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1.
Artigo em Inglês | MEDLINE | ID: mdl-32130356

RESUMO

This review provides a general overview on the positivity and persistence of Zika virus (ZIKV) in female genital tract (FGT) of non-pregnant women and animals, as well as in cell cultures, and its influence on FGT health. We performed a systematic review based on the PRISMA statement to identify studies focused on "Zika virus" and "non-pregnant female" in PubMed, Embase, Scopus Scholar and Web of Knowledge databases of full-text papers and abstracts published in English, with no restrictions regarding the initial date of publication, up to August 2019. Our search terms yielded 625 records, that were 108 after removal of duplicates, leaving 517 items for title and abstract reviews. Of these, 475 did not meet the inclusion criteria, leaving 42 records for full-text review and resulting in the exclusion of 6 additional records. The remaining 36 met our inclusion criteria. Variations were observed regarding the presence and persistence of ZIKV in lower and upper genital samples. However, the FGT was the place in which ZIKV RNA has been detected, sometimes for relatively long periods, even after the clearance from blood and urine. In addition to the vagina and cervix, the endometrium, uterus and ovary (oocytes and follicles) could also be involved in persistent ZIKV infections. Further prospective studies are needed to assess the effect of ZIKV on FGT health.


Assuntos
Doenças dos Genitais Femininos/virologia , Genitália Feminina/virologia , Infecção por Zika virus/virologia , Zika virus/genética , Feminino , Humanos
2.
Viruses ; 12(2)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991674

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving the potential that previous exposure to DENV could alter clinical features of ZIKV infection. To investigate this, we performed a retrospective case-control study in which we compared Canadian travellers who had been infected with ZIKV and had serological findings indicating previous DENV or other flavivirus exposure (n = 16) to those without any previous exposure (n = 44). Patient samples were collected between February 2016 and September 2017 and submitted to Public Health Ontario for testing. ZIKV infection was determined using real-time RT-PCR and antibodies against DENV were identified by the plaque-reduction neutralization test. The mean time from symptom onset to sample collection was 5 days for both groups; the magnitude of viremia was not statistically different (Ct values: 35.6 vs. 34.9, p-value = 0.2). Clinical scores were also similar. Our findings indicate that previous DENV or other flavivirus exposure did not result in greater viremia or a higher illness score.


Assuntos
Anticorpos Antivirais/sangue , Vírus da Dengue/imunologia , Viremia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/isolamento & purificação , Adulto , Canadá , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Doença Relacionada a Viagens
3.
Int J Infect Dis ; 90: 104-110, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678190

RESUMO

OBJECTIVE: To evaluate the clinical, laboratory, and immune characteristics of Zika virus (ZIKV)-associated encephalitis in pediatric patients after the epidemic in Huila, southern Colombia. METHODS: A pediatric neuro-surveillance hospital study was conducted in a referral health center in southern Colombia, from October 2016 to October 2017. Cases of encephalitis were confirmed by nucleic acid amplification tests and serological methods in cerebrospinal fluid (CSF), plasma, and/or urine. Levels of six cytokines were evaluated by flow cytometry. Patients underwent daily clinical and laboratory follow-up. RESULTS: Twenty children with probable encephalitis were included for further studies and 16 of them were confirmed. Four cases of bacterial meningoencephalitis (Streptococcus pneumoniae, group B Streptococcus, Staphylococcus epidermidis, and Escherichia coli) and 12 cases of viral encephalitis were identified, six of them associated with ZIKV infection. Other viral encephalitis cases were caused by herpes viruses (n=3), enterovirus (n=2), and dengue virus type 2 (DENV-2; n=1) infections. ZIKV-associated encephalitis symptoms subsided faster than those of patients with encephalitis caused by other agents. CSF analysis revealed lymphocytic pleocytosis. Compared to healthy controls, children with ZIKV-associated encephalitis presented modest plasma interleukin (IL)-10 but not IL-2, IL-4, IL-6, interferon gamma (IFN-γ), or tumor necrosis factor alpha (TNF-α). Cytokine expression was differentially regulated, as dramatically elevated IL-6, IL-10, and IFN-γ levels were observed in CSF but not in paired plasma samples in one of the patients with ZIKV detectable in CSF. CONCLUSIONS: This study provides evidence that ZIKV is responsible for pediatric encephalitis in endemic areas, and the local presence of the virus may induce cephalic but not systemic expression of cytokines.


Assuntos
Encefalite Viral/virologia , Infecção por Zika virus/virologia , Adolescente , Criança , Pré-Escolar , Colômbia , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Encefalite Viral/diagnóstico , Encefalite Viral/imunologia , Feminino , Humanos , Lactente , Interferon gama/sangue , Interferon gama/líquido cefalorraquidiano , Masculino , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Zika virus/isolamento & purificação , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/imunologia
4.
Int J Infect Dis ; 92: 160-170, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31884173

RESUMO

OBJECTIVE: The re-emergence and spread of tropical viruses to new areas has raised a wave of concern worldwide. In order to treat patients at an early stage and prevent the diffusion of an outbreak, early diagnosis, and therefore fast and adequate detection, is needed. To this end, a multiplex reverse transcription real-time polymerase chain reaction TaqMan method was designed to detect Zika (ZIKV) and chikungunya (CHIKV) viruses simultaneously. METHODS: Two methods targeting different genome segments were selected from the literature for each virus. These were adapted for high genome coverage and combined in a four-plex assay that was thoroughly validated in-house. The SCREENED tool was used to evaluate the sequence coverage of the method. RESULTS: The full validation approach showed that the new four-plex method allows the specific and sensitive identification and discrimination of ZIKV and CHIKV in routine samples. The combination of two targets per virus allowing almost 100% coverage of about 500 genomes is shown for the first time. CONCLUSIONS: PCR is a reliable user-friendly technique that can be applied in remote areas. Such multiplex methods enable early and efficient diagnosis, leading to rapid treatment and effective confinement in outbreak cases. They may also serve as an aid for surveillance, and the full validation permits easy method-transfer allowing worldwide harmonization.


Assuntos
Febre de Chikungunya/diagnóstico , Vírus Chikungunya/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Infecção por Zika virus/diagnóstico , Zika virus/isolamento & purificação , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/virologia , Vírus Chikungunya/classificação , Vírus Chikungunya/genética , Surtos de Doenças , Humanos , Sensibilidade e Especificidade , Zika virus/classificação , Zika virus/genética , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/virologia
5.
Nat Commun ; 10(1): 5677, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831806

RESUMO

An important goal of the Zika virus (ZIKV) vaccine is to prevent a congenital syndrome in fetuses of pregnant women, but studies directly evaluating maternal vaccination for ZIKV are lacking. Here we report maternal vaccination using a live-attenuated ZIKV vaccine (3'UTR-∆10-LAV) in a pregnant mouse model. Maternal immunization with 3'UTR-∆10-LAV does not cause any adverse effects on pregnancy, fetal development, or offspring behavior. One maternal immunization fully protects dams against ZIKV infection and in utero transmission. Although neutralizing antibody alone is sufficient to prevent in utero transmission, a higher neutralizing titer is required to protect pregnant mice against in utero transmission than that required to protect non-pregnant mice against viral infection. The immunized dams transfer maternal antibodies to pups, which protect neonates against ZIKV infection. Notably, pregnancy weakens maternal T cell response to 3'UTR-∆10-LAV vaccination. Our results suggest that, besides vaccinating non-pregnant individuals, 3'UTR-∆10-LAV may also be considered for maternal vaccination.


Assuntos
Imunidade , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Vacinação , Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Gravidez , Linfócitos T/imunologia , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico , Vacinas Virais/efeitos adversos , Vacinas Virais/uso terapêutico , Zika virus/genética , Infecção por Zika virus/virologia
6.
Nat Commun ; 10(1): 5730, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844054

RESUMO

In 2015 and 2016, Zika virus (ZIKV) swept through dengue virus (DENV) endemic areas of Latin America. These viruses are of the same family, share a vector and may interact competitively or synergistically through human immune responses. We examine dengue incidence from Brazil and Colombia before, during, and after the Zika epidemic. We find evidence that dengue incidence was atypically low in 2017 in both countries. We investigate whether subnational Zika incidence is associated with changes in dengue incidence and find mixed results. Using simulations with multiple assumptions of interactions between DENV and ZIKV, we find cross-protection suppresses incidence of dengue following Zika outbreaks and low periods of dengue incidence are followed by resurgence. Our simulations suggest correlations in DENV and ZIKV reproduction numbers could complicate associations between ZIKV incidence and post-ZIKV DENV incidence and that periods of low dengue incidence are followed by large increases in dengue incidence.


Assuntos
Dengue/epidemiologia , Surtos de Doenças/estatística & dados numéricos , Doenças Endêmicas/estatística & dados numéricos , Infecção por Zika virus/epidemiologia , Anticorpos Antivirais/imunologia , Brasil/epidemiologia , Colômbia/epidemiologia , Reações Cruzadas/imunologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Monitoramento Epidemiológico , Humanos , Incidência , Modelos de Interação Espacial , Análise de Regressão , Zika virus/imunologia , Zika virus/patogenicidade , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
7.
BMC Infect Dis ; 19(1): 1081, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878895

RESUMO

BACKGROUND: The European Commission (EC) Horizon 2020 (H2020)-funded ZIKAlliance Consortium designed a multicentre study including pregnant women (PW), children (CH) and natural history (NH) cohorts. Clinical sites were selected over a wide geographic range within Latin America and the Caribbean, taking into account the dynamic course of the ZIKV epidemic. METHODS: Recruitment to the PW cohort will take place in antenatal care clinics. PW will be enrolled regardless of symptoms and followed over the course of pregnancy, approximately every 4 weeks. PW will be revisited at delivery (or after miscarriage/abortion) to assess birth outcomes, including microcephaly and other congenital abnormalities according to the evolving definition of congenital Zika syndrome (CZS). After birth, children will be followed for 2 years in the CH cohort. Follow-up visits are scheduled at ages 1-3, 4-6, 12, and 24 months to assess neurocognitive and developmental milestones. In addition, a NH cohort for the characterization of symptomatic rash/fever illness was designed, including follow-up to capture persisting health problems. Blood, urine, and other biological materials will be collected, and tested for ZIKV and other relevant arboviral diseases (dengue, chikungunya, yellow fever) using RT-PCR or serological methods. A virtual, decentralized biobank will be created. Reciprocal clinical monitoring has been established between partner sites. Substudies of ZIKV seroprevalence, transmission clustering, disabilities and health economics, viral kinetics, the potential role of antibody enhancement, and co-infections will be linked to the cohort studies. DISCUSSION: Results of these large cohort studies will provide better risk estimates for birth defects and other developmental abnormalities associated with ZIKV infection including possible co-factors for the variability of risk estimates between other countries and regions. Additional outcomes include incidence and transmission estimates of ZIKV during and after pregnancy, characterization of short and long-term clinical course following infection and viral kinetics of ZIKV. STUDY REGISTRATIONS: clinicaltrials.gov NCT03188731 (PW cohort), June 15, 2017; clinicaltrials.gov NCT03393286 (CH cohort), January 8, 2018; clinicaltrials.gov NCT03204409 (NH cohort), July 2, 2017.


Assuntos
Arbovirus/isolamento & purificação , Microcefalia/complicações , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia , Zika virus/imunologia , Adulto , Arbovirus/genética , Região do Caribe/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Coinfecção , Feminino , Seguimentos , Humanos , Lactente , América Latina/epidemiologia , Microcefalia/epidemiologia , Microcefalia/virologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Cuidado Pré-Natal , Estudos Prospectivos , Risco , Estudos Soroepidemiológicos , Zika virus/isolamento & purificação , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
8.
BMC Infect Dis ; 19(1): 963, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718580

RESUMO

BACKGROUND: Colombia was the second most affected country during the American Zika virus (ZIKV) epidemic, with over 109,000 reported cases. Despite the scale of the outbreak, limited genomic sequence data were available from Colombia. We sought to sequence additional samples and use genomic epidemiology to describe ZIKV dynamics in Colombia. METHODS: We sequenced ZIKV genomes directly from clinical diagnostic specimens and infected Aedes aegypti samples selected to cover the temporal and geographic breadth of the Colombian outbreak. We performed phylogeographic analysis of these genomes, along with other publicly-available ZIKV genomes from the Americas, to estimate the frequency and timing of ZIKV introductions to Colombia. RESULTS: We attempted PCR amplification on 184 samples; 19 samples amplified sufficiently to perform sequencing. Of these, 8 samples yielded sequences with at least 50% coverage. Our phylogeographic reconstruction indicates two separate introductions of ZIKV to Colombia, one of which was previously unrecognized. We find that ZIKV was first introduced to Colombia in February 2015 (95%CI: Jan 2015 - Apr 2015), corresponding to 5 to 8 months of cryptic ZIKV transmission prior to confirmation in September 2015. Despite the presence of multiple introductions, we find that the majority of Colombian ZIKV diversity descends from a single introduction. We find evidence for movement of ZIKV from Colombia into bordering countries, including Peru, Ecuador, Panama, and Venezuela. CONCLUSIONS: Similarly to genomic epidemiological studies of ZIKV dynamics in other countries, we find that ZIKV circulated cryptically in Colombia. More accurately dating when ZIKV was circulating refines our definition of the population at risk. Additionally, our finding that the majority of ZIKV transmission within Colombia was attributable to transmission between individuals, rather than repeated travel-related importations, indicates that improved detection and control might have succeeded in limiting the scale of the outbreak within Colombia.


Assuntos
Genoma Viral , Infecção por Zika virus/virologia , Zika virus/genética , Aedes/virologia , Animais , Colômbia/epidemiologia , Surtos de Doenças , Evolução Molecular , Variação Genética , Humanos , Filogenia , Filogeografia , Zika virus/classificação , Zika virus/isolamento & purificação , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/transmissão
9.
BMC Infect Dis ; 19(1): 986, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752731

RESUMO

BACKGROUND: Zika virus (ZIKV) infection gained public health concern after the 2015 outbreak in Brazil, when microcephaly rates increased in babies born from infected mothers. It was demonstrated that ZIKV causes a congenital Zika virus syndrome, including various alterations in the development of the central nervous system. Although the infection of cells from the nervous system has been well documented, less is known in respect of ZIKV ability to infect immune cells. Herein, we investigated if peripheral blood mononuclear cells (PBMCs), freshly-isolated from healthy donors, could be infected by ZIKV. METHODS: PBMCs from healthy donors were isolated and cultured in medium with ZIKV strain Rio-U1 (MOI = 0.1). Infection was analyzed by RT-qPCR and flow cytometry. RESULTS: We detected the ZIKV RNA in PBMCs from all donors by RT-qPCR analysis. The detection of viral antigens by flow cytometry revealed that PBMC from more than 50% the donors were infected by ZIKV, with CD3+CD4+ T cells, CD3-CD19+ B cells and CD3+CD8+ T cells being, respectively, the most frequently infected subpopulations, followed by CD14+ monocytes. Additionally, we observed high variability in PBMC infection rates among different donors, either by numbers or type infected cells. CONCLUSIONS: These findings raise the hypothesis that PBMCs can act as a reservoir of the virus, which may facilitate viral dissemination to different organs, including immune-privileged sites.


Assuntos
Leucócitos Mononucleares/virologia , Infecção por Zika virus/virologia , Zika virus/isolamento & purificação , Antígenos CD19/genética , Antígenos CD19/imunologia , Linfócitos B/imunologia , Brasil , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Humanos , Leucócitos Mononucleares/imunologia , Monócitos/imunologia , Monócitos/virologia , Reação em Cadeia da Polimerase em Tempo Real , Zika virus/genética , Zika virus/fisiologia , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/genética , Infecção por Zika virus/imunologia
10.
Emerg Microbes Infect ; 8(1): 1668-1678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31735122

RESUMO

Since its emergence in Yap Island in 2007, Zika virus (ZIKV) has affected all continents except Europe. Despite the hundreds of cases imported to European countries from ZIKV-infested regions, no local cases have been reported in localities where the ZIKV-competent mosquito Aedes albopictus is well established. Here we analysed the vector competence of European Aedes (aegypti and albopictus) mosquitoes to different genotypes of ZIKV. We demonstrate that Ae. albopictus from France was less susceptible to the Asian ZIKV than to the African ZIKV. Critically we show that effective crossing of anatomical barriers (midgut and salivary glands) after an infectious blood meal depends on a viral load threshold to trigger: (i) viral dissemination from the midgut to infect mosquito internal organs and (ii) viral transmission from the saliva to infect a vertebrate host. A viral load in body ≥4800 viral copies triggered dissemination and ≥12,000 viral copies set out transmission. Only 27.3% and 18.2% of Ae. albopictus Montpellier mosquitoes meet respectively these two criteria. Collectively, these compelling results stress the poor ability of Ae. albopictus to sustain a local transmission of ZIKV in Europe and provide a promising tool to evaluate the risk of ZIKV transmission in future outbreaks.


Assuntos
Aedes/fisiologia , Mosquitos Vetores/fisiologia , Infecção por Zika virus/transmissão , Zika virus/fisiologia , Aedes/genética , Aedes/virologia , Animais , Europa (Continente) , Feminino , Humanos , Mosquitos Vetores/genética , Mosquitos Vetores/virologia , Carga Viral , Zika virus/genética , Infecção por Zika virus/virologia
11.
Arch Virol ; 164(12): 3027-3034, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31598845

RESUMO

The rate of evolution of viral genomes is a fundamental parameter for understanding the origin and spread of epidemics. For instance, molecular dating is one of the many practical outcomes of evolutionary rate estimation. In this sense, the rate of evolution of ZIKV merits attention, because it has been shown to be higher than the average rate reported for other flaviviruses. It has been hypothesized that the higher rate of ZIKV evolution is due to a bias related to the analysis of sequences collected within a short time range, which would increase the chance of sampling slightly deleterious nucleotide polymorphisms. To investigate this hypothesis, we assembled datasets with different ranges of sampling times and also decomposed the ZIKV evolutionary rate into synonymous and non-synonymous rates. Our results demonstrated that the rate of ZIKV evolution is time dependent and that the observed increase in short-term rates is largely accounted for by a higher non-synonymous rate, suggesting the presence of slightly deleterious variants not yet eliminated by purifying selection. On the other hand, we show that synonymous rates were less impacted by the range of sampling times, generating timescales with reduced uncertainty. We conclude that, for inferring the ZIKV timescale and reconstructing the history of epidemics, synonymous changes are the most appropriate substitution type to be examined. We were able to obtain ZIKV divergence times that were time independent and exhibited greater precision than previous estimates. This observation should also hold for other serially sampled fast-evolving pathogens with evidence of time dependence of evolutionary rates.


Assuntos
Evolução Molecular , Infecção por Zika virus/virologia , Zika virus/genética , Genoma Viral , Humanos , Cinética , Filogenia , Zika virus/química , Zika virus/classificação , Zika virus/isolamento & purificação
12.
Nat Commun ; 10(1): 4606, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601808

RESUMO

The current leading Zika vaccine candidates in clinical testing are based on live or killed virus platforms, which have safety issues, especially in pregnant women. Zika subunit vaccines, however, have shown poor performance in preclinical studies, most likely because the antigens tested do not display critical quaternary structure epitopes present on Zika E protein homodimers that cover the surface of the virus. Here, we produce stable recombinant E protein homodimers that are recognized by strongly neutralizing Zika specific monoclonal antibodies. In mice, the dimeric antigen stimulate strongly neutralizing antibodies that target epitopes that are similar to epitopes recognized by human antibodies following natural Zika virus infection. The monomer antigen stimulates low levels of E-domain III targeting neutralizing antibodies. In a Zika challenge model, only E dimer antigen stimulates protective antibodies, not the monomer. These results highlight the importance of mimicking the highly structured flavivirus surface when designing subunit vaccines.


Assuntos
Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Vacinas Virais/imunologia , Zika virus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Epitopos/imunologia , Feminino , Humanos , Camundongos Endogâmicos C57BL , Multimerização Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Células Vero , Proteínas do Envelope Viral/genética , Zika virus/genética , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
13.
PLoS Negl Trop Dis ; 13(10): e0007451, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31584946

RESUMO

INTRODUCTION: Epidemic forecasting and prediction tools have the potential to provide actionable information in the midst of emerging epidemics. While numerous predictive studies were published during the 2016-2017 Zika Virus (ZIKV) pandemic, it remains unknown how timely, reproducible, and actionable the information produced by these studies was. METHODS: To improve the functional use of mathematical modeling in support of future infectious disease outbreaks, we conducted a systematic review of all ZIKV prediction studies published during the recent ZIKV pandemic using the PRISMA guidelines. Using MEDLINE, EMBASE, and grey literature review, we identified studies that forecasted, predicted, or simulated ecological or epidemiological phenomena related to the Zika pandemic that were published as of March 01, 2017. Eligible studies underwent evaluation of objectives, data sources, methods, timeliness, reproducibility, accessibility, and clarity by independent reviewers. RESULTS: 2034 studies were identified, of which n = 73 met the eligibility criteria. Spatial spread, R0 (basic reproductive number), and epidemic dynamics were most commonly predicted, with few studies predicting Guillain-Barré Syndrome burden (4%), sexual transmission risk (4%), and intervention impact (4%). Most studies specifically examined populations in the Americas (52%), with few African-specific studies (4%). Case count (67%), vector (41%), and demographic data (37%) were the most common data sources. Real-time internet data and pathogen genomic information were used in 7% and 0% of studies, respectively, and social science and behavioral data were typically absent in modeling efforts. Deterministic models were favored over stochastic approaches. Forty percent of studies made model data entirely available, 29% provided all relevant model code, 43% presented uncertainty in all predictions, and 54% provided sufficient methodological detail to allow complete reproducibility. Fifty-one percent of predictions were published after the epidemic peak in the Americas. While the use of preprints improved the accessibility of ZIKV predictions by a median of 119 days sooner than journal publication dates, they were used in only 30% of studies. CONCLUSIONS: Many ZIKV predictions were published during the 2016-2017 pandemic. The accessibility, reproducibility, timeliness, and incorporation of uncertainty in these published predictions varied and indicates there is substantial room for improvement. To enhance the utility of analytical tools for outbreak response it is essential to improve the sharing of model data, code, and preprints for future outbreaks, epidemics, and pandemics.


Assuntos
Previsões , Saúde Pública , Infecção por Zika virus/epidemiologia , Zika virus , Bases de Dados Factuais , Surtos de Doenças/estatística & dados numéricos , Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/virologia , Humanos , Modelos Estatísticos , Modelos Teóricos , Pandemias , Reprodutibilidade dos Testes , Infecção por Zika virus/virologia
14.
EBioMedicine ; 47: 269-283, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31501074

RESUMO

BACKGROUND: Flaviviruses such as Zika cause sporadic pandemic outbreaks worldwide. There is an urgent need for anti-Zika virus (ZIKV) drugs to prevent mother-to-child transmission of ZIKV, new infections in high-risk populations, and the infection of medical personnel in ZIKV-affected areas. METHODS: Here, we showed that the small molecule 6-deoxyglucose-diphyllin (DGP) exhibited anti-ZIKV activity both in vitro and in vivo. DGP potently blocked ZIKV infection across all human and monkey cell lines tested. DGP also displayed broad-spectrum antiviral activity against other flaviviruses. Remarkably, DGP prevented ZIKV-induced mortality in mice lacking the type I interferon receptor (Ifnar1-/-). Cellular and virological experiments showed that DGP blocked ZIKV at a pre-fusion step or during fusion, which prevented the delivery of viral contents into the cytosol of the target cell. Mechanistic studies revealed that DGP prevented the acidification of endosomal/lysosomal compartments in target cells, thus inhibiting ZIKV fusion with cellular membranes and infection. FINDINGS: These investigations revealed that DGP inhibits ZIKV infection in vitro and in vivo. INTERPRETATION: The small molecule DGP has great potential for preclinical studies and the ability to inhibit ZIKV infection in humans.


Assuntos
Antivirais/farmacologia , Benzodioxóis/farmacologia , Lignanas/farmacologia , Zika virus/efeitos dos fármacos , Animais , Antivirais/química , Benzodioxóis/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Endossomos/virologia , Flavivirus/efeitos dos fármacos , Glicosilação , Humanos , Lignanas/química , Camundongos , Camundongos Knockout , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peso Molecular , Receptor de Interferon alfa e beta/deficiência , Células Vero , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/virologia
15.
Nat Commun ; 10(1): 4430, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562326

RESUMO

Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. However the virus journey, from the bloodstream to tissues through a mature endothelium, remains unclear. Here, we show that ZIKV-infected monocytes represent suitable carriers for viral dissemination to the CNS using human primary monocytes, cerebral organoids derived from embryonic stem cells, organotypic mouse cerebellar slices, a xenotypic human-zebrafish model, and human fetus brain samples. We find that ZIKV-exposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia. This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. Together, our data show that ZIKV manipulates the monocyte adhesive properties and enhances monocyte transmigration and viral dissemination to neural cells. Monocyte transmigration may represent an important mechanism required for viral tissue invasion and persistence that could be specifically targeted for therapeutic intervention.


Assuntos
Moléculas de Adesão Celular/metabolismo , Monócitos/metabolismo , Monócitos/virologia , Neurônios/metabolismo , Migração Transendotelial e Transepitelial/fisiologia , Infecção por Zika virus/metabolismo , Zika virus/fisiologia , Zika virus/patogenicidade , Animais , Adesão Celular/fisiologia , Sobrevivência Celular , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Cerebelo/patologia , Cerebelo/virologia , Modelos Animais de Doenças , Células-Tronco Embrionárias , Endotélio/virologia , Feminino , Humanos , Monócitos/patologia , Neurônios/patologia , Neurônios/virologia , Organoides/metabolismo , Organoides/patologia , Peixe-Zebra , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
16.
PLoS Negl Trop Dis ; 13(9): e0007747, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539394

RESUMO

BACKGROUND: Zika virus (ZIKV) and Dengue virus (DENV) are often co-endemic. The high protein-sequence homology of flaviviruses renders IgG induced by and directed against them highly cross-reactive against their antigen(s), as observed on a large set of sera, leading to poorly reliable sero-diagnosis. METHODS: We selected Domain III of the ZIKV Envelope (ZEDIII) sequence, which is virus specific. This recombinant domain was expressed and purified for the specific detection of ZEDIII-induced IgG by ELISA from ZIKV-RT-PCR-positive, ZIKV-IgM-positive, flavivirus-positive but ZIKV-negative, or flavivirus-negative sera. We also assessed the reactivity of ZEDIII-specific human antibodies against EDIII of DENV serotype 4 (D4EDIII) as a specific control. Sera from ZEDIII-immunized mice were also tested. RESULTS: Cross-reactivity of IgG from 5,600 sera against total inactivated DENV or ZIKV was high (71.0% [69.1; 72.2]), whereas the specificity and sensitivity calculated using a representative cohort (242 sera) reached 90% [84.0; 95.8] and 92% [84.5; 99.5], respectively, using a ZEDIII-based ELISA. Moreover, purified human IgG against D2EDIII or D4EDIII did not bind to ZEDIII and we observed no D4EDIII reactivity with ZIKV-induced mouse polyclonal IgGs. CONCLUSIONS: We developed a ZEDIII-based ELISA that can discriminate between past or current DENV and ZIKV infections, allowing the detection of a serological scar from other flaviviruses. This could be used to confirm exposure of pregnant women or to follow the spread of an endemic disease.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Infecção por Zika virus/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Dengue/diagnóstico , Dengue/imunologia , Vírus da Dengue/imunologia , Feminino , Humanos , Imunoglobulina G , Lactente , Masculino , Camundongos , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Zika virus/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
17.
Nat Commun ; 10(1): 4344, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554802

RESUMO

Innate immune responses to Zika virus (ZIKV) are dampened in the lower female reproductive tract (LFRT) compared to other tissues, but the mechanism that underlies this vulnerability is poorly understood. Using tissues from uninfected and vaginally ZIKV-infected macaques and mice, we show that low basal expression of RNA-sensing pattern recognition receptors (PRRs), or their co-receptors, in the LFRT contributes to high viral replication in this tissue. In the LFRT, ZIKV sensing provides limited protection against viral replication, and the sensors are also minimally induced after vaginal infection. While IFNα/ß receptor signaling offers minimal protection in the LFRT, it is required to prevent dissemination of ZIKV to other tissues, including the upper FRT. Our findings support a role for RNA-sensing PRRs in the dampened innate immunity against ZIKV in the LFRT compared to other tissues and underlie potential implications for systemic dissemination upon heterosexual transmission of ZIKV in women.


Assuntos
Genitália Feminina/imunologia , Imunidade Inata/imunologia , RNA Viral/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Feminino , Regulação Viral da Expressão Gênica , Genitália Feminina/metabolismo , Genitália Feminina/virologia , Humanos , Imunidade Inata/genética , Macaca mulatta , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Viral/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Receptor de Interferon alfa e beta/metabolismo , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismo , Vagina/imunologia , Vagina/metabolismo , Vagina/virologia , Replicação Viral/genética , Replicação Viral/imunologia , Zika virus/genética , Zika virus/fisiologia , Infecção por Zika virus/genética , Infecção por Zika virus/virologia
18.
PLoS Negl Trop Dis ; 13(9): e0007695, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31527907

RESUMO

Zika virus infection is associated with the development of Guillain-Barré syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients.


Assuntos
Gangliosídeos/imunologia , Síndrome de Guillain-Barré/sangue , Infecção por Zika virus/sangue , Zika virus/fisiologia , Autoanticorpos , Brasil , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/virologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/virologia
19.
Int J Infect Dis ; 88: 49-59, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499212

RESUMO

INTRODUCTION: While death due to Zika virus (ZIKV) infection has been described, reports of fatal cases have been infrequent and no systematic reviews on the subject have been published. METHODS: A systematic review of the literature in four databases was performed to assess fatal outcomes of postnatal ZIKV infection and the available evidence that links ZIKV infection to death. RESULTS: Three hundred and eleven articles were retrieved; 20 of them were epidemiological reports from surveillance agencies and ministries of health. After screening by abstract and title, 59 articles were selected for full-text assessment. Of these, 35 were excluded (with reasons) and 24 were finally included for qualitative analysis. A total of 51 reported deaths associated with ZIKV infection in nine countries were identified. The majority of cases (56.9%) were not related to Guillain-Barré syndrome. Cases from three countries accounted for 67.6% of the deaths. ZIKV infection was laboratory-confirmed in the majority of cases (64.7%). DISCUSSION: ZIKV was not considered to be a dangerous, and much less a lethal pathogen, until very recently. However, an increasing number of fatalities have been published in the literature since the first death was reported in 2016. Additional research is needed to elucidate factors that may mediate the pathogenesis of severe, atypical, and fatal disease.


Assuntos
Infecção por Zika virus/epidemiologia , Zika virus/fisiologia , Américas/epidemiologia , Humanos , Infecção por Zika virus/mortalidade , Infecção por Zika virus/virologia
20.
Genomics Proteomics Bioinformatics ; 17(3): 319-331, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31494268

RESUMO

Proteins usually associate with other molecules physically to execute their functions. Identifying these interactions is important for the functional analysis of proteins. Previously, we reported the parallel analysis of translated ORFs (PLATO) to couple ribosome display of full-length ORFs with affinity enrichment of mRNA/protein/ribosome complexes for the "bait" molecules, followed by the deep sequencing analysis of mRNA. However, the sample processing, from extraction of precipitated mRNA to generation of DNA libraries, includes numerous steps, which is tedious and may cause the loss of materials. Barcoded PLATO (PLATO-BC), an improved platform was further developed to test its application for protein interaction discovery. In this report, we tested the antisera-antigen interaction using serum samples from patients with inclusion body myositis (IBM). Tripartite motif containing 21 (TRIM21) was identified as a potentially new IBM autoantigen. We also expanded the application of PLATO-BC to identify protein interactions for JQ1, single ubiquitin peptide, and NS5 protein of Zika virus. From PLATO-BC analyses, we identified new protein interactions for these "bait" molecules. We demonstrate that Ewing sarcoma breakpoint region 1 (EWSR1) binds to JQ1 and their interactions may interrupt the EWSR1 association with acetylated histone H4. RIO kinase 3 (RIOK3), a newly identified ubiquitin-binding protein, is preferentially associated with K63-ubiquitin chain. We also find that Zika NS5 protein interacts with two previously unreported host proteins, par-3 family cell polarity regulator (PARD3) and chromosome 19 open reading frame 53 (C19orf53), whose attenuated expression benefits the replication of Zika virus. These results further demonstrate that PLATO-BC is capable of identifying novel protein interactions for various types of "bait" molecules.


Assuntos
Fases de Leitura Aberta/genética , Mapeamento de Interação de Proteínas/métodos , Anticorpos/metabolismo , Células HEK293 , Humanos , Peptídeos/metabolismo , Ligação Proteica , Ubiquitina/metabolismo , Zika virus/fisiologia , Infecção por Zika virus/genética , Infecção por Zika virus/virologia
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