Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.153
Filtrar
1.
Nat Commun ; 12(1): 1102, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597521

RESUMEN

The four-dengue virus (DENV) serotypes infect several hundred million people annually. For the greatest safety and efficacy, tetravalent DENV vaccines are designed to stimulate balanced protective immunity to all four serotypes. However, this has been difficult to achieve. Clinical trials with a leading vaccine demonstrated that unbalanced replication and immunodominance of one vaccine component over others can lead to low efficacy and vaccine enhanced severe disease. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. Here we report, our study to determine if TV003 stimulate balanced and serotype-specific (TS) neutralizing antibody (nAb) responses to each serotype. Serum samples from twenty-one dengue-naive individuals participated under study protocol CIR287 (ClinicalTrials.gov NCT02021968) are analyzed 6 months after vaccination. Most subjects (76%) develop TS nAbs to 3 or 4 DENV serotypes, indicating immunity is induced by each vaccine component. Vaccine-induced TS nAbs map to epitopes known to be targets of nAbs in people infected with wild type DENVs. Following challenge with a partially attenuated strain of DENV2, all 21 subjects are protected from the efficacy endpoints. However, some vaccinated individuals develop post challenge nAb boost, while others mount post-challenge antibody responses that are consistent with sterilizing immunity. TV003 vaccine induced DENV2 TS nAbs are associated with sterilizing immunity. Our results indicate that nAbs to TS epitopes on each serotype may be a better correlate than total levels of nAbs currently used for guiding DENV vaccine development.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Dengue/inmunología , Formación de Anticuerpos/inmunología , Especificidad de Anticuerpos/inmunología , Dengue/prevención & control , Dengue/virología , Vacunas contra el Dengue/administración & dosificación , Virus del Dengue/clasificación , Epítopos/inmunología , Humanos , Serotipificación , Especificidad de la Especie , Resultado del Tratamiento , Vacunación/métodos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología
2.
Front Immunol ; 11: 572567, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33101294

RESUMEN

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.


Asunto(s)
Decidua/inmunología , Placenta/inmunología , Virosis/inmunología , Inmunidad Adaptativa/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Dengue/inmunología , Dengue/patología , Femenino , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/patología , Hepatitis E/inmunología , Hepatitis E/patología , Humanos , Tolerancia Inmunológica/inmunología , Inmunidad Innata/inmunología , Gripe Humana/inmunología , Gripe Humana/patología , Fiebre de Lassa/inmunología , Fiebre de Lassa/patología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , Embarazo
3.
PLoS One ; 15(10): e0238609, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33112881

RESUMEN

INTRODUCTION: Although immune responses to the Japanese Encephalitis virus (JEV), and the dengue viruses (DENV) have a potential to modulate the immune responses to each other, this has been poorly investigated. Therefore, we developed an ELISA to identify JEV specific, DENV non cross-reactive antibody responses by identifying JEV specific, highly conserved regions of the virus and proceeded to investigate if the presence of JEV specific antibodies associate with dengue disease severity. METHODOLOGY AND RESULTS: 22 JEV specific peptides were identified from highly conserved regions of the virus and the immunogenicity and specificity of these peptides were assessed in individuals who were non-immune to JEV and DENV (JEV-DENV-, N = 30), those who were only immune to the JEV and not DENV (JEV+DENV-, N = 30), those who were only immune to DENV(JEV-DENV+, N = 30) and in those who were immune to both viruses (JEV+DENV+, N = 30). 7/22 peptides were found to be highly immunogenic and specific and these 7 peptides were used as a pool to further evaluate JEV-specific responses. All 30/30 JEV+DENV- and 30/30 JEV+DENV+ individuals, and only 3/30 (10%) JEV-DENV+ individuals responded to this pool. We further evaluated this pool of 7 peptides in patients following primary and secondary dengue infection during the convalescent period and found that the JEV-specific peptides, were unlikely to cross react with DENV IgG antibodies. We further compared this in-house ELISA developed with the peptide pool with an existing commercial JEV IgG assay to identify JEV-specific IgG following vaccination, and our in-house ELISA was found to be more sensitive. We then proceeded to investigate if the presence of JEV-specific antibodies were associated with dengue disease severity, and we found that those who had past severe dengue (n = 175) were significantly more likely (p<0.0001) to have JEV-specific antibodies than those with past non-severe dengue (n = 175) (OR 5.3, 95% CI 3.3 to 8.3). CONCLUSIONS: As our data show that this assay is highly sensitive and specific for detection of JEV-specific antibody responses, it would be an important tool to determine how JEV seropositivity modulate dengue immunity and disease severity when undertaking dengue vaccine trials.


Asunto(s)
Anticuerpos Antivirales/sangre , Virus de la Encefalitis Japonesa (Especie)/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Especificidad de Anticuerpos , Niño , Secuencia Conservada , Reacciones Cruzadas , Dengue/inmunología , Dengue/virología , Virus del Dengue/clasificación , Virus del Dengue/genética , Virus del Dengue/inmunología , Virus de la Encefalitis Japonesa (Especie)/genética , Encefalitis Japonesa/epidemiología , Encefalitis Japonesa/inmunología , Encefalitis Japonesa/virología , Ensayo de Inmunoadsorción Enzimática/estadística & datos numéricos , Femenino , Voluntarios Sanos , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Sensibilidad y Especificidad , Estudios Seroepidemiológicos , Serogrupo , Sri Lanka/epidemiología , Vacunación , Proteínas Virales/genética , Proteínas Virales/inmunología , Adulto Joven
4.
Euro Surveill ; 25(36)2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32914745

RESUMEN

In August 2020, during the coronavirus disease (COVID-19) pandemic, five locally acquired cases of dengue virus type 1 were detected in a family cluster in Vicenza Province, North-East Italy where Aedes albopictus mosquitoes are endemic. The primary case was an importation from West Sumatra, Indonesia. This is the first outbreak of autochthonous dengue reported in Italy. During the COVID-19 pandemic, screening of febrile travelers from endemic countries is crucial in areas where competent vectors are present.


Asunto(s)
Virus del Dengue/aislamiento & purificación , Dengue/diagnóstico , Viaje , Adulto , Preescolar , Dengue/epidemiología , Dengue/inmunología , Dengue/virología , Virus del Dengue/genética , Brotes de Enfermedades , Transmisión de Enfermedad Infecciosa , Femenino , Fiebre/etiología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Indonesia , Italia/epidemiología , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
PLoS Pathog ; 16(8): e1008754, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32776975

RESUMEN

Arbovirus infection of Aedes aegypti salivary glands (SGs) determines transmission. However, there is a dearth of knowledge on SG immunity. Here, we characterized SG immune response to dengue, Zika and chikungunya viruses using high-throughput transcriptomics. We also describe a transcriptomic response associated to apoptosis, blood-feeding and lipid metabolism. The three viruses differentially regulate components of Toll, Immune deficiency (IMD) and c-Jun N- terminal Kinase (JNK) pathways. However, silencing of the Toll and IMD pathway components showed variable effects on SG infection by each virus. In contrast, regulation of the JNK pathway produced consistent responses in both SGs and midgut. Infection by the three viruses increased with depletion of the activator Kayak and decreased with depletion of the negative regulator Puckered. Virus-induced JNK pathway regulates the complement factor, Thioester containing protein-20 (TEP20), and the apoptosis activator, Dronc, in SGs. Individual and co-silencing of these genes demonstrate their antiviral effects and that both may function together. Co-silencing either TEP20 or Dronc with Puckered annihilates JNK pathway antiviral effect. Upon infection in SGs, TEP20 induces antimicrobial peptides (AMPs), while Dronc is required for apoptosis independently of TEP20. In conclusion, we revealed the broad antiviral function of JNK pathway in SGs and showed that it is mediated by a TEP20 complement and Dronc-induced apoptosis response. These results expand our understanding of the immune arsenal that blocks arbovirus transmission.


Asunto(s)
Aedes/inmunología , Apoptosis , Fiebre Chikungunya/inmunología , Proteínas del Sistema Complemento/inmunología , Dengue/inmunología , Sistema de Señalización de MAP Quinasas , Glándulas Salivales/inmunología , Infección por el Virus Zika/inmunología , Aedes/virología , Animales , Fiebre Chikungunya/metabolismo , Fiebre Chikungunya/prevención & control , Fiebre Chikungunya/virología , Virus Chikungunya/inmunología , Proteínas del Sistema Complemento/metabolismo , Dengue/metabolismo , Dengue/prevención & control , Dengue/virología , Virus del Dengue/inmunología , Femenino , Interacciones Huésped-Patógeno , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Insectos Vectores/inmunología , Insectos Vectores/virología , Glándulas Salivales/virología , Transcriptoma , Replicación Viral , Virus Zika/inmunología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/prevención & control , Infección por el Virus Zika/virología
6.
Nat Rev Immunol ; 20(10): 633-643, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32782358

RESUMEN

Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Acrecentamiento Dependiente de Anticuerpo/efectos de los fármacos , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Leucocitos/efectos de los fármacos , Neumonía Viral/tratamiento farmacológico , Receptores de IgG/inmunología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/efectos adversos , Anticuerpos Antivirales/biosíntesis , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Dengue/tratamiento farmacológico , Dengue/inmunología , Dengue/virología , Virus del Dengue/efectos de los fármacos , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Humanos , Leucocitos/inmunología , Leucocitos/virología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , Receptores de IgG/antagonistas & inhibidores , Receptores de IgG/genética , Virus del SRAS/efectos de los fármacos , Virus del SRAS/inmunología , Virus del SRAS/patogenicidad , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/virología , Transducción de Señal , Internalización del Virus/efectos de los fármacos
7.
PLoS Negl Trop Dis ; 14(8): e0008535, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32813703

RESUMEN

Dengue fever occurs worldwide and about 1% of cases progress to severe haemorrhage and shock. Dengue is endemic in Guatemala and its surveillance system could document long term trends. We analysed 17 years of country-wide dengue surveillance data in Guatemala to describe epidemiological trends from 2000 to 2016.Data from the national dengue surveillance database were analysed to describe dengue serotype frequency, seasonality, and outbreaks. We used Poisson regression models to compare the number of cases each year with subsequent years and to estimate incidence ratios within serotype adjusted by age and gender. 91,554 samples were tested. Dengue was confirmed by RT-qPCR, culture or NS1-ELISA in 7097 (7.8%) cases and was IgM ELISA-positive in 19,290 (21.1%) cases. DENV1, DENV2, DENV3, and DENV4 were detected in 2218 (39.5%), 2580 (45.9%), 591 (10.5%), and 230 (4.1%) cases. DENV1 and DENV2 were the predominant serotypes, but all serotypes caused epidemics. The largest outbreak occurred in 2010 with 1080 DENV2 cases reported. The incidence was higher among adults during epidemic years, with significant increases in 2005, 2007, and 2013 DENV1 outbreaks, the 2010 DENV2 and 2003 DENV3 outbreaks. Adults had a lower incidence immediately after epidemics, which is likely linked to increased immunity.


Asunto(s)
Dengue/diagnóstico , Dengue/epidemiología , Adolescente , Adulto , Anticuerpos Antivirales/inmunología , Niño , Preescolar , Dengue/inmunología , Virus del Dengue/inmunología , Brotes de Enfermedades , Ensayo de Inmunoadsorción Enzimática , Femenino , Guatemala/epidemiología , Humanos , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Serogrupo , Serotipificación/métodos , Adulto Joven
8.
Mem Inst Oswaldo Cruz ; 115: e200225, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32813814

RESUMEN

In the near future, the overlap of Coronavirus disease 2019 (COVID-19) and dengue epidemics is a concrete threat in tropical regions. Co-epidemics of COVID-19 and dengue could be an overwhelming challenge for health systems in low- and middle-income countries. In this work, we investigated potential serological cross-reactions between COVID-19 and dengue patients. Among 32 COVID-19 positive sera, no positive Dengue virus (DENV) IgG/IgM results were observed. On the other hand, one false-positive result was observed among 44 DENV-positive sera tested for COVID-19 antibodies with each of the two rapid tests used. Further data on accuracy of COVID-19 diagnostic test are urgently warranted.


Asunto(s)
Anticuerpos Antivirales/inmunología , Infecciones por Coronavirus/inmunología , Reacciones Cruzadas , Dengue/inmunología , Neumonía Viral/inmunología , Betacoronavirus/inmunología , Virus del Dengue/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Pandemias
9.
J Virol ; 94(18)2020 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-32611757

RESUMEN

Dengue virus (DENV) is responsible for the most prevalent and significant arthropod-borne viral infection of humans. The leading DENV vaccines are based on tetravalent live-attenuated virus platforms. In practice, it has been challenging to induce balanced and effective responses to each of the four DENV serotypes because of differences in the replication efficiency and immunogenicity of individual vaccine components. Unlike live vaccines, tetravalent DENV envelope (E) protein subunit vaccines are likely to stimulate balanced immune responses, because immunogenicity is replication independent. However, E protein subunit vaccines have historically performed poorly, in part because the antigens utilized were mainly monomers that did not display quaternary-structure epitopes found on E dimers and higher-order structures that form the viral envelope. In this study, we compared the immunogenicity of DENV2 E homodimers and DENV2 E monomers. The stabilized DENV2 homodimers, but not monomers, were efficiently recognized by virus-specific and flavivirus cross-reactive potently neutralizing antibodies that have been mapped to quaternary-structure epitopes displayed on the viral surface. In mice, the dimers stimulated 3-fold-higher levels of virus-specific neutralizing IgG that recognized epitopes different from those recognized by lower-level neutralizing antibodies induced by monomers. The dimer induced a stronger E domain I (EDI)- and EDII-targeted response, while the monomer antigens stimulated an EDIII epitope response and induced fusion loop epitope antibodies that are known to facilitate antibody-dependent enhancement (ADE). This study shows that DENV E subunit antigens that have been designed to mimic the structural organization of the viral surface are better vaccine antigens than E protein monomers.IMPORTANCE Dengue virus vaccine development is particularly challenging because vaccines have to provide protection against four different dengue virus stereotypes. The leading dengue virus vaccine candidates in clinical testing are all based on live-virus vaccine platforms and struggle to induce balanced immunity. Envelope subunit antigens have the potential to overcome these limitations but have historically performed poorly as vaccine antigens, because the versions tested previously were presented as monomers and not in their natural dimer configuration. This study shows that the authentic presentation of DENV2 E-based subunits has a strong impact on antibody responses, underscoring the importance of mimicking the complex protein structures that are found on DENV particle surfaces when designing subunit vaccines.


Asunto(s)
Anticuerpos Monoclonales/biosíntesis , Anticuerpos Antivirales/biosíntesis , Vacunas contra el Dengue/administración & dosificación , Dengue/prevención & control , Epítopos/inmunología , Vacunación/métodos , Proteínas del Envoltorio Viral/inmunología , Animales , Acrecentamiento Dependiente de Anticuerpo , Chlorocebus aethiops , Reacciones Cruzadas , Dengue/inmunología , Dengue/patología , Dengue/virología , Vacunas contra el Dengue/genética , Vacunas contra el Dengue/inmunología , Virus del Dengue/efectos de los fármacos , Virus del Dengue/genética , Virus del Dengue/inmunología , Modelos Animales de Enfermedad , Epítopos/química , Epítopos/genética , Femenino , Células HEK293 , Humanos , Inmunogenicidad Vacunal , Ratones , Ratones Endogámicos BALB C , Isoformas de Proteínas/administración & dosificación , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Multimerización de Proteína/efectos de los fármacos , Vacunas de Subunidad , Células Vero , Proteínas del Envoltorio Viral/administración & dosificación , Proteínas del Envoltorio Viral/genética
10.
Am J Trop Med Hyg ; 103(3): 970-975, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32602433

RESUMEN

Nine criteria regarding the infectious agent, mode of transmission, portal of entry, route of spread, target organs, target cells, pathologic lesions, incubation period, and modifiable spectrum of disease and outcomes appropriate to the intended experimental purpose are described. To provide context for each criterion, mouse models of two vector-borne zoonotic infectious diseases, scrub typhus and dengue, are summarized. Application of the criteria indicates that intravenous inoculation of Orientia tsutsugamushi into inbred mice is the best current model for life-threatening scrub typhus, and intradermal inoculation accurately models sublethal human scrub typhus, whereas the immunocompromised mouse models of dengue provide disease outcomes most closely associated with human dengue. In addition to addressing basic questions of immune and pathogenic mechanisms, mouse models are useful for preclinical testing of experimental vaccines and therapeutics. The nine criteria serve as guidelines to evaluate and compare models of vector-borne infectious diseases.


Asunto(s)
Virus del Dengue/inmunología , Dengue/inmunología , Modelos Animales de Enfermedad , Huésped Inmunocomprometido , Orientia tsutsugamushi/inmunología , Tifus por Ácaros/inmunología , Animales , Dengue/patología , Dengue/virología , Virus del Dengue/patogenicidad , Humanos , Periodo de Incubación de Enfermedades Infecciosas , Inyecciones Intradérmicas , Inyecciones Intravenosas , Hígado/microbiología , Hígado/virología , Tejido Linfoide/microbiología , Tejido Linfoide/virología , Ratones , Ratones Noqueados , Orientia tsutsugamushi/patogenicidad , Tifus por Ácaros/microbiología , Tifus por Ácaros/patología , Bazo/microbiología , Bazo/virología
11.
Am J Trop Med Hyg ; 103(3): 1223-1227, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32618241

RESUMEN

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.


Asunto(s)
Dengue/diagnóstico , Dengue Grave/diagnóstico , Adolescente , Adulto , Anciano , Niño , Preescolar , Cuidados Críticos , Dengue/inmunología , Dengue/terapia , Dengue/virología , Femenino , Fluidoterapia , Hospitalización , Hospitales Privados , Humanos , India , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Dengue Grave/inmunología , Dengue Grave/terapia , Dengue Grave/virología , Atención Terciaria de Salud , Adulto Joven
12.
PLoS Negl Trop Dis ; 14(7): e0007278, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32614855

RESUMEN

BACKGROUND: The frequency and magnitude of dengue epidemics has increased dramatically throughout the tropics in the past 40 years due to unplanned urbanization, globalization and lack of effective mosquito control. The commercial capital of Tanzania, Dar es Salaam, is now experiencing regular dengue outbreaks. Three dengue serotypes have been detected in Dar es Salaam (DNV 1, 2 and 3). Without adequate vector monitoring and control, further outbreaks will certainly occur. METHODS/FINDINGS: A case series study followed 97 individuals with confirmed dengue fever (NS1 and/or IgM on rapid diagnostic test and/or PCR positive) to their households in Kinondoni, Dar es Salaam during the 2014 outbreak from a random sample of 202 confirmed cases at Mwananyamala Hospital. Kinondoni wards of Manzese, Mwananyamala, Tandale and Mabibo had the highest number of confirmed cases: 18, 13, 13 and 9 respectively. Individuals were interviewed by questionnaire on dengue prevention practices and houses were inspected for mosquito breeding sites to validate a Habitat Suitability Score (HSS). This is a tool devised to predict the productivity of any potential breeding habitats (PBHs) before the rains begin. There were 12 /312 positive Aedes breeding habitats. Drums/barrels, flowerpots and tyres were the most common breeding habitats. The HSS correctly identified 9/12 of Aedes breeding habitats. Larviciding is already conducted in urban Tanzania for malaria control and the HSS may be a useful means to train individuals on productive Aedes aegypti breeding sites should this program be extended to include dengue control. The population remains poorly informed about dengue transmission and prevention: 22% of respondents said dengue is spread from one person to another and 60% first heard about dengue when already sick. Less than 20% of respondents used personal protection and >80% thought bednets protected against dengue. Mobile phones were owned by almost all individuals followed up and have the potential of being the prime medium for dissemination of information on dengue prevention.


Asunto(s)
Aedes , Dengue/prevención & control , Ecosistema , Conocimientos, Actitudes y Práctica en Salud , Control de Mosquitos , Adolescente , Adulto , Aedes/fisiología , Anciano , Anciano de 80 o más Años , Animales , Cruzamiento , Dengue/epidemiología , Dengue/inmunología , Composición Familiar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tanzanía/epidemiología , Adulto Joven
13.
Proc Natl Acad Sci U S A ; 117(27): 15947-15954, 2020 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-32576686

RESUMEN

The cytosolic DNA sensor cGMP-AMP synthase (cGAS) synthesizes the noncanonical cyclic dinucleotide 2'3'-cGAMP to activate the adaptor protein stimulator of IFN genes (STING), thus awakening host immunity in response to DNA pathogen infection. However, dengue virus (DENV), an RNA virus without a DNA stage in its life cycle, also manipulates cGAS-STING-mediated innate immunity by proteolytic degradation of STING. Here, we found that the sensitivity of STING to DENV protease varied with different human STING haplotypes. Exogenous DNA further enhanced DENV protease's ability to interact and cleave protease-sensitive STING. DNA-enhanced STING cleavage was reduced in cGAS-knockdown cells and triggered by the cGAS product 2'3'-cGAMP. The source of DNA may not be endogenous mitochondrial DNA but rather exogenous reactivated viral DNA. Cells producing 2'3'-cGAMP by overexpressing cGAS or with DNA virus reactivation enhanced STING cleavage in neighboring cells harboring DENV protease. DENV infection reduced host innate immunity in cells with the protease-sensitive STING haplotype, whose homozygote genotype frequency was found significantly reduced in Taiwanese people with dengue fever. Therefore, the human STING genetic background and DNA pathogen coinfection may be the missing links contributing to DENV pathogenesis.


Asunto(s)
Dengue/enzimología , Endopeptidasas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleótidos Cíclicos/metabolismo , Células A549 , ADN Viral/genética , Dengue/inmunología , Endopeptidasas/genética , Haplotipos , Humanos , Evasión Inmune , Inmunidad Innata , Nucleótidos Cíclicos/genética
14.
Nat Commun ; 11(1): 3177, 2020 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-32576819

RESUMEN

Vascular permeability and plasma leakage are immune-pathologies of severe dengue virus (DENV) infection, but the mechanisms underlying the exacerbated inflammation during DENV pathogenesis are unclear. Here, we demonstrate that TLR2, together with its co-receptors CD14 and TLR6, is an innate sensor of DENV particles inducing inflammatory cytokine expression and impairing vascular integrity in vitro. Blocking TLR2 prior to DENV infection in vitro abrogates NF-κB activation while CD14 and TLR6 block has a moderate effect. Moreover, TLR2 block prior to DENV infection of peripheral blood mononuclear cells prevents activation of human vascular endothelium, suggesting a potential role of the TLR2-responses in vascular integrity. TLR2 expression on CD14 + + classical monocytes isolated in an acute phase from DENV-infected pediatric patients correlates with severe disease development. Altogether, these data identify a role for TLR2 in DENV infection and provide insights into the complex interaction between the virus and innate receptors that may underlie disease pathogenesis.


Asunto(s)
Virus del Dengue/metabolismo , Dengue/inmunología , Monocitos/metabolismo , Receptor Toll-Like 2/metabolismo , Permeabilidad Capilar , Quimiocinas/metabolismo , Niño , Preescolar , Citocinas/metabolismo , Dengue/virología , Endotelio Vascular/metabolismo , Femenino , Proteínas Ligadas a GPI/metabolismo , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Inflamación , Leucocitos Mononucleares/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Masculino , FN-kappa B/metabolismo , Receptores de IgG/metabolismo , Índice de Severidad de la Enfermedad , Receptor Toll-Like 6
15.
Nat Commun ; 11(1): 3112, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32561757

RESUMEN

Previous flavivirus (dengue and Zika viruses) studies showed largely spherical particles either with smooth or bumpy surfaces. Here, we demonstrate flavivirus particles have high structural plasticity by the induction of a non-spherical morphology at elevated temperatures: the club-shaped particle (clubSP), which contains a cylindrical tail and a disc-like head. Complex formation of DENV and ZIKV with Fab C10 stabilize the viruses allowing cryoEM structural determination to ~10 Å resolution. The caterpillar-shaped (catSP) Fab C10:ZIKV complex shows Fabs locking the E protein raft structure containing three E dimers. However, compared to the original spherical structure, the rafts have rotated relative to each other. The helical tail structure of Fab C10:DENV3 clubSP showed although the Fab locked an E protein dimer, the dimers have shifted laterally. Morphological diversity, including clubSP and the previously identified bumpy and smooth-surfaced spherical particles, may help flavivirus survival and immune evasion.


Asunto(s)
Anticuerpos Antivirales/metabolismo , Virus del Dengue/ultraestructura , Proteínas del Envoltorio Viral/metabolismo , Virus Zika/ultraestructura , Aedes , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antivirales/inmunología , Línea Celular , Microscopía por Crioelectrón , Dengue/inmunología , Dengue/terapia , Dengue/virología , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Virus del Dengue/metabolismo , Evasión Inmune , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Mesocricetus , Multimerización de Proteína , Propiedades de Superficie , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/ultraestructura , Acoplamiento Viral , Virus Zika/inmunología , Virus Zika/metabolismo , Infección por el Virus Zika
16.
Cytometry A ; 97(7): 662-667, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32506725

RESUMEN

SARS-CoV-2 pandemic and recurrent dengue epidemics in tropical countries have turned into a global health threat. While both virus-caused infections may only reveal light symptoms, they can also cause severe diseases. Here, we review the possible antibody-dependent enhancement (ADE) occurrence, known for dengue infections, when there is a second infection with a different virus strain. Consequently, preexisting antibodies do not neutralize infection, but enhance it, possibly by triggering Fcγ receptor-mediated virus uptake. No clinical data exist indicating such mechanism for SARS-CoV-2, but previous coronavirus infections or infection of SARS-CoV-2 convalescent with different SARS-CoV-2 strains could promote ADE, as experimentally shown for antibodies against the MERS-CoV or SARS-CoV spike S protein. © 2020 International Society for Advancement of Cytometry.


Asunto(s)
Acrecentamiento Dependiente de Anticuerpo/inmunología , Betacoronavirus/inmunología , Coinfección/inmunología , Virus del Dengue/inmunología , Receptores de IgG/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Dengue/inmunología , Dengue/patología , Humanos , Citometría de Imagen/métodos , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , Virus del SRAS/inmunología , Internalización del Virus
17.
Am J Trop Med Hyg ; 103(1): 112-119, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32431270

RESUMEN

This study describes the natural history of dengue virus (DENV) infection in rhesus monkeys exposed to the bites of DENV-infected Aedes aegypti mosquitoes. Dengue virus-infected mosquitoes were generated by either intrathoracic inoculation or by oral feeding on viremic blood meals. Each of the six rhesus monkeys that were fed upon by intrathoracically infected mosquitoes developed non-structural protein 1 (NS1) antigenemia and an IgM response; viremia was detected in 4/6 individuals. No virological or immunological evidence of DENV infection was detected in the three monkeys exposed to mosquitoes that had been orally infected with DENV. These results demonstrate the utility of mosquito-borne challenge of rhesus monkeys with DENV.


Asunto(s)
Aedes/virología , Anticuerpos Antivirales/sangre , Virus del Dengue/inmunología , Dengue/inmunología , Inmunoglobulina M/sangre , Mosquitos Vectores/virología , Viremia/inmunología , Animales , Dengue/sangre , Dengue/diagnóstico , Dengue/transmisión , Virus del Dengue/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Macaca mulatta , Proyectos Piloto , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas no Estructurales Virales/genética , Viremia/sangre , Viremia/diagnóstico , Viremia/transmisión
18.
PLoS Negl Trop Dis ; 14(5): e0008285, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32463814

RESUMEN

Little is known about the contribution of virus-specific and cross-reacting antibodies (Abs) or the cellular immune response generated by a primary dengue (DENV) infection on the course of a secondary zika (ZIKV) infection in vivo. Here we show that the length of time between DENV/ZIKV infections has a qualitative impact on controlling early ZIKV replication. Depletion of DENV2-specific Abs in sera confirmed that those type-specific Abs do not contribute to ZIKV control. We show that the magnitude and durability of the neutralizing antibodies (nAbs) induced by a secondary ZIKV infection is modest compared to the response induced after a secondary heterologous DENV infection. Our in vivo results are showing a complex interplay between the cellular and innate immune responses characterized by a high frequency of plasmacytoid dendritic cells (pDC) correlating with an increase in the frequency of DENV antigen specific T cells and a significant control of ZIKV replication which is time dependent. Taken together, our results suggest that early after ZIKV infection other mechanisms such as the innate and cellular immune responses may play a predominant role in controlling ZIKV replication. Regardless of the time elapsed between infections there was no evidence of in vivo antibody-dependent enhancement (ADE) of ZIKV by DENV immunity. These findings have pivotal implications while interpreting ZIKV pathogenesis in flavivirus-experimented populations, diagnostic results interpretation and vaccine designs and schedules among others.


Asunto(s)
Dengue/inmunología , Inmunidad Celular , Inmunidad Humoral , Inmunidad Innata , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/prevención & control , Virus Zika/inmunología , Animales , Células Dendríticas/inmunología , Factores Inmunológicos , Macaca mulatta , Masculino , Linfocitos T/inmunología , Factores de Tiempo
19.
Am J Trop Med Hyg ; 103(1): 100-111, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32342838

RESUMEN

Dengue is endemic in Brazil. The dengue surveillance system's reliance on passive reporting may underestimate disease incidence and cannot detect asymptomatic/pauci-symptomatic cases. In this 3-year prospective cohort study (NCT01391819) in 5- to 13-year-old children from nine schools in Fortaleza (N = 2,117), we assessed dengue virus (DENV) infection seroprevalence by IgG indirect ELISA at yearly visits and disease incidence through active and enhanced passive surveillance. Real-time quantitative polymerase chain reaction (RT-qPCR) and DENV IgM/IgG capture ELISA were used for diagnosis. We further characterized confirmed and probable cases with a plaque reduction neutralization test. At enrollment, 54.1% (95% CI: 46.6, 61.4) of children were DENV IgG positive. The annual incidence of laboratory-confirmed symptomatic dengue cases was 11.0 (95% CI: 7.3, 14.7), 18.1 (10.4, 25.7), and 10.2 (0.7, 19.7), and of laboratory-confirmed or probable dengue cases with neutralizing antibody profile evocative of dengue exposure was 13.2 (6.6, 19.9), 18.7 (5.3, 32.2), and 8.4 (2.4, 19.2) per 1,000 child-years in 2012, 2013, and 2014, respectively. By RT-qPCR, we identified 14 DENV-4 cases in 2012-2013 and seven DENV-1 cases in 2014. During the course of the study, 32.8% of dengue-naive children experienced a primary infection. Primary inapparent dengue infection was detected in 20.3% (95% CI: 13.6, 29.1) of dengue-naive children in 2012, 8.7% (6.9, 10.9) in 2013, and 5.1% (4.4, 6.0) in 2014. Our results confirmed the high dengue endemicity in Fortaleza, with active and enhanced passive surveillance detecting three to five times more cases than the National System of Disease Notification.


Asunto(s)
Anticuerpos Antivirales/sangre , Virus del Dengue/inmunología , Dengue/epidemiología , Inmunoglobulina G/sangre , Adolescente , Infecciones Asintomáticas , Brasil/epidemiología , Niño , Preescolar , Dengue/diagnóstico , Dengue/inmunología , Dengue/virología , Virus del Dengue/clasificación , Virus del Dengue/genética , Notificación de Enfermedades/estadística & datos numéricos , Monitoreo Epidemiológico , Femenino , Humanos , Incidencia , Masculino , Pruebas de Neutralización , Estudios Prospectivos , Estudios Seroepidemiológicos , Índice de Severidad de la Enfermedad
20.
Am J Trop Med Hyg ; 103(1): 132-141, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32342848

RESUMEN

Dengue disease and its causative agents, the dengue viruses (DENV-1-4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03B-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03B). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03B according to the following regimens: 0-1 month (M), 0-1-6 M, or 0-3 M. Participants received DPIV+AS03B or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03B for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0-1-6 M versus 0-1 M) based on neutralizing antibody titers to each DENV type (DENV-1-4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0-1 M versus 0-3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03B doses than placebo; the number of grade 3 AEs was low (≤ 4.5% after DPIV+AS03B; ≤ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03B appeared higher for three-dose (0-1-6 M) than two-dose (0-1 M and 0-3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0-3 M and 0-1-6 M regimens were more immunogenic than the 0-1 M regimen.


Asunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , Vacunas contra el Dengue/administración & dosificación , Virus del Dengue/inmunología , Dengue/prevención & control , Vacunación/métodos , Adulto , Dengue/inmunología , Dengue/virología , Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/biosíntesis , Femenino , Voluntarios Sanos , Humanos , Inmunogenicidad Vacunal , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Vacunas Atenuadas , Vacunas de Subunidad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...