Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.160
Filtrar
1.
Sci Rep ; 11(1): 19713, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611200

RESUMO

The novel coronavirus disease 2019 (COVID-19) presents with non-specific clinical features. This may result in misdiagnosis or delayed diagnosis, and lead to further transmission in the community. We aimed to derive early predictors to differentiate COVID-19 from influenza and dengue. The study comprised 126 patients with COVID-19, 171 with influenza and 180 with dengue, who presented within 5 days of symptom onset. All cases were confirmed by reverse transcriptase polymerase chain reaction tests. We used logistic regression models to identify demographics, clinical characteristics and laboratory markers in classifying COVID-19 versus influenza, and COVID-19 versus dengue. The performance of each model was evaluated using receiver operating characteristic (ROC) curves. Shortness of breath was the strongest predictor in the models for differentiating between COVID-19 and influenza, followed by diarrhoea. Higher lymphocyte count was predictive of COVID-19 versus influenza and versus dengue. In the model for differentiating between COVID-19 and dengue, patients with cough and higher platelet count were at increased odds of COVID-19, while headache, joint pain, skin rash and vomiting/nausea were indicative of dengue. The cross-validated area under the ROC curve for all four models was above 0.85. Clinical features and simple laboratory markers for differentiating COVID-19 from influenza and dengue are identified in this study which can be used by primary care physicians in resource limited settings to determine if further investigations or referrals would be required.


Assuntos
COVID-19/patologia , Dengue/patologia , Influenza Humana/patologia , Adulto , Área Sob a Curva , COVID-19/complicações , COVID-19/virologia , Estudos de Coortes , Dengue/complicações , Dengue/virologia , Diagnóstico Diferencial , Diarreia/etiologia , Feminino , Febre/etiologia , Humanos , Influenza Humana/complicações , Influenza Humana/virologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , RNA Viral/análise , RNA Viral/metabolismo , Curva ROC , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Vômito/etiologia , Adulto Jovem
2.
J Gen Virol ; 102(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34665110

RESUMO

Viperin has antiviral function against many viruses, including dengue virus (DENV), when studied in cells in culture. Here, the antiviral actions of viperin were defined both in vitro and in a mouse in vivo model of DENV infection. Murine embryonic fibroblasts (MEFs) derived from mice lacking viperin (vip-/-) showed enhanced DENV infection, accompanied by increased IFN-ß and induction of ISGs; IFIT1 and CXCL-10 but not IRF7, when compared to wild-type (WT) MEFs. In contrast, subcutaneous challenge of immunocompetent WT and vip-/- mice with DENV did not result in enhanced infection. Intracranial infection with DENV resulted in body weight loss and neurological disease with a moderate increase in mortality in vip-/- compared with WT mice, although this was not accompanied by altered brain morphology, immune cell infiltration or DENV RNA level in the brain. Similarly, DENV induction of IFN-ß, IFIT1, CXCL-10, IRF7 and TNF-α was not significantly different in WT and vip-/- mouse brain, although there was a modest but significant increase in DENV induction of IL-6 and IfI27la in the absence of viperin. NanoString nCounter analysis confirmed no significant difference in induction of a panel of inflammatory genes in WT compared to vip-/- DENV-infected mouse brains. Further, polyI:C stimulation of bone marrow-derived macrophages (BMDMs) induced TNF-α, IFN-ß, IL-6 and Nos-2, but responses were not different in BMDMs generated from WT or vip-/- mice. Thus, while there is significant evidence of anti-DENV actions of viperin in some cell types in vitro, for DENV infection in vivo a lack of viperin does not affect systemic or brain susceptibility to DENV or induction of innate and inflammatory responses.


Assuntos
Antivirais , Vírus da Dengue/imunologia , Vírus da Dengue/fisiologia , Dengue/imunologia , Dengue/virologia , Imunidade Inata , Proteínas/fisiologia , Animais , Encéfalo/imunologia , Encéfalo/virologia , Células Cultivadas , Inflamação , Fator Regulador 7 de Interferon/genética , Interferon beta/biossíntese , Interferon beta/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteínas/genética , Replicação Viral
3.
Nat Commun ; 12(1): 5374, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508072

RESUMO

The mosquito Aedes aegypti is the principal vector for arboviruses including dengue/yellow fever, chikungunya, and Zika virus, infecting hundreds of millions of people annually. Unfortunately, traditional control methodologies are insufficient, so innovative control methods are needed. To complement existing measures, here we develop a molecular genetic control system termed precision-guided sterile insect technique (pgSIT) in Aedes aegypti. PgSIT uses a simple CRISPR-based approach to generate flightless females and sterile males that are deployable at any life stage. Supported by mathematical models, we empirically demonstrate that released pgSIT males can compete, suppress, and even eliminate mosquito populations. This platform technology could be used in the field, and adapted to many vectors, for controlling wild populations to curtail disease in a safe, confinable, and reversible manner.


Assuntos
Aedes/virologia , Infertilidade Masculina/veterinária , Controle de Mosquitos/métodos , Mosquitos Vetores/virologia , Aedes/genética , Animais , Animais Geneticamente Modificados , Arbovírus , Febre de Chikungunya/prevenção & controle , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Dengue/prevenção & controle , Dengue/transmissão , Dengue/virologia , Feminino , Humanos , Infertilidade Masculina/genética , Masculino , Modelos Biológicos , Mosquitos Vetores/genética , Febre Amarela/prevenção & controle , Febre Amarela/transmissão , Febre Amarela/virologia , Zika virus , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
4.
J Adv Res ; 32: 37-44, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34484824

RESUMO

Introduction: Dengue and Malaria are the most important mosquito-borne viral diseases affecting humans. Fever is transmitted between human hosts by infected female aedes mosquitoes. The modeling study of viral infections is very useful to show how the virus replicates in an infected individual and how the human antibody response acts to control that replication, which antibody playing a key role in controlling infection. Objectives: Optimal control of a novel variable-order nonlinear model of dengue virus is studied in the present work. Bang-bang control is suggested to minimize the viral infection as well as quick clearance of the virus from the host. Necessary conditions for the control problem are given. The variable-order derivatives are given in the sense of Caputo. Moreover, the parameters of the proposed model are dependent on the same variable-order fractional power. Two numerical schemes are constructed for solving the optimality systems. Comparative studies and numerical simulations are implemented. The variable-order fractional derivative can be describe the effects of long variable memory of time dependent systems than the integer order and fractional order derivatives. Methods: Both the nonstandard generalized fourth order Runge-Kutta and the nonstandard generalized Euler methods are presented. Results: We have successfully applied a kind of Pontryagin's maximum principle with bang-bang control and were able to reduce the viraemia level by adding the dose of DI particles. The nonstandard generalized fourth order Runge-Kutta method has the best results than nonstandard generalized Euler method. Conclusion: The combination of the variable-order fractional derivative and bang-bang control in the Dengue mathematical model improves the dynamics of the model. The nonstandard generalized Euler method and the nonstandard generalized fourth order Runge-Kutta method can be used to study the variable order fractional optimal control problem simply.


Assuntos
Vírus da Dengue , Dengue/virologia , Modelos Teóricos , Aedes , Animais , Feminino , Humanos , Viremia/virologia , Replicação Viral
5.
Sci Rep ; 11(1): 18000, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504185

RESUMO

Serologic tests to detect specific IgGs to antigens related to viral infections are urgently needed for diagnostics and therapeutics. We present a diagnostic method for serotype-specific IgG identification of dengue infection by a competitive enzyme-linked immunosorbent assay (ELISA), using high-affinity unnatural-base-containing DNA (UB-DNA) aptamers that recognize the four categorized serotypes. Using UB-DNA aptamers specific to each serotype of dengue NS1 proteins (DEN-NS1), we developed our aptamer-antibody sandwich ELISA for dengue diagnostics. Furthermore, IgGs highly specific to DEN-NS1 inhibited the serotype-specific NS1 detection, inspiring us to develop the competitive ELISA format for dengue serotype-specific IgG detection. Blood samples from Singaporean patients with primary or secondary dengue infections confirmed the highly specific IgG detection of this format, and the IgG production initially reflected the serotype of the past infection, rather than the recent infection. Using this dengue competitive ELISA format, cross-reactivity tests of 21 plasma samples from Singaporean Zika virus-infected patients revealed two distinct patterns: 8 lacked cross-reactivity, and 13 were positive with unique dengue serotype specificities, indicating previous dengue infection. This antigen-detection ELISA and antibody-detection competitive ELISA combination using the UB-DNA aptamers identifies both past and current viral infections and will facilitate specific medical care and vaccine development for infectious diseases.


Assuntos
Anticorpos Antivirais/imunologia , Afinidade de Anticorpos , Aptâmeros de Nucleotídeos/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Imunoglobulina G/imunologia , Sorogrupo , Testes Sorológicos/métodos , Proteínas não Estruturais Virais/imunologia , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Reações Cruzadas , Dengue/sangue , Dengue/diagnóstico , Dengue/virologia , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Imunoglobulina G/sangue , Sensibilidade e Especificidade , Zika virus/imunologia , Infecção por Zika virus/sangue , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
6.
J Gen Virol ; 102(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34342561

RESUMO

Dengue virus (DENV) is the most prevalent pathogen of the Flaviviridae family. Due to the considerable increase in DENV incidence and spread, symptoms such as CNS involvement have increased. Heparan sulphate (HS) was the first molecule identified as an adhesion factor for DENV in mammalian cells. Viral phenotypes with different HS interactions are associated with various clinical symptoms, including neurological alterations. Here, using in silico analyses, in vitro studies, and the in vivo mouse model, we characterized two natural circulating DENV3 genotype I (GI) lineage 1 (L1) in Brazil-DENV3 MG-20 (from Minas Gerais) and DENV3 PV_BR (from Rondônia) that present divergent neurovirulent profiles and sensitivity to sulphated molecules. We identified substitutions at the viral envelope (E) in positions 62 and 123 as likely responsible for the differences in neurovirulence. The E62K and E123Q substitutions in DENV3 MG-20 and DENV3 PV_BR, respectively, greatly influenced in silico electrostatic density and heparin docking results. In vivo, mice inoculated with DENV3 MG-20 died, but not those infected with DENV3 PV_BR. The clinical symptoms, such as paralysis of the lower limbs and meningoencephalitis, and histopathology, also differed between the inoculated groups. In vitro heparin and heparinases assays further demonstrated the biological impact of these substitutions. Other characteristics that have been previously associated with alterations in cell tropism and neurovirulence, such as changes in the size of lysis plaques and differences in cytopathic effects in glioblastoma cells, were also observed.


Assuntos
Vírus da Dengue/classificação , Vírus da Dengue/genética , Dengue/virologia , Genótipo , Heparitina Sulfato/metabolismo , Proteínas do Envelope Viral/química , Animais , Sítios de Ligação , Encéfalo/patologia , Comunicação Celular , Linhagem Celular , Dengue/patologia , Vírus da Dengue/fisiologia , Modelos Animais de Doenças , Feminino , Heparina , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Fenótipo , Filogenia , Conformação Proteica , Proteínas do Envelope Viral/classificação , Proteínas do Envelope Viral/genética , Virulência , Ligação Viral
7.
Viruses ; 13(7)2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34372606

RESUMO

As demonstrated with the novel coronavirus pandemic, rapid and accurate diagnosis is key to determine the clinical characteristic of a disease and to improve vaccine development. Once the infected person is identified, hematological findings may be used to predict disease outcome and offer the correct treatment. Rapid and accurate diagnosis and clinical parameters are pivotal to track infections during clinical trials and set protection status. This is also applicable for re-emerging diseases like dengue fever, which causes outbreaks in Asia and Latin America every 4 to 5 years. Some areas in the US are also endemic for the transmission of dengue virus (DENV), the causal agent of dengue fever. However, significant number of DENV infections in rural areas are diagnosed solely by clinical and hematological findings because of the lack of availability of ELISA or PCR-based tests or the infrastructure to implement them in the near future. Rapid diagnostic tests (RDT) are a less sensitive, yet they represent a timely way of detecting DENV infections. The purpose of this study was to determine whether there is an association between hematological findings and the probability for an NS1-based DENV RDT to detect the DENV NS1 antigen. We also aimed to describe the hematological parameters that are associated with the diagnosis through each test.


Assuntos
COVID-19/diagnóstico , COVID-19/epidemiologia , Dengue/diagnóstico , Adolescente , Adulto , Ásia/epidemiologia , Criança , Pré-Escolar , Colômbia/epidemiologia , Dengue/virologia , Vírus da Dengue/isolamento & purificação , Testes Diagnósticos de Rotina/métodos , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Masculino , Pandemias , Reação em Cadeia da Polimerase , Kit de Reagentes para Diagnóstico , SARS-CoV-2/isolamento & purificação , Adulto Jovem
8.
Viruses ; 13(7)2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34372551

RESUMO

BACKGROUND: In 2015-2016, a large Zika virus (ZIKV) outbreak occurred in the Americas. Although the exact ZIKV antibody kinetics after infection are unknown, recent evidence indicates the rapid waning of ZIKV antibodies in humans. Therefore, we aimed to determine the levels of ZIKV antibodies more than three years after a ZIKV infection. METHODS: We performed ZIKV virus neutralization tests (VNT) and a commercial ZIKV non-structural protein 1 (NS1) IgG ELISA in a cohort of 49 participants from Suriname who had a polymerase-chain-reaction-confirmed ZIKV infection more than three years ago. Furthermore, we determined the presence of antibodies against multiple dengue virus (DENV) antigens. RESULTS: The ZIKV seroprevalence in this cohort, assessed with ZIKV VNT and ZIKV NS1 IgG ELISA, was 59.2% and 63.3%, respectively. There was, however, no correlation between these two tests. Furthermore, we did not find evidence of a potential negative influence of DENV immunity on ZIKV antibody titers. CONCLUSIONS: ZIKV seroprevalence, assessed with two commonly used serological tests, was lower than expected in this cohort of participants who had a confirmed previous ZIKV infection. This can have implications for future ZIKV seroprevalence studies and possibly for the duration of immunological protection after a ZIKV infection.


Assuntos
Anticorpos Neutralizantes/análise , Infecção por Zika virus/imunologia , Zika virus/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/análise , Anticorpos Antivirais/imunologia , Estudos de Coortes , Reações Cruzadas/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Testes de Neutralização/métodos , Estudos Soroepidemiológicos , Testes Sorológicos/métodos , Suriname , Zika virus/patogenicidade , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia
9.
J Gen Virol ; 102(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34410905

RESUMO

The capsid protein (C) of dengue virus is required for viral infectivity as it packages viral RNA genome into infectious particles. C exists as a homodimer that forms via hydrophobic interactions between the α2 and α4 helices of monomers. To identify C region(s) important for virus particle production, a complementation system was employed in which single-round infectious particles are generated by trans-encapsidation of a viral C-deleted genome by recombinant C expressed in mosquito cells. Mutants harbouring a complete α3 deletion, or a dual Ile65-/Trp69-to-Ala substitution in the α3 helix, exhibited reduced production of infectious virus. Unexpectedly, higher proportions of oligomeric C were detected in cells expressing both mutated forms as compared with the wild-type counterpart, indicating that the α3 helix, through its internal hydrophobic residues, may down-modulate oligomerization of C during particle formation. Compared with wild-type C, the double Ile65-/Trp69 to Ala mutations appeared to hamper viral infectivity but not C and genomic RNA incorporation into the pseudo-infectious virus particles, suggesting that increased C oligomerization may impair DENV replication at the cell entry step.


Assuntos
Proteínas do Capsídeo , Capsídeo/metabolismo , Vírus da Dengue/metabolismo , Dengue/virologia , Aedes , Sequência de Aminoácidos , Animais , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Chlorocebus aethiops , Humanos , Células Vero , Montagem de Vírus , Replicação Viral
10.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452505

RESUMO

Viral infection is a global public health threat causing millions of deaths. A suitable small animal model is essential for viral pathogenesis and host response studies that could be used in antiviral and vaccine development. The tree shrew (Tupaia belangeri or Tupaia belangeri chinenesis), a squirrel-like non-primate small mammal in the Tupaiidae family, has been reported to be susceptible to important human viral pathogens, including hepatitis viruses (e.g., HBV, HCV), respiratory viruses (influenza viruses, SARS-CoV-2, human adenovirus B), arboviruses (Zika virus and dengue virus), and other viruses (e.g., herpes simplex virus, etc.). The pathogenesis of these viruses is not fully understood due to the lack of an economically feasible suitable small animal model mimicking natural infection of human diseases. The tree shrew model significantly contributes towards a better understanding of the infection and pathogenesis of these important human pathogens, highlighting its potential to be used as a viable viral infection model of human viruses. Therefore, in this review, we summarize updates regarding human viral infection in the tree shrew model, which highlights the potential of the tree shrew to be utilized for human viral infection and pathogenesis studies.


Assuntos
Modelos Animais de Doenças , Tupaia , Viroses , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/virologia , Animais , COVID-19/virologia , Dengue/imunologia , Dengue/patologia , Dengue/virologia , Infecções por HIV/virologia , Hepatite B/imunologia , Hepatite B/virologia , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/imunologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
11.
Front Immunol ; 12: 677874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335578

RESUMO

Background: Early biomarkers of progression to severe dengue are urgently required to enable effective patient management and control treatment costs. Innate immune cells, which comprise the earliest responders to infection and along with the cytokines and chemokines they secrete, play a vital role in orchestrating the subsequent adaptive immune response and have been implicated in the enhancement of infection and "cytokine storm" associated with dengue severity. We investigated the early innate immune cytokine profile of dengue patients during acute phase of disease in a prospective blinded study that included subjects with acute dengue and febrile controls from four major hospitals in Bengaluru, India along with healthy controls. We used intracellular cytokine staining and flow cytometry to identify innate immune biomarkers that can predict progression to severe dengue. Results: Dengue infection resulted in enhanced secretion of multiple cytokines by all queried innate immune cell subsets, dominated by TNF-α from CD56+CD3+ NKT cells, monocyte subsets, and granulocytes along with IFN-γ from CD56+CD3+ NKT cells. Of note, significantly higher proportions of TNF-α secreting granulocytes and monocyte subsets at admission were associated with mild dengue and minimal symptoms. Dengue NS1 antigenemia used as a surrogate of viral load directly correlated with proportion of cytokine-secreting innate immune cells and was significantly higher in those who went on to recover with minimal symptoms. In patients with secondary dengue or those with bleeding or elevated liver enzymes who revealed predisposition to severe outcomes, early activation as well as efficient downregulation of innate responses were compromised. Conclusion: Our findings suggested that faulty/delayed kinetics of innate immune activation and downregulation was a driver of disease severity. We identified IFN-γ +CD56+CD3+ NKT cells and IL-6+ granulocytes at admission as novel early biomarkers that can predict the risk of progression to severity (composite AUC = 0.85-0.9). Strong correlations among multiple cytokine-secreting innate cell subsets revealed that coordinated early activation of the entire innate immune system in response to dengue virus infection contributed to resolution of infection and speedy recovery.


Assuntos
Citocinas/sangue , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Dengue/sangue , Dengue/imunologia , Granulócitos/imunologia , Imunidade Inata , Células T Matadoras Naturais/imunologia , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Dengue/epidemiologia , Dengue/virologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
12.
Viruses ; 13(7)2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34372598

RESUMO

Dengue virus (DENV) infection causes a spectrum of dengue diseases that have unclear underlying mechanisms. Nonstructural protein 1 (NS1) is a multifunctional protein of DENV that is involved in DENV infection and dengue pathogenesis. This study investigated the potential post-translational modification of DENV NS1 by phosphorylation following DENV infection. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), 24 potential phosphorylation sites were identified in both cell-associated and extracellular NS1 proteins from three different cell lines infected with DENV. Cell-free kinase assays also demonstrated kinase activity in purified preparations of DENV NS1 proteins. Further studies were conducted to determine the roles of specific phosphorylation sites on NS1 proteins by site-directed mutagenesis with alanine substitution. The T27A and Y32A mutations had a deleterious effect on DENV infectivity. The T29A, T230A, and S233A mutations significantly decreased the production of infectious DENV but did not affect relative levels of intracellular DENV NS1 expression or NS1 secretion. Only the T230A mutation led to a significant reduction of detectable DENV NS1 dimers in virus-infected cells; however, none of the mutations interfered with DENV NS1 oligomeric formation. These findings highlight the importance of DENV NS1 phosphorylation that may pave the way for future target-specific antiviral drug design.


Assuntos
Vírus da Dengue/química , Vírus da Dengue/patogenicidade , Proteínas não Estruturais Virais/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Cromatografia Líquida , Dengue/virologia , Vírus da Dengue/genética , Células Hep G2 , Humanos , Cinética , Fosforilação , Ligação Proteica , Análise de Sequência de Proteína , Espectrometria de Massas em Tandem , Células Vero , Proteínas não Estruturais Virais/genética , Replicação Viral
13.
BMC Infect Dis ; 21(1): 639, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215212

RESUMO

BACKGROUND: Infection by chikungunya (CHIKV) and dengue virus (DENV) can cause a wide spectrum of clinical features, many of which are undifferentiated. Cytokines, which broadly also include chemokines and growth factors, have been shown to play a role in protective immunity as well as DENV and CHIKV pathogenesis. However, differences in cytokine response to both viruses remain poorly understood, especially in patients from countries where both viruses are endemic. Our study is therefore aimed to provide a comparative profiling of cytokine response induced by acute DENV and CHIKV infections in patients with similar disease stages and in experimental in vitro infections. METHODS: By using multiplex immunoassay, we compared host cytokine profiles between acute CHIKV and DENV infections by analysing serum cytokine levels of IL-1α, IL-4, IL-5, IL-8, IL-13, RANTES, MCP-3, eotaxin, PDGF-AB/BB, and FGF-2 from the sera of acute chikungunya and dengue fever patients. We further investigated the cytokine profile responses using experimental in vitro CHIKV and DENV infections of peripheral blood mononuclear cells (PBMCs). RESULTS: We found that both CHIKV and DENV-infected patients had an upregulated level of IL-8 and IL-4, with the highest IL-4 level observed in DENV-2 infected patients. Higher IL-8 level was also correlated with lower platelet count in dengue patients. IL-13 and MCP-3 downregulation was observed only in chikungunya patients, while conversely PDGF-AB/BB and FGF-2 downregulation was unique in dengue patients. Age-associated differential expression of IL-13, MCP-3, and IL-5 was also observed, while distinct kinetics of IL-4, IL-8, and FGF-2 expression between CHIKV and DENV-infected patients were identified. Furthermore, the unique pattern of IL-8, IL-13 and MCP-3, but not IL-4 expression was also recapitulated using experimental in vitro infection in PBMCs. CONCLUSIONS: Taken together, our study identified common cytokine response profile characterized by upregulation of IL-8 and IL-4 between CHIKV and DENV infection. Downregulation of IL-13 and MCP-3 was identified as a unique cytokine response profile of acute CHIKV infection, while distinct downregulation of PDGF-AB/BB and FGF-2 characterized the response from acute DENV infection. Our study provides an important overview of the host cytokine responses between CHIKV and DENV infection, which is important to further understand the mechanism and pathology of these diseases.


Assuntos
Febre de Chikungunya/imunologia , Vírus Chikungunya/imunologia , Citocinas/metabolismo , Vírus da Dengue/imunologia , Dengue/imunologia , Adolescente , Adulto , Idoso , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/metabolismo , Febre de Chikungunya/virologia , Criança , Pré-Escolar , Estudos Transversais , Citocinas/imunologia , Dengue/epidemiologia , Dengue/metabolismo , Dengue/virologia , Feminino , Humanos , Indonésia/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
14.
Viruses ; 13(6)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208667

RESUMO

Dengue fever, caused by the mosquito-borne dengue virus (DENV), has been endemic in Myanmar since 1970 and it has become a significant public health burden. It is crucial that circulating DENV strains are identified and monitored, and that their transmission efficiency and association with disease severity is understood. In this study, we analyzed DENV-1, DENV-2, DENV-3, and DENV-4 serotypes in 1235 serum samples collected in Myanmar between 2017 and 2019. Whole-genome sequencing of DENV-1-4 demonstrated that most DENV-1-4 strains had been circulating in Myanmar for several years. We also identified the emergence of DENV-3 genotype-I in 2017 samples, which persisted through 2018 and 2019. The emergence of the strain coincided with a period of increased DENV-3 cases and marked changes in the serotype dynamics. Nevertheless, we detected no significant differences between serum viral loads, disease severity, and infection status of individuals infected with different DENV serotypes during the 3-year study. Our results not only identify the spread of a new DENV-3 genotype into Yangon, Myanmar, but also support the importance of DENV evolution in changing the epidemic dynamics in endemic regions.


Assuntos
Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/virologia , Vírus da Dengue/classificação , Vírus da Dengue/genética , Dengue/epidemiologia , Dengue/virologia , Genótipo , Adolescente , Substituição de Aminoácidos , Criança , Pré-Escolar , Dengue/diagnóstico , Dengue/história , Vírus da Dengue/isolamento & purificação , Surtos de Doenças , Variação Genética , Genoma Viral , História do Século XXI , Humanos , Mianmar , Filogenia , Estudos Soroepidemiológicos , Sorogrupo , Sequenciamento Completo do Genoma
15.
J Med Virol ; 93(11): 6073-6076, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34289153

RESUMO

The Cook Island government has made several efforts to ensure zero confirmed cases and transmission of COVID-19, especially among visiting travelers. However, the Cook Island ministry of health has to deal with the new strain of dengue fever outbreak, known as dengue fever type 2 (DEN-2), by adopting several measures to control its spread, especially in the affected parts of the subtropical country. This paper aims to describe the dengue fever response taken in Cook Island and suggest recommendations to control the risk of transmission in endemic parts of the world.


Assuntos
Dengue/epidemiologia , Surtos de Doenças , COVID-19/diagnóstico , COVID-19/epidemiologia , Dengue/diagnóstico , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/classificação , Doenças Endêmicas , Humanos , Controle de Mosquitos , Polinésia/epidemiologia , Sorogrupo
16.
PLoS Negl Trop Dis ; 15(7): e0009556, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252106

RESUMO

BACKGROUND: The introduction of the bacterium Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Evidence of a reduction in dengue case incidence following field releases of wMel-infected Ae. aegypti has been reported previously from a cluster randomised controlled trial in Indonesia, and quasi-experimental studies in Indonesia and northern Australia. METHODOLOGY/PRINCIPAL FINDINGS: Following pilot releases in 2015-2016 and a period of intensive community engagement, deployments of adult wMel-infected Ae. aegypti mosquitoes were conducted in Niterói, Brazil during 2017-2019. Deployments were phased across four release zones, with a total area of 83 km2 and a residential population of approximately 373,000. A quasi-experimental design was used to evaluate the effectiveness of wMel deployments in reducing dengue, chikungunya and Zika incidence. An untreated control zone was pre-defined, which was comparable to the intervention area in historical dengue trends. The wMel intervention effect was estimated by controlled interrupted time series analysis of monthly dengue, chikungunya and Zika case notifications to the public health surveillance system before, during and after releases, from release zones and the control zone. Three years after commencement of releases, wMel introgression into local Ae. aegypti populations was heterogeneous throughout Niterói, reaching a high prevalence (>80%) in the earliest release zone, and more moderate levels (prevalence 40-70%) elsewhere. Despite this spatial heterogeneity in entomological outcomes, the wMel intervention was associated with a 69% reduction in dengue incidence (95% confidence interval 54%, 79%), a 56% reduction in chikungunya incidence (95%CI 16%, 77%) and a 37% reduction in Zika incidence (95%CI 1%, 60%), in the aggregate release area compared with the pre-defined control area. This significant intervention effect on dengue was replicated across all four release zones, and in three of four zones for chikungunya, though not in individual release zones for Zika. CONCLUSIONS/SIGNIFICANCE: We demonstrate that wMel Wolbachia can be successfully introgressed into Ae. aegypti populations in a large and complex urban setting, and that a significant public health benefit from reduced incidence of Aedes-borne disease accrues even where the prevalence of wMel in local mosquito populations is moderate and spatially heterogeneous. These findings are consistent with the results of randomised and non-randomised field trials in Indonesia and northern Australia, and are supportive of the Wolbachia biocontrol method as a multivalent intervention against dengue, chikungunya and Zika.


Assuntos
Aedes/microbiologia , Aedes/virologia , Febre de Chikungunya/transmissão , Dengue/transmissão , Controle de Mosquitos/métodos , Wolbachia/fisiologia , Infecção por Zika virus/transmissão , Aedes/fisiologia , Animais , Brasil/epidemiologia , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/virologia , Vírus Chikungunya/fisiologia , Dengue/epidemiologia , Dengue/virologia , Vírus da Dengue/fisiologia , Feminino , Humanos , Incidência , Masculino , Mosquitos Vetores/microbiologia , Mosquitos Vetores/fisiologia , Mosquitos Vetores/virologia , Zika virus/fisiologia , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/virologia
17.
Parasit Vectors ; 14(1): 376, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34311776

RESUMO

BACKGROUND: Dengue fever is the most rapidly spreading mosquito-borne viral disease globally. More than 2.5 billion people live in dengue-endemic areas. Previous studies suggested an interrelationship between diabetes mellitus (DM) and dengue hemorrhagic fever (DHF). Conversely, glycolysis is a critical metabolic pathway for optimal dengue virus (DENV) replication. However, little is known concerning the effect of glucose on DENV replication in mosquitoes. In this study, we investigated the impact of glucose on DENV replication in mosquitoes Aedes aegypti. METHODS: Mosquitoes (Ae. aegypti UGAL/Rockefeller strain) were orally infected with DENV (serotype 2, 16681 strain) through infectious blood feeding. The DENV infection and transmission rates were determined by examining mosquito bodies and saliva, respectively, for DENV positivity at different time points after infection. In addition, a reverse genetic approach was applied by introducing double-stranded RNA against genes of interest into the mosquitoes to inhibit gene expression. RESULTS: Our data revealed a significant increase of DENV genome levels in mosquitoes consuming an infectious blood meal supplemented with glucose, suggesting that blood glucose is an important factor for viral replication. Interestingly, a significant increase of DENV E protein levels was detected in the saliva 4 days faster in mosquitoes that consumed infectious blood meals supplemented with glucose than in those consuming infectious blood meals alone. Furthermore, we perform RNAi to silence AKT or TOR and investigate the molecular mechanism regulating the glucose-mediated enhancement of viral replication. Silencing of AKT or TOR significantly reduced DENV titers in mosquitoes. CONCLUSIONS: This study suggested that blood glucose is beneficial to DENV replication and that it facilitates virus transmission in mosquitoes via AKT and TOR signaling. Therefore, our results strengthen our understanding of dengue fever and DM co-morbidity and possibly reveal new targets for specific antiviral therapies.


Assuntos
Aedes/virologia , Glicemia , Vírus da Dengue/efeitos dos fármacos , Dengue/transmissão , Mosquitos Vetores/virologia , Transdução de Sinais/efeitos dos fármacos , Animais , Dengue/virologia , Vírus da Dengue/fisiologia , Feminino , Humanos , Interferência de RNA , Sorogrupo , Replicação Viral/efeitos dos fármacos
18.
PLoS Negl Trop Dis ; 15(7): e0009641, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34329306

RESUMO

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.


Assuntos
Vírus da Dengue , Dengue/imunologia , Troca Materno-Fetal , Infecção por Zika virus/patologia , Zika virus , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/metabolismo , Antígenos Virais , Dengue/virologia , Feminino , Transmissão Vertical de Doenças Infecciosas , Placenta , Gravidez , RNA Viral , Replicação Viral
19.
PLoS Pathog ; 17(7): e1008603, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34310658

RESUMO

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with ß-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.


Assuntos
Dengue/patologia , Células Endoteliais/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas não Estruturais Virais/metabolismo , Animais , Permeabilidade Capilar/fisiologia , Adesão Celular/fisiologia , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/metabolismo , Humanos , Camundongos , Junções Íntimas/metabolismo
20.
Nat Commun ; 12(1): 3266, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075032

RESUMO

The epidemic emergence of relatively rare and geographically isolated flaviviruses adds to the ongoing disease burden of viruses such as dengue. Structural analysis is key to understand and combat these pathogens. Here, we present a chimeric platform based on an insect-specific flavivirus for the safe and rapid structural analysis of pathogenic viruses. We use this approach to resolve the architecture of two neurotropic viruses and a structure of dengue virus at 2.5 Å, the highest resolution for an enveloped virion. These reconstructions allow improved modelling of the stem region of the envelope protein, revealing two lipid-like ligands within highly conserved pockets. We show that these sites are essential for viral growth and important for viral maturation. These findings define a hallmark of flavivirus virions and a potential target for broad-spectrum antivirals and vaccine design. We anticipate the chimeric platform to be widely applicable for investigating flavivirus biology.


Assuntos
Infecções por Flavivirus/terapia , Flavivirus/ultraestrutura , Proteínas do Envelope Viral/ultraestrutura , Vírion/ultraestrutura , Aedes/virologia , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Linhagem Celular , Chlorocebus aethiops , Microscopia Crioeletrônica , Dengue/terapia , Dengue/virologia , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/farmacologia , Desenho de Fármacos , Flavivirus/efeitos dos fármacos , Flavivirus/imunologia , Flavivirus/patogenicidade , Infecções por Flavivirus/virologia , Humanos , Mesocricetus , Modelos Moleculares , Conformação Molecular , Mutagênese Sítio-Dirigida , Mutação Puntual , Células Vero , Proteínas do Envelope Viral/metabolismo , Vacinas Virais/farmacologia , Vacinas Virais/uso terapêutico , Vírion/efeitos dos fármacos , Vírion/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...