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Resultados 1 - 20 de 23.006

Pyrethroids Use: Threats on Metabolic-Mediated Resistance Mechanisms in the Primary Dengue Vector Aedes aegypti (Diptera: Culicidae).

J Med Entomol; 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715464


The emergence of pyrethroid resistance in Aedes aegypti (L.) has limited the success of vector control. Early detection of resistance could assist authorities in deciding well-suited control strategies to minimize operational failures of Ae. aegypti control. Herein, biochemical analysis was performed to investigate the mechanisms involved in pyrethroid resistance in nine populations of Indonesian Ae. aegypti. Enzymes of adult Ae. aegypti such as esterases (ESTs), glutathione-S-transferases (GSTs), and mixed-function oxidases (MFOs) were characterized. Elevated MFO activity was correlated with resistance phenotype, indicating the role of this enzyme in contributing to pyrethroid resistance. No significant correlations were shown between pyrethroid resistance phenotype and α-ESTs, suggesting that marginally exceeded enzyme levels relative to the reference strain in some pyrethroid-susceptible populations were causative factor for insecticide resistance in other groups of insecticides. However, significant correlation was demonstrated between ß-ESTs and pyrethroid resistance phenotype. The lowest enzyme levels in GSTs indicated that this enzyme was not predominant in causing pyrethroid resistance, despite the presence of significant correlations. Because metabolic detoxification fails to comprehensively explain the pyrethroid resistance in some Indonesian Ae. aegypti, additional mechanisms such as altered target sites in voltage-gated sodium channel may also contribute to the high pyrethroid resistance in Ae. aegypti.

Dengue and chikungunya seroprevalence among Qatari nationals and immigrants residing in Qatar.

PLoS One; 14(1): e0211574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30703150


The objective of this study is to characterize the seroprevalence of anti-dengue (DENV) and anti-chikungunya (CHIKV) antibodies among blood donors residing in Qatar who are Middle East and North Africa (MENA) nationals and non-nationals. Sera were collected from adult blood donors in Qatar from 2013 to 2016 and tested for anti-DENV and anti-CHIKV IgG using commercial microplate enzyme-linked immunosorbent assays. Age-specific seroprevalence was summarized by region/nationality: Asia (India, Philippines), Middle East (Iran, Jordan, Lebanon, Pakistan, Palestine, Syria, Yemen), North Africa (Egypt, Sudan), Qatar. The adjusted odds of anti-DENV and anti-CHIKV IgG seropositivity was estimated by logistic regression. Among 1,992 serum samples tested, Asian nationals had higher adjusted odds of being seropositive for anti-DENV antibodies compared to nationals of the Middle East (aOR 0.05, 95% CI 0.04-0.07), North Africa (aOR 0.14, 95% CI 0.10-0.20), and Qatar (aOR 0.01, 95% CI 0.01-0.03). Asian nationals also had higher adjusted odds of being seropositive for anti-CHIKV antibodies compared to those from the Middle East (aOR 0.14, 95% CI 0.07-0.27), North Africa (aOR 0.50, 95% CI 0.26-0.96), and Qatar (aOR 0.38, 95% CI 0.15-0.96). The adjusted odds of being anti-DENV seropositive was higher among anti-CHIKV seropositive adults, and vice versa (aOR 1.94, 95% CI 1.09-3.44), suggesting co-circulation of these viruses. DENV and CHIKV exposure is lower in Qatar and MENA nationals compared to Asian nationals suggesting a lower burden of DENV and CHIKV disease in the MENA. Antibodies to both viruses were detected in nationals from most MENA countries, supporting the need to better understand the regional epidemiology of these viruses.

Correction: Small-Molecule Inhibitors of Dengue-Virus Entry.

PLoS Pathog; 15(1): e1007553, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30703168


[This corrects the article DOI: 10.1371/journal.ppat.1002627.].

Mutagenesis of the dengue virus NS4A protein reveals a novel cytosolic N-terminal domain responsible for virus-induced cytopathic effects and intramolecular interactions within the N-terminus of NS4A.

J Gen Virol; 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707666


The NS4A protein of dengue virus (DENV) has a cytosolic N terminus and four transmembrane domains. NS4A participates in RNA replication and the host antiviral response. However, the roles of amino acid residues within the N-terminus of NS4A during the life cycle of DENV are not clear. Here we explore the function of DENV NS4A by introducing a series of alanine substitutions into the N-terminus of NS4A in the context of a DENV infectious clone or subgenomic replicon. Nine of 17 NS4A mutants displayed a lethal phenotype due to the impairment of RNA replication. M2 and M14 displayed a more than 10 000-fold reduction in viral yields and moderate defects in viral replication by a replicon assay. Sequencing analyses of pseudorevertant viruses derived from M2 and M14 viruses revealed one consensus reversion mutation, A21V, within NS4A. The A21V mutation apparently rescued viral RNA replication in the M2 and M14 mutants although not to wild-type (WT) levels but resulted in 100- and 1000-fold lower titres than that of the WT, respectively. M2 Rev1 (M2+A21V) and M14 Rev1 (M14+A21V) mutants displayed phenotypes of smaller plaque size and WT-like assembly/secretion by a transpackaging assay. A defect in the virus-induced cytopathic effect (CPE) was observed in HEK-293 cells infected with either M2 Rev1 or M14 Rev1 mutant virus by MitoCapture staining, cell proliferation and lactate dehydrogenase release assays. In conclusion, the results revealed the essential roles of the N-terminal NS4A in both RNA replication and virus-induced CPE. Intramolecular interactions in the N-terminus of NS4A were implicated.

Potential for sylvatic and urban Aedes mosquitoes from Senegal to transmit the new emerging dengue serotypes 1, 3 and 4 in West Africa.

PLoS Negl Trop Dis; 13(2): e0007043, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30759080


Dengue fever (DEN) is the most common arboviral disease in the world and dengue virus (DENV) causes 390 million annual infections around the world, of which 240 million are inapparent and 96 million are symptomatic. During the past decade a changing epidemiological pattern has been observed in Africa, with DEN outbreaks reported in all regions. In Senegal, all DENV serotypes have been reported. These important changes in the epidemiological profile of DEN are occurring in a context where there is no qualified vaccine against DEN. Further there is significant gap of knowledge on the vector bionomics and transmission dynamics in the African region to effectively prevent and control epidemics. Except for DENV-2, few studies have been performed with serotypes 1, 3, and 4, so this study was undertaken to fill out this gap. We assessed the vector competence of Aedes (Diceromyia) furcifer, Ae. (Diceromyia) taylori, Ae. (Stegomyia) luteocephalus, sylvatic and urban Ae. (Stegomyia) aegypti populations from Senegal for DENV-1, DENV-3 and DENV-4 using experimental oral infection. Whole bodies and wings/legs were tested for DENV presence by cell culture assays and saliva samples were tested by real time RT-PCR to estimate infection, disseminated infection and transmission rates. Our results revealed a low capacity of sylvatic and urban Aedes mosquitoes from Senegal to transmit DENV-1, DENV-3 and DENV-4 and an impact of infection on their mortality. The highest potential transmission rate was 20% despite the high susceptibility and disseminated infection rates up to 93.7% for the 3 Ae. aegypti populations tested, and 84.6% for the sylvatic vectors Ae. furcifer, Ae. taylori and Ae. luteocephalus.

Modelling spatio-temporal data of dengue fever using generalized additive mixed models.

Spat Spatiotemporal Epidemiol; 28: 1-13, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30739650


Epidemiological studies have revealed a complex association between weather and dengue transmission. Our aim is the development of a Spatio-temporal modelling of dengue fever via a Generalized Additive mixed model (GAMM). The structure is based on unknown smoother functions for climatic and a set of non-climatic covariates. All the climatic covariates were found statistically significant with optimal lagged effect and the smoothed curves fairly captured the real dynamic on dengue fever. It was also found that critical levels of dengue cases were reached with temperature between 26 °C and 30 °C. The findings also revealed for the first time that the El Niño phenomenon fluctuating between 26.5 °C and 28.0 °C had the worse impact on dengue transmission. This study brings together a large dataset from different sources including Ministry of Health from Venezuela. It was also benefited from a remote satellite climatic data provided by the National Aeronautics and Space Administration (NASA).

Mathematical modeling of dengue epidemic: control methods and vaccination strategies.

Theory Biosci; 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30740641


Dengue is, in terms of death and economic cost, one of the most important infectious diseases in the world. So, its mathematical modeling can be a valuable tool to help us to understand the dynamics of the disease and to infer about its spreading by the proposition of control methods. In this paper, control strategies, which aim to eliminate the Aedes aegypti mosquito, as well as proposals for the vaccination campaign are evaluated. In our mathematical model, the mechanical control is accomplished through the environmental support capacity affected by a discrete function that represents the removal of breedings. Chemical control is carried out using insecticide and larvicide. The efficiency of vaccination is studied through the transfer of a fraction of individuals, proportional to the vaccination rate, from the susceptible to the recovered compartments. Our major find is that the dengue fever epidemic is only eradicated with the use of an immunizing vaccine because control measures, directed against its vector, are not enough to halt the disease spreading. Even when the infected mosquitoes are eliminated from the system, the susceptible ones are still present, and infected humans cause dengue fever to reappear in the human population.

Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice.

Cell Rep; 26(6): 1585-1597.e4, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30726740


Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development.

Focused Dengue Vaccine Development; Outwitting Nature's Design.

Pathog Dis; 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30726906


The four DENV serotypes are mosquito-borne pathogens that belong to the Flavivirus genus. These viruses present a major global health burden, being endemic in over 120 countries, causing ∼390 million reported infections yearly, with clinical symptoms ranging from mild fever to severe and potentially fatal hemorrhagic syndromes. Development of a safe and efficacious DENV vaccine is challenging because of the need to induce immunity against all 4 serotypes simultaneously, as immunity against one serotype can potentially enhance disease caused by a heterotypic secondary infection. So far, live-virus particle-based vaccine approaches struggle with inducing protective tetravalent immunity, while recombinant subunit approaches that use the envelope protein (E) as the major antigen, are gaining promise in preclinical studies. However, E-based subunits require further development and characterization to be used as effective vaccine antigens against DENV. In this review we will address the shortcomings of recombinant E-based antigens and will discuss potential solutions to enhance E-based subunit antigen immunogenicity and vaccine efficacy.

Risk of transfusion-associated dengue: screening of blood donors from Pune, western India.

Transfusion; 59(2): 458-462, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30727040


BACKGROUND: Dengue, a mosquito-borne viral disease, is endemic in >125 countries worldwide. The threat of blood-borne transmission of dengue virus (DENV) has been documented. STUDY DESIGN AND METHODS: This study was conducted to assess the potential magnitude of transfusion-associated dengue, by determination of DENV seromarkers in blood donations from Pune, India, during two dengue seasons (2016 and 2017). These included DENV nonstructural protein 1 (NS1), anti-DENV immunoglobulin (Ig) M, anti-DENV IgG (enzyme-linked immunosorbent assay), and DENV RNA (reverse transcription-polymerase chain reaction). RESULTS: NS1 (IgM) reactivity was 1 of 209, 0.48% (11/209, 5.3%) in 2016 and 2 of 311, 0.64% (20/311, 6.4%) in 2017. Of the 34 NS1/IgM reactives, 1 NS1-reactive donor and 10 IgM-reactive donors exhibited evidence of secondary infection. DENV RNA was not detected in any of the 34 NS1/IgM reactives. Among the NS1/IgM negatives, anti-DENV IgG reactivity was high in 2016 (75%) and further increased in 2017 (87%, p = 0.002). CONCLUSION: Although RNA negative, detection of 34 NS1/IgM-reactive donations, of which 11 had evidence of secondary infection, suggests the need for further evaluation on the basis of potential risk to recipients of either dengue transmission or increased risk of secondary infection. These would include multicenter studies followed by cost-benefit analyses.

Heterogeneities in dengue spatial-temporal transmission in Brazilian cities and its influence on the optimal age of vaccination.

BMC Public Health; 19(1): 155, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30727988


BACKGROUND: The development of a safe and effective vaccine is considered crucial for dengue transmission control since vetor control has been failed; some potential candidates are currently in test, and in this context theoretical studies are necessary to evaluate vaccination strategies such as the age groups that should be vaccinated, the percentage of the population at risk, and the target geographic regions to make dengue control feasible and optimal. METHODS: A partial differential model is used to mimics dengue transmission in human population in order to estimate the optimal vaccination age, using data collected from dengue reported cases in ten cities of Brazil from 2001 to 2014. For this purpose, the basic reproduction number of the disease was minimized assuming a single-dose vaccination strategy, equal vaccine efficacy for all circulating serotypes, and no vaccine failure. Numerical methods were used to assess the optimal vaccination age and its confidence age range. RESULTS: The results reveal complex spatial-temporal patterns associated to the disease transmission, highlighting the heterogeneity in defining the target population for dengue vaccination. However, the values obtained for the optimal age of vaccination, as targeting individuals under 13 years old, are compatible with the ones reported in similar studies in Brazil. The results also show that the optimal age for vaccination in general does not match with the age of the highest number of cases. CONCLUSIONS: The variation of the optimal age for vaccination across the country reflects heterogeneities in dengue spatial-temporal transmission in Brazilian cities, and can be used to define the target population and cities to optimize vaccination strategies in a context of high cost and low quantity of available vaccine.

Comparison of stochastic and deterministic frameworks in dengue modelling.

Math Biosci; 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30735695


We perform estimations of compartment models for dengue transmission in rural Cambodia with increasing complexity regarding both model structure and the account for stochasticity. On the one hand, we successively account for three embedded sources of stochasticity: observation noise, demographic variability and environmental hazard. On the other hand, complexity in the model structure is increased by introducing vector-borne transmission, explicit asymptomatic infections and interacting virus serotypes. Using two sources of case data from dengue epidemics in Kampong Cham (Cambodia), models are estimated in the bayesian framework, with Markov Chain Monte Carlo and Particle Markov Chain Monte Carlo. We highlight the advantages and drawbacks of the different formulations in a practical setting. Although in this case the deterministic models provide a good approximation of the mean trajectory for a low computational cost, the stochastic frameworks better reflect and account for parameter and simulation uncertainty.

Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy.

Immunity; 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30737148


Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts. ZIKV-infected human placental tissues also showed increased replication in the presence of DENV antibodies, which was reversed by FcγR blocking antibodies. Furthermore, ZIKV-mediated fetal pathogenesis was enhanced in mice in the presence of a DENV-reactive monoclonal antibody, but not in the presence of the LALA variant, indicating a dependence on FcγR engagement. Our data suggest a possible mechanism for the recent increase in severe pregnancy outcomes after ZIKV infection in DENV-endemic areas.

Long-term immunogenicity and safety of tetravalent dengue vaccine (CYD-TDV) in healthy populations in Singapore and Vietnam: 4-year follow-up of randomized, controlled, Phase II trials.

Hum Vaccin Immunother; 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30724660


Dengue is prevalent in the Asia-Pacific region. Participants of two immunogenicity and safety phase II studies conducted in Singapore and Vietnam (NCT0088089 and NCT00875524, respectively) were followed for up to four years after third vaccine dose of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV). Participants (2-45 years) received three doses of CYD-TDV or control at 0, 6, and 12 months. Dengue plaque reduction neutralization test (PRNT ) antibody titers were measured in both studies. Cytokine-producing antigen-specific CD4+ and CD8+ T cells were quantified to assess cell-mediated immunity (CMI) in Singapore. Post-hoc analyses were carried out for participants aged <9 and ≥9 years old. Related and fatal serious adverse events were collected during long-term follow-up. Of participants who received ≥1 CYD-TDV injection in Singapore (n = 1198) and Vietnam (n = 180), 87% and 92% participants completed long-term follow-up, respectively. At four years, geometric mean titers (GMTs) in participants who received CYD-TDV ranged from 30.2 1/dil (95% CI 23.9-38.3) to 73.7 (49.3-110) in Vietnam and 9.73 1/dil (95% CI 8.28-11.4) to 21.8 (18.9-25.1) in Singapore. Interferon and interleukin-13 levels were lower at four years than one year post-vaccination but were still present. Tumor necrosis factor- α levels at four years were similar to those after the third vaccine dose. Seropositivity rates were higher at year four in participants who were seropositive vs. seronegative at baseline in both studies. No safety concerns were identified. CYD-TDV demonstrated long-term immunogenicity and was well-tolerated for four years after the third vaccine dose.

Feasibility of feeding Aedes aegypti mosquitoes on dengue virus-infected human volunteers for vector competence studies in Iquitos, Peru.

PLoS Negl Trop Dis; 13(2): e0007116, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30753180


BACKGROUND: Transmission of dengue virus (DENV) from humans to mosquitoes represents a critical component of dengue epidemiology. Examinations of this process have generally been hampered by a lack of methods that adequately represent natural acquisition of DENV by mosquitoes from humans. In this study, we assessed artificial and natural blood feeding methods based on rates of DENV infection and dissemination within mosquitoes for use in a field-based epidemiological cohort study in Iquitos, Peru. METHODOLOGY/PRINCIPAL FINDINGS: Our study was implemented, stepwise, between 2011 and 2015. Participants who were 5 years and older with 5 or fewer days of fever were enrolled from ongoing clinic- and neighborhood-based studies on dengue in Iquitos. Wild type, laboratory-reared Aedes aegypti were fed directly on febrile individuals or on blood collected from participants that was either untreated or treated with EDTA. Mosquitoes were tested after approximately 14 days of extrinsic incubation for DENV infection and dissemination. A total of 58 participants, with viremias ranging from 1.3 × 102 to 2.9 × 106 focus-forming units per mL of serum, participated in one or more feeding methods. DENV infection and dissemination rates were not significantly different following direct and indirect-EDTA feeding; however, they were significantly lower for mosquitoes that fed indirectly on blood with no additive. Relative to direct feeding, infection rates showed greater variation following indirect-EDTA than indirect-no additive feeding. Dissemination rates were correlated across all feeding methods. No differences were detected in DENV infection or dissemination rates in mosquitoes fed directly on participants with different dengue illness severity. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates the feasibility of using direct and indirect feeding methods for field-based studies on vector competence. Direct mosquito feeding is preferable in terms of logistical ease, biosecurity, and reliability.

The use of folic acid in dengue: has it any value?

Trop Doct; : 49475519827110, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755107


Folic acid is used in dengue patients. Our study aims to compare the duration of recovery of thrombocytopenia in patients with dengue infection who received folic acid and those who did not. We retrospectively reviewed the medical records of adult patients admitted over six years with a diagnosis of dengue. Of 2216 patients, 1464 fulfilled the inclusion criteria. Group A were those patients who received folic acid and group B were those who did not. A total of 1322 (90.3%) patients received folic acid. The mean time period required for platelets to double the nadir was 1.7 (±2.2) days in both groups A and B ( P = 0.89). In conclusion, there is no significant difference in the recovery of thrombocytopenia in patients with dengue fever who received folic and those who did not receive folic acid.

Peripheral serotonin causes dengue-induced thrombocytopenia through 5HT receptors.

Blood; 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755421


Dengue virus (DENV) is the most prevalent vector-borne viral pathogen, infecting millions of patients annually. Thrombocytopenia, a reduction in circulating platelet counts, is the most consistent sign of DENV-induced disease, independent of disease severity. However, the mechanisms leading to DENV-induced thrombocytopenia are unknown. Here, we show that thrombocytopenia is caused by serotonin, derived from mast cells (MCs), which are immune cells that are present in the perivascular space and a major peripheral source of serotonin. We show that during DENV infection, MCs release serotonin, which prompts platelet activation, aggregation and enhanced phagocytosis, dependent on 5HT receptors. MC-deficiency in mice or pharmacological inhibition of MCs reversed thrombocytopenia. Furthermore, reconstitution of MC-deficient mice with wild-type MCs, but not MCs lacking serotonin synthesis due to deficiency in the enzyme tryptophan hydroxylase-1 (TPH1), restored the thrombocytopenic phenotype. Exogenous serotonin was also sufficient to overcome the effects of drugs that inhibit platelet activation in vitro and to restore thrombocytopenia in DENV-infected MC-deficient mice. Therapeutic targeting of 5HT receptors during DENV infection effectively prevented thrombocytopenia in mice. Similarly, serotonin derived from DENV-activated human MCs led to increased human platelet activation. Thus MC-derived serotonin is a previously unidentified mechanism of DENV-induced thrombocytopenia and a potential therapeutic target.
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