15/inmunología , Activación de Linfocitos , Interleucina-18/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/inmunología , Preescolar , Dengue/inmunología , Dengue/virología , Dengue Grave/inmunología , Dengue Grave/virología , Adolescente , Antígeno CD56/inmunología , Interferón Tipo I/inmunologíaRESUMEN
According to the WHO 2009 classification, dengue with warning signs is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which can be a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4+CD8+ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8+ DP cells were distinct from CD4+ Single Positive (SP) T cells but co-clustered with CD8+ SP cells, indicating a largely similar transcriptional profile. Twenty significant differentially expressed (DE) genes were identified between CD4+CD8+ DP and CD8+ SP cells. These genes encode OX40 and CCR4 proteins as well as other molecules associated with cell signaling on the cell surface (NT5E, MXRA8, and PTPRK). While comparing the profile of gene expression in CD4+CD8+ DP cells from patients with and without warning signs of plasma leakage, similar expression profile was observed, implying a role of CD4+CD8+ DP cells in plasma leakage through a quantitative increase rather than functional alteration. This study provided novel insight into the host immune response during the acute febrile phase of DENV infection and the role of CD4+CD8+ DP T cells in the pathogenesis of plasma leakage.
Asunto(s)
Dengue/sangre , Dengue/inmunología , Subgrupos de Linfocitos T/metabolismo , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Femenino , Humanos , Recuento de Linfocitos , Masculino , Plasma , Dengue Grave/sangre , Dengue Grave/inmunología , Subgrupos de Linfocitos T/inmunología , Transcriptoma , Adulto JovenRESUMEN
BACKGROUND: Increased levels of inflammatory cytokines are associated with severe dengue evolution, but the source of such hypercytokinemia is elusive. We investigated the contribution of innate lymphocytes, innate lymphoid cells (ILCs), and natural killer (NK) cells in cytokine production in early dengue infection. METHODS: Peripheral blood mononuclear cells of individuals with dengue without warning signs (DWS-) and dengue with warning signs and severe dengue (SD) presentation combined (DWS+) were obtained between 2 and 7 days since fever onset and submitted to flow cytometry without specific antigen stimulation to evaluate cytokines in ILC and NK cell subpopulations. RESULTS: ILCs and NK cells were found to be important sources of cytokines during dengue. ILCs of the DWS+/SD group displayed higher production of interferon gamma (IFN-γ) and interleukin (IL) 4/IL-13 when compared to DWS- individuals. On the other hand, NK Eomes+ cells of DWS- patients displayed higher IFN-γ production levels compared with the DWS+/SD group. Interestingly, when NK cells were identified by CD56 expression, DWS+/SD displayed higher frequency of IL-17 production compared with the DWS- group. CONCLUSIONS: These results indicate that ILCs and NK cells are important sources of inflammatory cytokines during acute dengue infection and display distinct profiles associated with different clinical forms.
Asunto(s)
Citocinas/metabolismo , Interferón gamma , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Dengue Grave , Citocinas/inmunología , Humanos , Inmunidad Innata , Leucocitos Mononucleares , Subgrupos Linfocitarios/metabolismo , Linfocitos , Dengue Grave/sangre , Dengue Grave/inmunologíaRESUMEN
Background. Dengue virus (DENV) infection is the most common arboviral disease that affects tropical and subtropical regions. Based on the clinical hallmarks, the different severities of patients range from mild dengue fever (MDF) to severe dengue diseases (SDDs) and include dengue hemorrhagic fever or dengue shock syndrome. These are commonly associated with cytokine release syndrome (CRS). The types and levels of cytokines/chemokines, which are suppressed or enhanced, are varied, indicating CRS's pathogenic and host defensive effects. Principal Finding. In this study, we created an integrated and precise multiplex panel of cytokine/chemokine assays based on our literature analysis to monitor dengue CRS. A 24-plex panel of cytokines/chemokines was evaluated to measure the plasma levels of targeting factors in dengue patients with an MDF and SDD diagnosis without or with comorbidities. As identified in sixteen kinds of cytokines/chemokines, ten were significantly (P < 0.05) (10/16) increased, one was significantly (P < 0.01) (1/16) decreased, and five were potentially (5/16) altered in all dengue patients (n = 30) in the acute phase of disease onset. Compared to MDF, the levels of IL-8 (CXCL-8) and IL-18 in SDD were markedly (P < 0.05) increased, accompanied by positively increased IL-6 and TNF-α and decreased IFN-γ and RANTES. With comorbidities, SDD significantly (P < 0.01) portrayed elevated IL-18 accompanied by increased IL-6 and decreased IFN-α2 and IL-12. In addition, decreased platelets were significantly (P < 0.05) associated with increased IL-18. Significance. These results demonstrate an efficient panel of dengue cytokine/chemokine assays used to explore the possible level of CRS during the acute phase of disease onset; also, we are the first to report the increase of IL-18 in severe dengue with comorbidity compared to severe dengue without comorbidity and mild dengue.
Asunto(s)
Interleucina-18/sangre , Dengue Grave/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Virus del Dengue/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-18/inmunología , Masculino , Persona de Mediana Edad , Dengue Grave/sangre , Dengue Grave/inmunología , Dengue Grave/virología , Adulto JovenRESUMEN
Dengue is a mosquito-borne viral disease causing significant health and economic burdens globally. The dengue virus (DENV) comprises four serotypes (DENV1-4). Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF). Complement system activation induces inflammation and tissue injury, contributing to disease pathogenesis. However, in asymptomatic or primary infections, protective immunity largely results from the complement system's lectin pathway (LP), which is activated through foreign glycan recognition. Differences in N-glycans displayed on the DENV envelope membrane influence the lectin pattern recognition receptor (PRR) binding efficiency. The important PRR, mannan binding lectin (MBL), mediates DENV neutralization through (1) a complement activation-independent mechanism via direct MBL glycan recognition, thereby inhibiting DENV attachment to host target cells, or (2) a complement activation-dependent mechanism following the attachment of complement opsonins C3b and C4b to virion surfaces. The serum concentrations of lectin PRRs and their polymorphisms influence these LP activities. Conversely, to escape the LP attack and enhance the infectivity, DENV utilizes the secreted form of nonstructural protein 1 (sNS1) to counteract the MBL effects, thereby increasing viral survival and dissemination.
Asunto(s)
Lectina de Unión a Manosa de la Vía del Complemento , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Dengue/inmunología , Dengue/virología , Animales , Humanos , Evasión Inmune , Lectina de Unión a Manosa/sangre , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Lectina de Unión a Manosa/metabolismo , Polimorfismo de Nucleótido Simple , Polisacáridos/inmunología , Polisacáridos/metabolismo , Receptores de Reconocimiento de Patrones/sangre , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , Dengue Grave/inmunología , Dengue Grave/virología , Proteínas no Estructurales Virales/metabolismo , VirulenciaRESUMEN
Elevated frequency of afucosylated IgG1 antibodies during dengue virus infection is associated with prior infection and predicts severe disease.
Asunto(s)
Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/metabolismo , Virus del Dengue/inmunología , Procesamiento Proteico-Postraduccional/fisiología , Dengue Grave/inmunología , Glicosilación , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/metabolismo , Dengue Grave/patologíaRESUMEN
Although antiviral antibodies generally confer protective functions, antibodies against dengue virus (DENV) are associated with enhanced disease susceptibility. Antibodies can mediate DENV infection of leukocytes via Fcγ receptors, likely contributing to dengue disease pathogenesis. To determine if this mechanism accounts for variable disease severity, we examined Fab and Fc structures of anti-DENV antibodies from patients before and after infection and with variable disease outcomes. Neither antibody titers nor neutralizing activity correlated with disease severity in DENV-infected populations. Rather, DENV infection induced a specific increase in immunoglobulin G1 (IgG1) afucosylation, and the levels of afucosylated IgG1 were predictive of dengue disease severity. Thus, the IgG1 fucosylation status represents a robust prognostic tool for dengue disease, highlighting the key role of the Fc glycan structure in dengue pathogenesis.
Asunto(s)
Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/química , Virus del Dengue/inmunología , Dengue/inmunología , Fucosa/análisis , Dengue Grave/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Acrecentamiento Dependiente de Anticuerpo , Niño , Coinfección/inmunología , Dengue/fisiopatología , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/química , Inmunoglobulina G/inmunología , Masculino , Receptores de IgG/química , Receptores de IgG/inmunología , Dengue Grave/fisiopatología , Índice de Severidad de la Enfermedad , Infección por el Virus Zika/inmunologíaRESUMEN
Introducción: El dengue es la enfermedad viral transmitida por artrópodos que más morbilidad y mortalidad ocasiona mundialmente. En el mundo actual, esta arbovirosis se considera la décima causa de muerte sobre todo en edades pediátricas. Objetivo: Caracterizar el comportamiento clínico y de laboratorio del choque por dengue en niños a partir de un año de edad. Métodos: Se realizó un estudio de corte transversal. Se estudiaron 19 pacientes con diagnóstico de choque por dengue. Para el análisis estadístico se utilizaron medidas de resumen como frecuencias, porcentaje, rango, mediana y moda. Resultados: Los signos de choque por dengue predominaron en los pacientes mayores de 5 años, femeninos y blancos, normopesos con antecedentes de salud. La mayoría ingresó al cuarto día; la fiebre fue el principal motivo de ingreso. El aumento progresivo del hematocrito fue el principal signo de alarma, y la hipotensión sin otra manifestación de choque constituyó la manifestación clínica más frecuente. Las soluciones cristaloides fueron las más utilizadas con muy buena respuesta clínica. Conclusiones: Todos los pacientes evolucionaron satisfactoriamente; no hubo ningún fallecimiento por dengue a pesar de que la mayoría fueron hospitalizados durante la fase crítica de la enfermedad, existiendo una identificación adecuada de los signos de alarma, y un adecuado control y tratamiento de las formas clínicas de choque por dengue(AU)
Introduction: Dengue is the arthropod-borne disease causing the highest morbidity and mortality worldwide. This condition is currently considered the tenth leading cause of death in the world, mainly in pediatric ages. Objective: Characterize the clinical and laboratory behavior of dengue shock in children aged one year and over. Methods: A cross-sectional study was conducted of 19 patients diagnosed with dengue shock. Statistical analysis was based on the summary measurements frequency, percentage, range, median and mode. Results: Dengue shock signs prevailed in white female patients aged over five years, of normal weight and with a history of good health. Most were admitted on the fourth day; fever was the main reason for admission. Gradual hematocrit increase was the main warning sign, whereas hypotension without any other shock symptom was the most common clinical manifestation. Crystalloid solutions were the most frequently used, with a very good clinical response. Conclusions: All the patients evolved satisfactorily; no death occurred due to dengue, despite the fact that many patients were admitted during the critical stage of the disease; warning signs were appropriately identified and clinical manifestations of dengue shock were controlled and treated(AU)
Asunto(s)
Humanos , Lactante , Preescolar , Niño , Dengue Grave/diagnóstico , Dengue Grave/inmunología , Choque/complicaciones , Estudios TransversalesRESUMEN
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.
Asunto(s)
Fiebre Chikungunya/tratamiento farmacológico , Cloroquina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Mononucleosis Infecciosa/tratamiento farmacológico , Dengue Grave/tratamiento farmacológico , Verrugas/tratamiento farmacológico , Alphapapillomavirus/efectos de los fármacos , Alphapapillomavirus/inmunología , Alphapapillomavirus/patogenicidad , Antivirales/uso terapéutico , COVID-19/virología , Fiebre Chikungunya/inmunología , Fiebre Chikungunya/patología , Fiebre Chikungunya/virología , Virus Chikungunya/efectos de los fármacos , Virus Chikungunya/inmunología , Virus Chikungunya/patogenicidad , Virus del Dengue/efectos de los fármacos , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , VIH/efectos de los fármacos , VIH/inmunología , VIH/patogenicidad , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , Hepacivirus/efectos de los fármacos , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/patogenicidad , Humanos , Mononucleosis Infecciosa/inmunología , Mononucleosis Infecciosa/patología , Mononucleosis Infecciosa/virología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Dengue Grave/inmunología , Dengue Grave/patología , Dengue Grave/virología , Resultado del Tratamiento , Verrugas/inmunología , Verrugas/patología , Verrugas/virología , Tratamiento Farmacológico de COVID-19RESUMEN
The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.
Asunto(s)
Factor B del Complemento/metabolismo , Factor H de Complemento/metabolismo , Vía Alternativa del Complemento , Dengue/inmunología , Dengue Grave/inmunología , Animales , Acrecentamiento Dependiente de Anticuerpo , Factor B del Complemento/genética , Factor H de Complemento/genética , Dengue/virología , Virus del Dengue/inmunología , Virus del Dengue/fisiología , Modelos Animales de Enfermedad , Humanos , Interferones/metabolismo , Ratones , Regiones Promotoras Genéticas , Dengue Grave/virología , ViremiaRESUMEN
Dengue is the most prevalent arboviral disease in humans and a continually increasing global public health burden. To date, there are no approved antiviral therapies against dengue virus (DENV) and the only licensed vaccine, Dengvaxia, is exclusively indicated for individuals with prior DENV infection. Endothelial hyperpermeability and vascular leak, pathogenic hallmarks of severe dengue disease, can be directly triggered by DENV non-structural protein 1 (NS1). As such, anti-NS1 antibodies can prevent NS1-triggered endothelial dysfunction in vitro and pathogenesis in vivo. Recently, goose-derived anti-DENV immunoglobulin Y (IgY) antibodies were shown to neutralize DENV and Zika virus (ZIKV) infection without adverse effects, such as antibody-dependent enhancement (ADE). In this study, we used egg yolks from DENV-immunized geese to purify IgY antibodies specific to DENV NS1 epitopes. We determined that 2 anti-NS1 IgY antibodies, NS1-1 and NS1-8, were capable of neutralizing DENV infection in vitro. In addition, these antibodies did not cross-react with the DENV Envelope (E) protein nor enhance DENV or ZIKV infection in vitro. Intriguingly, NS1-8, but not NS1-1, partially blocked NS1-induced endothelial dysfunction in vitro while neither antibody blocked binding of soluble NS1 to cells. Finally, prophylactic treatment of mice with NS1-8 conferred significant protection against lethal DENV challenge. Although further research is needed to define the mechanism of action of these antibodies, our findings highlight the potential of anti-NS1 IgY as a promising prophylactic approach against DENV infection.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Virus del Dengue/inmunología , Dengue/inmunología , Dengue/prevención & control , Inmunización Pasiva , Inmunoglobulinas/administración & dosificación , Inmunoglobulinas/inmunología , Proteínas no Estructurales Virales/inmunología , Animales , Anticuerpos Neutralizantes/administración & dosificación , Acrecentamiento Dependiente de Anticuerpo , Chlorocebus aethiops , Dengue/terapia , Epítopos/inmunología , Femenino , Gansos/inmunología , Masculino , Ratones Endogámicos C57BL , Pruebas de Neutralización , Dengue Grave/inmunología , Dengue Grave/prevención & control , Células VeroRESUMEN
The COVID-19 pandemic has rapidly spread around the world with significant morbidity and mortality in a subset of patients including the elderly. The poorer outcomes are associated with 'cytokine storm-like' immune responses, otherwise referred to as 'hyperinflammation'. While most of the infected individuals show minimal or no symptoms and recover spontaneously, a small proportion of the patients exhibit severe symptoms characterized by extreme dyspnea and low tissue oxygen levels, with extensive damage to the lungs referred to as acute respiratory distress symptom (ARDS). The consensus is that the hyperinflammatory response of the host is akin to the cytokine storm observed during sepsis and is the major cause of death. Uncertainties remain on the factors that lead to hyperinflammatory response in some but not all individuals. Hyperinflammation is a common feature in different viral infections such as dengue where existing low-titer antibodies to the virus enhances the infection in immune cells through a process called antibody-dependent enhancement or ADE. ADE has been reported following vaccination or secondary infections with other corona, Ebola and dengue virus. Detailed analysis has shown that antibodies to any viral epitope can induce ADE when present in sub-optimal titers or is of low affinity. In this review we will discuss ADE in the context of dengue and coronavirus infections including Covid-19.
Asunto(s)
Acrecentamiento Dependiente de Anticuerpo/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/veterinaria , Peritonitis Infecciosa Felina/inmunología , Inflamación/patología , Pandemias/veterinaria , Neumonía Viral/inmunología , Neumonía Viral/veterinaria , Dengue Grave/inmunología , Animales , COVID-19 , Gatos , Citocinas/metabolismoRESUMEN
Endothelial dysfunction leading to vascular permeability and plasma leakage are characteristic features of severe dengue and sepsis. However, the mechanisms underlying these immune-pathologies remain unclear. The risk of severe dengue and sepsis development depend on patient-related and pathogen-related factors. Additionally, comorbidities increase the risk of severe disease and their incidence hampers correct diagnosis and treatments. To date, there is no efficient therapy to combat severe dengue and sepsis. Here, we discuss the differences and similarities between the pathogenesis of severe dengue and that of bacterial sepsis. We identify gaps in knowledge that need to be better understood in order to move towards the rational development and/or usage of therapeutic strategies to ameliorate severe dengue disease.
Asunto(s)
Virus del Dengue/fisiología , Sepsis/inmunología , Sepsis/patología , Dengue Grave/inmunología , Dengue Grave/patología , Animales , Permeabilidad Capilar , Virus del Dengue/genética , Humanos , Sepsis/fisiopatología , Sepsis/virología , Dengue Grave/fisiopatología , Dengue Grave/virologíaRESUMEN
Severe dengue can be lethal caused by manifestations such as severe bleeding, fluid accumulation and organ impairment. This study aimed to investigate the role of dengue non-structural 1 (NS1) protein and host factors contributing to severe dengue. Electrical cell-substrate impedance sensing system was used to investigate the changes in barrier function of microvascular endothelial cells treated NS1 protein and serum samples from patients with different disease severity. Cytokines and metabolites profiles were assessed using a multiplex cytokine assay and liquid chromatography mass spectrometry respectively. The findings showed that NS1 was able to induce the loss of barrier function in microvascular endothelium in a dose dependent manner, however, the level of NS1 in serum samples did not correlate with the extent of vascular leakage induced. Further assessment of host factors revealed that cytokines such as CCL2, CCL5, CCL20 and CXCL1, as well as adhesion molecule ICAM-1, that are involved in leukocytes infiltration were expressed higher in dengue patients in comparison to healthy individuals. In addition, metabolomics study revealed the presence of deregulated metabolites involved in the phospholipid metabolism pathway in patients with severe manifestations. In conclusion, disease severity in dengue virus infection did not correlate directly with NS1 level, but instead with host factors that are involved in the regulation of junctional integrity and phospholipid metabolism. However, as the studied population was relatively small in this study, these exploratory findings should be confirmed by expanding the sample size using an independent cohort to further establish the significance of this study.
Asunto(s)
Citocinas/sangre , Virus del Dengue/inmunología , Interacciones Huésped-Patógeno/inmunología , Dengue Grave/sangre , Proteínas no Estructurales Virales/sangre , Línea Celular , Citocinas/inmunología , Citocinas/metabolismo , Virus del Dengue/metabolismo , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Humanos , Fosfolípidos/metabolismo , Cultivo Primario de Células , Dengue Grave/inmunología , Dengue Grave/metabolismo , Dengue Grave/patología , Proteínas no Estructurales Virales/inmunologíaRESUMEN
Dengue-related mortality has significantly reduced with early and appropriate fluid resuscitation. However, we continue to see dengue-related fatalities in patients despite early intervention and advanced critical care support. This was a retrospective study conducted at a tertiary care private hospital in Mumbai, India. All patients dying of dengue in the calendar year 2017 were studied. Details related to age, gender, condition at presentation, laboratory parameters, treatment administered, and time to death were abstracted from case records. A total of 575 patients with a diagnosis of dengue were admitted to the hospital in 2017, of which 15 died (mortality rate 2.6%). Four patients died in the emergency medical unit; 11 patients who died after admission to the inpatient unit had multi-organ dysfunction at the time of presentation, with shock, severe liver dysfunction, and severe metabolic acidosis. Only 4/11 patients had hemoconcentration, and 10/11 patients had high white cell counts. In five patients where serum ferritin was performed, it was more than 40,000 ng/mL. Death occurred at a median time of 2 days after hospitalization despite good supportive care. Although there is scope for improvement of supportive care in these patients, it appears that other interventions are urgently needed to improve outcomes in severe dengue. This calls for more research into the immunopathology of dengue, evaluation of anti-inflammatory drugs, intravenous immunoglobulins, antivirals, and improved vaccines.