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1.
Annu Rev Immunol ; 36: 279-308, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29345964

RESUMO

Flaviviruses such as dengue (DENV), yellow fever (YFV), West Nile (WNV), and Zika (ZIKV) are human pathogens of global significance. In particular, DENV causes the most prevalent mosquito-borne viral diseases in humans, and ZIKV emerged from obscurity into the spotlight in 2016 as the etiologic agent of congenital Zika syndrome. Owing to the recent emergence of ZIKV as a global pandemic threat, the roles of the immune system during ZIKV infections are as yet unclear. In contrast, decades of DENV research implicate a dual role for the immune system in protection against and pathogenesis of DENV infection. As DENV and ZIKV are closely related, knowledge based on DENV studies has been used to prioritize investigation of ZIKV immunity and pathogenesis, and to accelerate ZIKV diagnostic, therapeutic, and vaccine design. This review discusses the following topics related to innate and adaptive immune responses to DENV and ZIKV: the interferon system as the key mechanism of host defense and viral target for immune evasion, antibody-mediated protection versus antibody-dependent enhancement, and T cell-mediated protection versus original T cell antigenic sin. Understanding the mechanisms that regulate the balance between immune-mediated protection and pathogenesis during DENV and ZIKV infections is critical toward development of safe and effective DENV and ZIKV therapeutics and vaccines.


Assuntos
Vírus da Dengue/fisiologia , Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Infecção por Zika virus/imunologia , Zika virus/fisiologia , Imunidade Adaptativa , Animais , Dengue/metabolismo , Dengue/prevenção & controle , Dengue/virologia , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Tropismo Viral , Vacinas Virais/imunologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
2.
Cell ; 185(25): 4826-4840.e17, 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36402135

RESUMO

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.


Assuntos
Imunoglobulina M , Gravidez , Infecção por Zika virus , Zika virus , Animais , Feminino , Camundongos , Gravidez/imunologia , Anticorpos Neutralizantes , Anticorpos Antivirais , Epitopos , Testes de Neutralização , Infecção por Zika virus/imunologia , Imunoglobulina M/imunologia , Imunoglobulina M/isolamento & purificação
3.
Cell ; 185(14): 2395-2397, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35803242

RESUMO

Flaviviruses, such as Dengue and Zika viruses, infect millions of people worldwide using mosquitos as vectors. In this issue of Cell, Zhang et al. reveal how these viruses manipulate the skin microbiome of infected hosts in a way that increases vector recruitment and viral spread. They propose vitamin A as a way to counteract the virus and decrease transmission.


Assuntos
Infecções por Flavivirus , Flavivirus , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pele , Animais , Culicidae/virologia , Dengue , Flavivirus/fisiologia , Infecções por Flavivirus/microbiologia , Infecções por Flavivirus/transmissão , Humanos , Publicações Periódicas como Assunto , Pele/metabolismo , Pele/microbiologia , Doenças Transmitidas por Vetores , Infecção por Zika virus
4.
Cell ; 184(25): 6015-6016, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34856127

RESUMO

In this issue of Cell, two studies apply powerful structural approaches to probe the modes of interaction between a broadly neutralizing antibody and a conserved epitope found on four dengue virus serotypes and Zika virus. These findings offer new insights into how a broadly neutralizing antibody surmounts antigenic and conformational variation.


Assuntos
Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Amplamente Neutralizantes , Reações Cruzadas , Humanos
5.
Cell ; 184(25): 6067-6080.e13, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34852238

RESUMO

The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics.


Assuntos
Anticorpos Neutralizantes , Vírus da Dengue , Dengue , Proteínas do Envelope Viral , Infecção por Zika virus , Zika virus , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Reações Cruzadas , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/fisiologia , Humanos , Ligação Proteica , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Zika virus/imunologia , Zika virus/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
6.
Cell ; 184(25): 6052-6066.e18, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34852239

RESUMO

The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes' geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.


Assuntos
Anticorpos Neutralizantes , Vírus da Dengue , Dengue , Proteínas do Envelope Viral , Infecção por Zika virus , Zika virus , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Linhagem Celular , Chlorocebus aethiops , Reações Cruzadas/imunologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/fisiologia , Drosophila melanogaster , Células HEK293 , Humanos , Ligação Proteica , Conformação Proteica , Células Vero , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Zika virus/imunologia , Zika virus/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
7.
Cell ; 178(5): 1057-1071.e11, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31442400

RESUMO

The Zika epidemic in the Americas has challenged surveillance and control. As the epidemic appears to be waning, it is unclear whether transmission is still ongoing, which is exacerbated by discrepancies in reporting. To uncover locations with lingering outbreaks, we investigated travel-associated Zika cases to identify transmission not captured by reporting. We uncovered an unreported outbreak in Cuba during 2017, a year after peak transmission in neighboring islands. By sequencing Zika virus, we show that the establishment of the virus was delayed by a year and that the ensuing outbreak was sparked by long-lived lineages of Zika virus from other Caribbean islands. Our data suggest that, although mosquito control in Cuba may initially have been effective at mitigating Zika virus transmission, such measures need to be maintained to be effective. Our study highlights how Zika virus may still be "silently" spreading and provides a framework for understanding outbreak dynamics. VIDEO ABSTRACT.


Assuntos
Epidemias , Genômica/métodos , Infecção por Zika virus/epidemiologia , Aedes/virologia , Animais , Cuba/epidemiologia , Humanos , Incidência , Controle de Mosquitos , Filogenia , RNA Viral/química , RNA Viral/metabolismo , Análise de Sequência de RNA , Viagem , Índias Ocidentais/epidemiologia , Zika virus/classificação , Zika virus/genética , Zika virus/isolamento & purificação , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
8.
Nat Immunol ; 22(8): 958-968, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34267374

RESUMO

Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and its antigenically related Zika virus (ZIKV) because vaccine may prime deleterious antibodies to enhance natural infections. Cross-reactive antibodies targeting the conserved fusion loop epitope (FLE) are known as the main sources of ADE. We design ZIKV immunogens engineered to change the FLE conformation but preserve neutralizing epitopes. Single vaccination conferred sterilizing immunity against ZIKV without ADE of DENV-serotype 1-4 infections and abrogated maternal-neonatal transmission in mice. Unlike the wild-type-based vaccine inducing predominately cross-reactive ADE-prone antibodies, B cell profiling revealed that the engineered vaccines switched immunodominance to dispersed patterns without DENV enhancement. The crystal structure of the engineered immunogen showed the dimeric conformation of the envelope protein with FLE disruption. We provide vaccine candidates that will prevent both ZIKV infection and infection-/vaccination-induced DENV ADE.


Assuntos
Anticorpos Facilitadores/imunologia , Antígenos Virais/imunologia , Reações Cruzadas/imunologia , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Zika virus/imunologia , Aedes , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Chlorocebus aethiops , Cricetinae , Vírus da Dengue/imunologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Vacinação , Células Vero , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle
9.
Nat Immunol ; 22(11): 1416-1427, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34663977

RESUMO

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.


Assuntos
COVID-19/imunologia , Citocinas/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , SARS-CoV-2/fisiologia , Ubiquitinas/metabolismo , Diferenciação Celular , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Citocinas/genética , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Evasão da Resposta Imune , Imunidade Inata , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Células-Tronco Pluripotentes/citologia , Ubiquitinação , Ubiquitinas/genética , Zika virus/fisiologia , Infecção por Zika virus/imunologia
10.
Cell ; 172(6): 1160-1162, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29522736

RESUMO

The emergence and spread of Zika virus in the Americas continues to challenge our disease surveillance systems. Virus genome sequencing during the epidemic uncovered the timescale of Zika virus transmission and spread. Yet, we are only beginning to explore how genomics can enhance our responses to emerging viruses.


Assuntos
Genoma Viral/genética , Genômica/métodos , Infecção por Zika virus/transmissão , Zika virus/genética , América/epidemiologia , Brasil/epidemiologia , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/transmissão , Doenças Transmissíveis Emergentes/virologia , Epidemias , Geografia , Humanos , Zika virus/patogenicidade , Infecção por Zika virus/virologia
11.
Cell ; 175(7): 1931-1945.e18, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30550790

RESUMO

Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms.


Assuntos
Vírus da Dengue , Dengue , Proteínas de Membrana , Proteínas Nucleares , Proteínas não Estruturais Virais , Infecção por Zika virus , Zika virus , Animais , Linhagem Celular Tumoral , Culicidae , Dengue/genética , Dengue/metabolismo , Dengue/patologia , Vírus da Dengue/genética , Vírus da Dengue/metabolismo , Vírus da Dengue/patogenicidade , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Mapeamento de Interação de Proteínas , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Zika virus/genética , Zika virus/metabolismo , Zika virus/patogenicidade , Infecção por Zika virus/genética , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia
12.
Cell ; 173(5): 1111-1122.e10, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29606355

RESUMO

The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.


Assuntos
Feto/virologia , Neurônios/patologia , Infecção por Zika virus/patologia , Zika virus/patogenicidade , Animais , Animais Recém-Nascidos , Apoptose , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Calcinose/patologia , Calcinose/veterinária , Feminino , Idade Gestacional , Macaca mulatta , Imageamento por Ressonância Magnética , Necrose , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Neurônios/virologia , Gravidez , Índice de Gravidade de Doença , Vasculite/patologia , Vasculite/veterinária , Infecção por Zika virus/veterinária , Infecção por Zika virus/virologia
13.
Cell ; 172(6): 1157-1159, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29522735

RESUMO

100 years after the infamous "Spanish flu" pandemic, the 2017-2018 flu season has been severe, with numerous infections worldwide. In between, there have been continuous, relentless attacks from (re-)emerging viruses. To fully understand viral pathogenesis and develop effective medical countermeasures, we must strengthen current surveillance and basic research efforts.


Assuntos
Vírus da Influenza A Subtipo H5N2/patogenicidade , Influenza Aviária/virologia , Infecção por Zika virus/virologia , Zika virus/patogenicidade , Animais , Aves , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/virologia , Humanos , Vírus da Influenza A/classificação , Vírus da Influenza A/patogenicidade , Influenza Aviária/epidemiologia , Influenza Humana/epidemiologia , Influenza Humana/virologia , Pandemias , Filogeografia , Infecção por Zika virus/epidemiologia
14.
Cell ; 172(3): 517-533.e20, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29249358

RESUMO

B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunidade Inata , Influenza Humana/imunologia , Interleucina-4/genética , Células Matadoras Naturais/imunologia , Infecção por Zika virus/imunologia , Animais , Galinhas , Cães , Centro Germinativo/citologia , Humanos , Interleucina-4/metabolismo , Macaca , Macrófagos/imunologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL
15.
Cell ; 169(4): 610-620.e14, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28457610

RESUMO

Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. ZIKV-specific neutralizing antibodies correlated with rapid clearance of virus in peripheral blood but remained undetectable in CSF for the duration of the study. Viral persistence in both CSF and LN correlated with upregulation of mechanistic target of rapamycin (mTOR), proinflammatory, and anti-apoptotic signaling pathways, as well as downregulation of extracellular matrix signaling pathways. These data raise the possibility that persistent or occult neurologic and lymphoid disease may occur following clearance of peripheral virus in ZIKV-infected individuals.


Assuntos
Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Animais , Líquido Cefalorraquidiano/virologia , Inflamação/imunologia , Trato Gastrointestinal Inferior/virologia , Linfonodos/virologia , Macaca mulatta , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
16.
Cell ; 169(4): 597-609.e11, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28475892

RESUMO

Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.


Assuntos
Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Infecção por Zika virus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Brasil , Feminino , Humanos , Memória Imunológica , Leucócitos Mononucleares/imunologia , Masculino , México , Camundongos , Infecção por Zika virus/sangue
17.
Cell ; 168(5): 755-757, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28235193

RESUMO

Three recent studies find that the single-pass transmembrane protein HAP2 mediates gamete fusion and is remarkably similar to class II fusion proteins found in viruses such as dengue and Zika.


Assuntos
Células Germinativas/metabolismo , Proteínas de Membrana/metabolismo , Dengue , Humanos , Zika virus , Infecção por Zika virus
18.
Cell ; 170(2): 273-283.e12, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28708997

RESUMO

The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with multiple viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted.


Assuntos
Vacinas Virais/administração & dosagem , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/fisiologia , Aedes/virologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Células Sanguíneas/virologia , Embrião de Mamíferos/virologia , Feminino , Feto/virologia , Humanos , Lipídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Organismos Livres de Patógenos Específicos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/virologia
19.
Cell ; 168(6): 1114-1125.e10, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28222903

RESUMO

The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.


Assuntos
RNA Mensageiro/administração & dosagem , Vacinas Virais/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Animais , Epitopos/imunologia , Feminino , Lipídeos/química , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Vacinas Virais/administração & dosagem , Zika virus/imunologia
20.
Cell ; 171(1): 229-241.e15, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28938115

RESUMO

Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Infecção por Zika virus/terapia , Zika virus/química , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/química , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/química , Microscopia Crioeletrônica , Epitopos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Alinhamento de Sequência , Proteínas do Envelope Viral/química , Zika virus/imunologia
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