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1.
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
2.
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
3.
PLoS Negl Trop Dis ; 13(12): e0007978, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31877200

RESUMO

The 2015-2017 epidemics of Zika virus (ZIKV) in the Americas caused widespread infection, followed by protective immunity. The timing and burden of the next Zika virus outbreak remains unclear. We used an agent-based model to simulate the dynamics of age-specific immunity to ZIKV, and predict the future age-specific risk using data from Managua, Nicaragua. We also investigated the potential impact of a ZIKV vaccine. Assuming lifelong immunity, the risk of a ZIKV outbreak will remain low until 2035 and rise above 50% in 2047. The imbalance in age-specific immunity implies that people in the 15-29 age range will be at highest risk of infection during the next ZIKV outbreak, increasing the expected number of congenital abnormalities. ZIKV vaccine development and licensure are urgent to attain the maximum benefit in reducing the population-level risk of infection and the risk of adverse congenital outcomes. This urgency increases if immunity is not lifelong.


Assuntos
Fatores Etários , Efeitos Psicossociais da Doença , Surtos de Doenças , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Simulação por Computador , Feminino , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Nicarágua/epidemiologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Adulto Jovem , Infecção por Zika virus/prevenção & controle
4.
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
5.
J Immunol Res ; 2019: 7239347, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565661

RESUMO

Zika virus (ZIKV), an emerging mosquito-borne flavivirus, has quickly spread in many regions around the world where dengue virus (DENV) is endemic. This represents a major health concern, given the high homology between these two viruses, which can result in cross-reactivity. The aim of this study was to determine the cross-reacting antibody response of the IgM and IgG classes against the recombinant envelope protein of ZIKV (rE-ZIKV) in sera from patients with acute-phase infection of different clinical forms of dengue, i.e., dengue fever (DF) and dengue hemorrhagic fever (DHF) (before the arrival of ZIKV in Mexico 2010), as well as acute-phase sera of ZIKV patients, together with the implications in neutralization and antibody-dependent enhancement. Differences in IgM responses were observed in a number of DF and DHF patients whose sera cross-reacted with the rE-ZIK antigen, with 42% recognition between acute-phase DHF and ZIKV but 27% recognition between DF and ZIKV. Regarding IgG antibodies, 71.5% from the DF group showed cross-reactivity to rE-ZIKV in contrast with 50% and only 25% of DHF and ZIKV serum samples, respectively, which specifically recognized the homologous antigen. The DHF group showed more enhancement of ZIKV infection of FCRγ-expressing cells compared to the DF group. Furthermore, the DHF group also showed a higher cross-neutralizing ability than that of DF. This is the first report where DF and DHF serum samples were evaluated for cross-reactivity against Zika protein and ZIKV. Furthermore, DENV serum samples cross-protect against ZIKV through neutralizing antibodies but at the same time mediate antibody-dependent enhancement in the sequential ZIKV infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Reações Cruzadas/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Adolescente , Adulto , Linhagem Celular , Criança , Pré-Escolar , Dengue/epidemiologia , Vírus da Dengue/genética , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Testes de Neutralização , Vigilância da População , Adulto Jovem , Zika virus/genética , Infecção por Zika virus/epidemiologia
6.
Cell Host Microbe ; 26(4): 493-503.e6, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600501

RESUMO

14-3-3 protein family members facilitate the translocation of RIG-I-like receptors (RLRs) to organelles that mediate downstream RLR signaling, leading to interferon production. 14-3-3ϵ promotes the cytosolic-to-mitochondrial translocation of RIG-I, while 14-3-3η facilitates MDA5 translocation to mitochondria. We show that the NS3 protein of Zika virus (ZIKV) antagonizes antiviral gene induction by RIG-I and MDA5 by binding to and sequestering the scaffold proteins 14-3-3ϵ and 14-3-3η. 14-3-3-binding is mediated by a negatively charged RLDP motif in NS3 that is conserved in ZIKV strains of African and Asian lineages and is similar to the one found in dengue and West Nile viruses. ZIKV NS3 is sufficient to inhibit the RLR-14-3-3ϵ/η interaction and to suppress antiviral signaling. Mutational perturbation of 14-3-3ϵ/η binding in a recombinant ZIKV leads to enhanced innate immune responses and impaired growth kinetics. Our study provides molecular understanding of immune evasion functions of ZIKV, which may guide vaccine and anti-flaviviral therapy development.


Assuntos
Proteínas 14-3-3/metabolismo , Evasão da Resposta Imune/imunologia , Peptídeo Hidrolases/metabolismo , Proteínas Virais/metabolismo , Infecção por Zika virus/imunologia , Zika virus/imunologia , Células A549 , Animais , Linhagem Celular , Proteína DEAD-box 58/antagonistas & inibidores , Células HEK293 , Células HeLa , Humanos , Imunidade Inata/imunologia , Helicase IFIH1 Induzida por Interferon/antagonistas & inibidores , Interferon beta/imunologia , Mitocôndrias/metabolismo , Peptídeo Hidrolases/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Células Vero , Proteínas Virais/genética , Zika virus/genética
7.
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
8.
PLoS Negl Trop Dis ; 13(10): e0007763, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589611

RESUMO

Defining cases of Zika virus (ZIKV) infection is a critical challenge for epidemiological research. Due to ZIKV's overlapping clinical features and potential immunologic cross-reactivity with other flaviviruses and the current lack of an optimal ZIKV-specific diagnostic assay, varying approaches for identifying ZIKV infections have been employed to date. This paper presents the laboratory results and diagnostic criteria developed by the Microcephaly Epidemic Research Group for defining cases of maternal ZIKV infection in a cohort of pregnant women with rash (N = 694) recruited during the declining 2015-2017 epidemic in northeast Brazil. For this investigation, we tested maternal sera for ZIKV by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Immunoglobulin (Ig) M and IgG3 enzyme-linked immunosorbent assays (ELISAs), and Plaque Reduction Neutralization Test (PRNT50). Overall, 23.8% of participants tested positive by qRT-PCR during pregnancy (range of detection: 0-72 days after rash onset). However, the inter-assay concordance was lower than expected. Among women with qRT-PCR-confirmed ZIKV and further testing, only 10.1% had positive IgM tests within 90 days of rash, and only 48.5% had ZIKV-specific PRNT50 titers ≥20 within 1 year of rash. Given the complexity of these data, we convened a panel of experts to propose an algorithm for identifying ZIKV infections in pregnancy based on all available lines of evidence. When the diagnostic algorithm was applied to the cohort, 26.9% of participants were classified as having robust evidence of a ZIKV infection during pregnancy, 4.0% as having moderate evidence, 13.3% as having limited evidence of a ZIKV infection but with uncertain timing, and 19.5% as having evidence of an unspecified flavivirus infection before or during pregnancy. Our findings suggest that integrating longitudinal data from nucleic acid and serologic testing may enhance diagnostic sensitivity and underscore the need for an on-going dialogue regarding the optimization of strategies for defining cases of ZIKV in research.


Assuntos
Exantema/epidemiologia , Exantema/imunologia , Complicações na Gravidez/imunologia , Infecção por Zika virus/complicações , Infecção por Zika virus/imunologia , Algoritmos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Brasil/epidemiologia , Estudos de Coortes , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Exantema/diagnóstico , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Testes de Neutralização , Gravidez , Zika virus/imunologia , Infecção por Zika virus/epidemiologia
9.
BMC Infect Dis ; 19(1): 884, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646973

RESUMO

BACKGROUND: We recently conducted a serosurvey of newly arrived workers in Taiwan from four Southeast Asian countries which revealed that 1% of the migrant workers had laboratory-confirmed recent Zika virus (ZIKV) infection. Taiwan, where Aedes mosquitoes are prevalent, has a close relationship with Southeast Asian countries. Up to now, 21 imported cases of ZIKV infection have been reported in Taiwan, but there has been no confirmed indigenous case. The aim of this serosurvey was to assess whether there was unrecognized ZIKV infections in Taiwan. METHODS: A total of 212 serum samples collected in a cross-sectional seroepidemiologic study conducted during the end of the 2015 dengue epidemic in Tainan, Taiwan, were analyzed. Anti-ZIKV IgM and IgG were tested using commercial enzyme-linked immunosorbent assays (ELISAs). Plaque reduction neutralization tests (PRNTs) for ZIKV and four dengue virus (DENV) serotypes were performed for samples with positive anti-ZIKV antibodies. A confirmed case of ZIKV infection was defined by ZIKV PRNT90 titer ratio ≥ 4 compared to four DENV serotypes. RESULTS: The mean age of the 212 participants was 54.0 years (standard deviation 13.7 years), and female was predominant (67.0%). Anti-ZIKV IgM and IgG were detected in 0 (0%) and 9 (4.2%) of the 212 participants, respectively. For the 9 samples with anti-ZIKV IgG, only 1 sample had 4 times higher ZIKV PRNT90 titers compared to PRNT90 titers against four dengue virus serotypes; this individual denied having traveled abroad. CONCLUSIONS: The results suggest that undetected indigenous ZIKV transmission might have occurred in Taiwan. The findings also suggest that the threat of epidemic transmission of ZIKV in Taiwan does exist due to extremely low-level of herd immunity. Our study also indicates that serological tests for ZIKV-specific IgG remain a big challenge due to cross-reactivity, even in dengue non-endemic countries.


Assuntos
Infecção por Zika virus/epidemiologia , Adulto , Idoso , Anticorpos Anti-Idiotípicos/sangue , Reações Cruzadas , Estudos Transversais , Dengue/epidemiologia , Dengue/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Estudos Soroepidemiológicos , Testes Sorológicos/métodos , Taiwan/epidemiologia , Infecção por Zika virus/imunologia
10.
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
11.
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
12.
Nat Commun ; 10(1): 4316, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541110

RESUMO

Zika virus (ZIKV) and dengue virus (DENV) are co-endemic in many parts of the world, but the impact of ZIKV infection on subsequent DENV infection is not well understood. Here we show in rhesus macaques that the time elapsed after ZIKV infection affects the immune response to DENV infection. We show that previous ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV. The time interval between ZIKV and subsequent DENV infection further affects the immune response. A mid-convalescent period of 10 months after ZIKV infection results in higher and more durable antibody and T cell responses to DENV infection than a short period of 2 months. In contrast, previous ZIKV infection does not affect DENV viremia or pro-inflammatory status. Collectively, we find no evidence of a detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the implementation of ZIKV vaccines that could also boost immunity against future DENV epidemics.


Assuntos
Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Linfócitos T/imunologia , Infecção por Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linhagem Celular , Reações Cruzadas/imunologia , Citocinas/metabolismo , Vírus da Dengue/imunologia , Humanos , Imunidade , Imunidade Celular , Macaca mulatta/imunologia , Masculino , Fatores de Tempo , Viremia , Zika virus/imunologia
13.
BMC Res Notes ; 12(1): 469, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366379

RESUMO

OBJECTIVE: Zika virus (ZIKV) has emerged as an important health problem worldwide. The aim of this study was to investigate the occurrence, geographical distribution and trend of immunoglobulin M (IgM) antibodies against ZIKV between 2009 and 2015 in Mozambique. RESULTS: The median age of participants was 3 years [interquartile range (IQR): 1.0-6.0 years)] and 56.5% (480/850) of them were male. Of the 850 samples, 42 (4.9%) were positive for IgM antibodies against ZIKV. Positive samples were found in 9 provinces of the country. Frequency of IgM antibodies against ZIKV was slightly higher in patients aged 5-9 years old, and in the north region of the country.


Assuntos
Anticorpos Antivirais/sangue , Febre/epidemiologia , Imunoglobulina M/sangue , Infecção por Zika virus/epidemiologia , Zika virus/imunologia , Adolescente , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Febre/diagnóstico , Febre/imunologia , Febre/virologia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Moçambique/epidemiologia , Estudos Retrospectivos , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
14.
PLoS Negl Trop Dis ; 13(8): e0007648, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31449521

RESUMO

Zika virus (ZIKV) is a newly-identified infectious cause of congenital disease. Transplacental transfer of maternal IgG to the fetus plays an important role in preventing many neonatal infections. However, antibody transfer may also have negative consequences, such as mediating enhancement of flavivirus infections in early life, or trafficking of virus immune complexes to the fetal compartment. ZIKV infection produces placental pathology which could lead to impaired IgG transfer efficiency as occurs in other maternal infections, such as HIV-1 and malaria. In this study, we asked whether ZIKV infection during pregnancy impairs transplacental transfer of IgG. We enrolled pregnant women with fever or rash in a prospective cohort in Vitoria, Brazil during the recent ZIKV epidemic. ZIKV and dengue virus (DENV)-specific IgG, ZIKV and DENV neutralizing antibodies, and routine vaccine antigen-specific IgG were measured in maternal samples collected around delivery and 20 paired cord blood samples. We concluded that 8 of these mothers were infected with ZIKV during pregnancy and 12 were ZIKV-uninfected. The magnitude of flavivirus-specific IgG, neutralizing antibody, and vaccine-elicited IgG were highly correlated between maternal plasma and infant cord blood in both ZIKV-infected and -uninfected mother-infant pairs. Moreover, there was no difference in the magnitude of plasma flavivirus-specific IgG levels between mothers and infants regardless of ZIKV infection status. Our data suggests that maternal ZIKV infection during pregnancy does not impair the efficiency of placental transfer of flavivirus-specific, functional, and vaccine-elicited IgG. These findings have implications for the neonatal outomes of maternal ZIKV infection and optimal administration of antibody-based ZIKV vaccines and therapeutics.


Assuntos
Anticorpos Antivirais/sangue , Sangue Fetal/imunologia , Imunoglobulina G/sangue , Complicações Infecciosas na Gravidez/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Brasil , Vírus da Dengue/imunologia , Feminino , Humanos , Gravidez , Estudos Prospectivos , Adulto Jovem
15.
Nat Biotechnol ; 37(10): 1163-1173, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451733

RESUMO

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.


Assuntos
Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pulmão/fisiologia , Infecção por Zika virus/virologia , Animais , Anticorpos Antivirais , Células Apresentadoras de Antígenos , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Citomegalovirus/fisiologia , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos SCID , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Tropismo/imunologia , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/imunologia
16.
Nat Commun ; 10(1): 3859, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455769

RESUMO

Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.


Assuntos
Switching de Imunoglobulina/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Knockout , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Células Vero , Infecção por Zika virus/virologia
17.
Nat Commun ; 10(1): 3889, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467282

RESUMO

The innate response to a pathogen is critical in determining the outcome of the infection. However, the interplay of different cellular responses that are activated following viral infection and their contribution to innate antiviral signalling has not been clearly established. This work shows that flaviviruses, including Dengue, Zika, West Nile and Tick-borne encephalitis viruses, activate the unfolded protein response before transcription of interferon regulatory factor 3 induced genes. Infection in conditions of unfolded protein response priming leads to early activation of innate antiviral responses and cell intrinsic inhibition of viral replication, which is interferon regulatory factor 3 dependent. These results demonstrate that the unfolded protein response is not only a physiological reaction of the cell to viral infection, but also synergizes with pattern recognition sensing to mount a potent antiviral response.


Assuntos
Antivirais/farmacologia , Infecções por Flavivirus/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Imunidade Inata/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Proteína DEAD-box 58/metabolismo , Dengue/imunologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Encefalite Transmitidos por Carrapatos/efeitos dos fármacos , Encefalite Transmitida por Carrapatos/imunologia , Endorribonucleases/metabolismo , Feminino , Humanos , Fator Regulador 3 de Interferon/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Transcriptoma , Células Vero , Replicação Viral/efeitos dos fármacos , Febre do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/imunologia
18.
BMC Res Notes ; 12(1): 326, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182146

RESUMO

OBJECTIVE: Increase in the evidence of global occurrence of Zika viral infection suggests that in Africa the circulation of the virus which causes 80% of asymptomatic infection could be undetected and/or overlooked. We sought to serologically detect Zika virus infection in febrile patients at Greater Accra Regional Hospital, Ghana. RESULTS: Of the 160 patient serum samples analyzed, 33 were found to have antibodies against Zika virus infection. Among the sero-positives 30 (91%) of the cases were anti-Zika virus IgM with the 21-30-year age group recording the highest number of 8 (26%) and 2 (7%) cases being the least for the 61 years and above age group. All sero-positive febrile patients developed at least one symptom consistent with Zika virus infection: 33 (100%) fever, 25 (76%) muscle pain, 24 (73%) joint pain, and conjunctivitis 2 (6%). Digestive symptoms recorded include 16 (49%) nausea, 12 (36%) vomiting and diarrhea 18 (55%). In addition, 28 (85%) loss of appetite, 14 (75%) rapid respiration and chest pain 15 (42%) were reported by seropositive febrile patients. Our data indicates exposure to Zika virus which suggests the possible circulation of the virus among febrile patients in Ghana with a sero-prevalence rate of 20.6%.


Assuntos
Anticorpos Antivirais/sangue , Artralgia/imunologia , Febre/imunologia , Mialgia/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Adolescente , Adulto , Idoso , Artralgia/diagnóstico , Artralgia/epidemiologia , Artralgia/fisiopatologia , Criança , Pré-Escolar , Conjuntivite Viral/diagnóstico , Conjuntivite Viral/epidemiologia , Conjuntivite Viral/imunologia , Conjuntivite Viral/fisiopatologia , Estudos Transversais , Diarreia/diagnóstico , Diarreia/epidemiologia , Diarreia/imunologia , Diarreia/fisiopatologia , Feminino , Febre/diagnóstico , Febre/epidemiologia , Febre/fisiopatologia , Gana/epidemiologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Mialgia/diagnóstico , Mialgia/epidemiologia , Mialgia/fisiopatologia , Náusea/diagnóstico , Náusea/epidemiologia , Náusea/imunologia , Náusea/fisiopatologia , Estudos Soroepidemiológicos , Vômito/diagnóstico , Vômito/epidemiologia , Vômito/imunologia , Vômito/fisiopatologia , Zika virus/crescimento & desenvolvimento , Zika virus/patogenicidade , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/fisiopatologia
19.
Nat Neurosci ; 22(8): 1276-1288, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235930

RESUMO

T cells clear virus from the CNS and dynamically regulate brain functions, including spatial learning, through cytokine signaling. Here we determined whether hippocampal T cells that persist after recovery from infection with West Nile virus (WNV) or Zika virus (ZIKV) impact hippocampal-dependent learning and memory. Using newly established models of viral encephalitis recovery in adult animals, we show that in mice that have recovered from WNV or ZIKV infection, T cell-derived interferon-γ (IFN-γ) signaling in microglia underlies spatial-learning defects via virus-target-specific mechanisms. Following recovery from WNV infection, mice showed presynaptic termini elimination with lack of repair, while for ZIKV, mice showed extensive neuronal apoptosis with loss of postsynaptic termini. Accordingly, animals deficient in CD8+ T cells or IFN-γ signaling in microglia demonstrated protection against synapse elimination following WNV infection and decreased neuronal apoptosis with synapse recovery following ZIKV infection. Thus, T cell signaling to microglia drives post-infectious cognitive sequelae that are associated with emerging neurotropic flaviviruses.


Assuntos
Transtornos Cognitivos/psicologia , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/psicologia , Microglia/imunologia , Sinapses/imunologia , Sinapses/patologia , Linfócitos T/imunologia , Animais , Apoptose , Linfócitos T CD8-Positivos/imunologia , Transtornos Cognitivos/etiologia , Feminino , Infecções por Flavivirus/patologia , Interferon gama , /psicologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interferon/genética , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/psicologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/psicologia
20.
Arch Virol ; 164(8): 2165-2170, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154511

RESUMO

Zika virus (ZIKV) circulation occurs between non-human primates (NHPs) in a sylvatic transmission cycle. To investigate evidence of flavivirus infection in NHPs in Zambia, we performed a plaque reduction neutralization test (PRNT) to quantify neutralizing antibodies. PRNT revealed that sera from NHPs (African green monkeys and baboons) exhibited neutralizing activity against ZIKV (34.4%; 33/96), whereas a PRNT for yellow fever virus using NHP sera showed no neutralization activity. ZIKV genomic RNA was not detected in splenic tissues from NHPs, suggesting that the presence of anti-ZIKV neutralizing antibodies represented resolved infections. Our evidence suggests that ZIKV is maintained in NHP reservoirs in Zambia.


Assuntos
Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Reações Cruzadas/imunologia , Vírus da Dengue/imunologia , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/virologia , Primatas , Testes Sorológicos/métodos , Zâmbia
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