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1.
Viruses ; 13(2)2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525328

RESUMO

There have been reports of neurological abnormalities associated with the Zika virus (ZIKV), such as congenital Zika syndrome (CZS) in children born to mothers infected during pregnancy. We investigated how the immune response to ZIKV during pregnancy is primed and conduct a thorough evaluation of the inflammatory and cytotoxic profiles as well as the expression of CCR5 and CX3CR1. We compared the reactivity of T cells to ZIKV peptides in convalescent mothers infected during pregnancy. The child's clinical outcome (i.e., born with or without CZS) was taken to be the variable. The cells were stimulated in vitro with ZIKV peptides and evaluated using the ELISPOT and flow cytometry assays. After in vitro stimulation with ZIKV peptides, we observed a tendency toward a higher Interferon gamma (IFN-γ)-producing T cell responses in mothers who had asymptomatic children and a higher CD107a expression in T cells in mothers who had children with CZS. We found a higher frequency of T cells expressing CD107a+ and co-expressing CX3CR1+CCR5+, which is much clearer in the T cells of mothers who had CZS children. We suggest that this differential profile influenced the clinical outcome of babies. These data need to be further investigated, including the evaluation of other ZIKV peptides and markers and functional assays.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Complicações Infecciosas na Gravidez/imunologia , Receptores CCR5/metabolismo , Linfócitos T/imunologia , Infecção por Zika virus/imunologia , Adulto , Estudos Transversais , Citotoxicidade Imunológica , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Gravidez , Resultado da Gravidez , Linfócitos T/metabolismo , Adulto Jovem , Zika virus/imunologia
2.
Viruses ; 13(1)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430059

RESUMO

BACKGROUND: Zika virus (ZIKV) infection during pregnancy usually shows only mild symptoms and is frequently subclinical. However, it can be vertically transmitted to the fetus, causing microcephaly and other congenital defects. During pregnancy, the immune environment modifications can alter the response to viruses in general and ZIKV in particular. OBJECTIVE: To describe the role of pregnancy in the systemic pro- and anti-inflammatory response during symptomatic ZIKV infection. MATERIALS AND METHODS: A multiplex assay was used to measure 25 cytokines, chemokines, and receptors in 110 serum samples from pregnant and nonpregnant women with and without ZIKV infection with and without symptoms. Samples were collected through an epidemiological surveillance system. RESULTS: Samples from pregnant women with ZIKV infection showed a higher viral load but had similar profiles of inflammatory markers as compared with nonpregnant infected women, except for CXCL10 that was higher in infected pregnant women. Notably, the presence of ZIKV in pregnancy favored a regulatory profile by significantly increasing anti-inflammatory cytokines such as interleukin (IL)-10, receptors IL-1RA, and IL-2R, but only those pro-inflammatory cytokines such as IL-6, interferon (IFN)-α, IFN-γ and IL-17 that are essential for the antiviral response. Interestingly, there were no differences between symptomatic and weakly symptomatic ZIKV-infected groups. CONCLUSION: Our results revealed a systemic anti-inflammatory cytokine and chemokine profile that could participate in the control of the virus. The anti-inflammatory response in pregnant women infected with ZIKA was characterized by high CXCL10, a cytokine that has been correlated with congenital malformations.


Assuntos
Quimiocina CXCL10/metabolismo , Citocinas/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/virologia , Carga Viral , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia , Zika virus/fisiologia , Adulto , Biomarcadores , Feminino , Humanos , Imunomodulação , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Trimestres da Gravidez , Adulto Jovem , Infecção por Zika virus/imunologia
3.
PLoS Pathog ; 16(12): e1009132, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370392

RESUMO

NK cells have been shown to display adaptive traits such as memory formation akin to T and B lymphocytes. Here we show that Zika virus infection induces memory like NK cells that express CD27. Strikingly, these cells exhibit stem-like features that include expansion capacity, self-renewal pathway, differentiation into effector cells, longer telomeres and gene signature associated with hematopoietic stem cell (HSC) progenitors. This subset shared transcriptional and epigenetic changes with memory CD8 T cells, stem cells and stem like T cells. These NK cells with memory and stem cell features, which we term "NK memory stem cells", demonstrated greater antiviral potential than CD27- or naïve CD27+ NK when adoptively transferred to Zika infected mice. Our results also suggest a role for the transcription factor TCF-1 in memory and stemness features of this NK subset. This study defines a unique TCF1hi CD27+ NK subset with memory capacity and stem cell features that play a role in antiviral immunity.


Assuntos
Memória Imunológica/imunologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Células-Tronco/imunologia , Infecção por Zika virus/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
4.
PLoS Pathog ; 16(12): e1009019, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33315931

RESUMO

Testicular invasion and persistence are features of Zika virus (ZIKV), but their mechanisms are still unknown. Here, we showed that S100A4+ macrophages, a myeloid macrophage subpopulation with susceptibility to ZIKV infection, facilitated ZIKV invasion and persistence in the seminiferous tubules. In ZIKV-infected mice, S100A4+ macrophages were specifically recruited into the interstitial space of testes and differentiated into interferon-γ-expressing M1 macrophages. With interferon-γ mediation, S100A4+ macrophages down-regulated Claudin-1 expression and induced its redistribution from the cytosol to nucleus, thus increasing the permeability of the blood-testis barrier which facilitated S100A4+ macrophages invasion into the seminiferous tubules. Intraluminal S100A4+ macrophages were segregated from CD8+ T cells and consequently helped ZIKV evade cellular immunity. As a result, ZIKV continued to replicate in intraluminal S100A4+ macrophages even when the spermatogenic cells disappeared. Deficiencies in S100A4 or interferon-γ signaling both reduced ZIKV infection in the seminiferous tubules. These results demonstrated crucial roles of S100A4+ macrophages in ZIKV infection in testes.


Assuntos
Macrófagos/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/imunologia , Infecção por Zika virus/imunologia , Animais , Claudina-1/genética , Claudina-1/metabolismo , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Viral , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Túbulos Seminíferos/virologia , Testículo/imunologia , Testículo/virologia , Replicação Viral/imunologia , Replicação Viral/fisiologia , Zika virus/imunologia , Infecção por Zika virus/virologia
5.
PLoS One ; 15(12): e0244587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378361

RESUMO

Our previous studies have shown that Zika virus (ZIKV) replicates in human prostate cells, suggesting that the prostate may serve as a long-term reservoir for virus transmission. Here, we demonstrated that the innate immune responses generated to three distinct ZIKV strains (all isolated from human serum) were significantly different and dependent on their passage history (in mosquito, monkey, or human cells). In addition, some of these phenotypic differences were reduced by a single additional cell culture passage, suggesting that viruses that have been passaged more than 3 times from the patient sample will no longer reflect natural phenotypes. Two of the ZIKV strains analyzed induced high levels of the IP-10 chemokine and IFNγ in human prostate epithelial and stromal mesenchymal stem cells. To further understand the importance of these innate responses on ZIKV replication, we measured the effects of IP-10 and its downstream receptor, CXCR3, on RNA and virus production in prostate cells. Treatment with IP-10, CXCR3 agonist, or CXCR3 antagonist significantly altered ZIKV viral gene expression, depending on their passage in cells of relevant hosts (mosquito or human). We detected differences in gene expression of two primary CXCR3 isoforms (CXCR3-A and CXCR3-B) on the two cell types, possibly explaining differences in viral output. Lastly, we examined the effects of IP-10, agonist, or antagonist on cell death and proliferation under physiologically relevant infection rates, and detected no significant differences. Although we did not measure protein expression directly, our results indicate that CXCR3 signaling may be a target for therapeutics, to ultimately stop sexual transmission of this virus.


Assuntos
Quimiocina CXCL10/metabolismo , Próstata/virologia , Receptores CXCR3/metabolismo , Infecção por Zika virus/imunologia , Zika virus/fisiologia , Animais , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Quimiocina CXCL10/genética , Culicidae/virologia , Regulação da Expressão Gênica , Haplorrinos/virologia , Humanos , Imunidade Inata , Masculino , Próstata/citologia , Próstata/imunologia , Receptores CXCR3/genética , Inoculações Seriadas , Transdução de Sinais , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/genética , Infecção por Zika virus/virologia
6.
J Immunol ; 205(11): 3083-3094, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33139490

RESUMO

Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term decidual stromal cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term decidual cells. ZIKV-infected decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human decidual cells, are gestational age dependent, and decidual cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.


Assuntos
Decídua , Idade Gestacional , Imunidade Inata , Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus/imunologia , Animais , Chlorocebus aethiops , Decídua/imunologia , Decídua/patologia , Decídua/virologia , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/patologia , Trofoblastos , Células Vero , Infecção por Zika virus/imunologia , Infecção por Zika virus/patologia , Infecção por Zika virus/transmissão
7.
Cell Rep ; 33(5): 108339, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147451

RESUMO

Here, we report our studies of immune-mediated regulation of Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the human cornea. We find that ZIKV can be transmitted via corneal transplantation in mice. However, in human corneal explants, we report that ZIKV does not replicate efficiently and that SARS-CoV-2 does not replicate at all. Additionally, we demonstrate that type III interferon (IFN-λ) and its receptor (IFNλR1) are expressed in the corneal epithelium. Treatment of human corneal explants with IFN-λ, and treatment of mice with IFN-λ eye drops, upregulates antiviral interferon-stimulated genes. In human corneal explants, blockade of IFNλR1 enhances replication of ZIKV and HSV-1 but not SARS-CoV-2. In addition to an antiviral role for IFNλR1 in the cornea, our results suggest that the human cornea does not support SARS-CoV-2 infection despite expression of ACE2, a SARS-CoV-2 receptor, in the human corneal epithelium.


Assuntos
Betacoronavirus/fisiologia , Córnea/virologia , Infecções por Coronavirus/transmissão , Herpesvirus Humano 1/fisiologia , Interferons/imunologia , Pneumonia Viral/transmissão , Zika virus/fisiologia , Animais , Betacoronavirus/imunologia , Córnea/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Herpes Simples/imunologia , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Replicação Viral/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
8.
Nat Commun ; 11(1): 5278, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077712

RESUMO

There are no licensed therapeutics or vaccines available against Zika virus (ZIKV) to counteract its potential for congenital disease. Antibody-based countermeasures targeting the ZIKV envelope protein have been hampered by concerns for cross-reactive responses that induce antibody-dependent enhancement (ADE) of heterologous flavivirus infection. Nonstructural protein 1 (NS1) is a membrane-associated and secreted glycoprotein that functions in flavivirus replication and immune evasion but is absent from the virion. Although some studies suggest that antibodies against ZIKV NS1 are protective, their activity during congenital infection is unknown. Here we develop mouse and human anti-NS1 monoclonal antibodies that protect against ZIKV in both non-pregnant and pregnant mice. Avidity of antibody binding to cell-surface NS1 along with Fc effector functions engagement correlate with protection in vivo. Protective mAbs map to exposed epitopes in the wing domain and loop face of the ß-platform. Anti-NS1 antibodies provide an alternative strategy for protection against congenital ZIKV infection without causing ADE.


Assuntos
Anticorpos Antivirais/administração & dosagem , Complicações Infecciosas na Gravidez/prevenção & controle , Proteínas não Estruturais Virais/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Anticorpos Antivirais/imunologia , Afinidade de Anticorpos , Anticorpos Facilitadores , Reações Cruzadas , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Zika virus/química , Zika virus/genética , Infecção por Zika virus/congênito , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
9.
PLoS Pathog ; 16(8): e1008754, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776975

RESUMO

Arbovirus infection of Aedes aegypti salivary glands (SGs) determines transmission. However, there is a dearth of knowledge on SG immunity. Here, we characterized SG immune response to dengue, Zika and chikungunya viruses using high-throughput transcriptomics. We also describe a transcriptomic response associated to apoptosis, blood-feeding and lipid metabolism. The three viruses differentially regulate components of Toll, Immune deficiency (IMD) and c-Jun N- terminal Kinase (JNK) pathways. However, silencing of the Toll and IMD pathway components showed variable effects on SG infection by each virus. In contrast, regulation of the JNK pathway produced consistent responses in both SGs and midgut. Infection by the three viruses increased with depletion of the activator Kayak and decreased with depletion of the negative regulator Puckered. Virus-induced JNK pathway regulates the complement factor, Thioester containing protein-20 (TEP20), and the apoptosis activator, Dronc, in SGs. Individual and co-silencing of these genes demonstrate their antiviral effects and that both may function together. Co-silencing either TEP20 or Dronc with Puckered annihilates JNK pathway antiviral effect. Upon infection in SGs, TEP20 induces antimicrobial peptides (AMPs), while Dronc is required for apoptosis independently of TEP20. In conclusion, we revealed the broad antiviral function of JNK pathway in SGs and showed that it is mediated by a TEP20 complement and Dronc-induced apoptosis response. These results expand our understanding of the immune arsenal that blocks arbovirus transmission.


Assuntos
Aedes/imunologia , Apoptose , Febre de Chikungunya/imunologia , Proteínas do Sistema Complemento/imunologia , Dengue/imunologia , Sistema de Sinalização das MAP Quinases , Glândulas Salivares/imunologia , Infecção por Zika virus/imunologia , Aedes/virologia , Animais , Febre de Chikungunya/metabolismo , Febre de Chikungunya/prevenção & controle , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Proteínas do Sistema Complemento/metabolismo , Dengue/metabolismo , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/imunologia , Feminino , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos Vetores/imunologia , Insetos Vetores/virologia , Glândulas Salivares/virologia , Transcriptoma , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
10.
J Exp Med ; 217(12)2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-32820330

RESUMO

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.


Assuntos
Imunogenicidade da Vacina/imunologia , Interferon Tipo I/antagonistas & inibidores , Interferon-alfa/imunologia , Receptor de Interferon alfa e beta/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Anticorpos Antivirais/imunologia , Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/imunologia , Modelos Animais de Doenças , Expressão Gênica/imunologia , Células HEK293 , Humanos , Memória Imunológica , Interferon-alfa/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Transfecção , Infecção por Zika virus/virologia
11.
Science ; 369(6507): 1123-1128, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32855339

RESUMO

The Zika pandemic sparked intense interest in whether immune interactions among dengue virus serotypes 1 to 4 (DENV1 to -4) extend to the closely related Zika virus (ZIKV). We investigated prospective pediatric cohorts in Nicaragua that experienced sequential DENV1 to -3 (2004 to 2015), Zika (2016 to 2017), and DENV2 (2018 to 2020) epidemics. Risk of symptomatic DENV2 infection and severe disease was elevated by one prior ZIKV infection, one prior DENV infection, or one prior DENV infection followed by one ZIKV infection, compared with being flavivirus-naïve. By contrast, multiple prior DENV infections reduced dengue risk. Further, although high preexisting anti-DENV antibody titers protected against DENV1, DENV3, and ZIKV disease, intermediate titers induced by previous ZIKV or DENV infection enhanced future risk of DENV2 disease and severity, as well as DENV3 severity. The observation that prior ZIKV infection can modulate dengue disease severity like a DENV serotype poses challenges to development of dengue and Zika vaccines.


Assuntos
Vírus da Dengue/imunologia , Dengue Grave/epidemiologia , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Anticorpos Antivirais/sangue , Vacinas contra Dengue/imunologia , Humanos , Imunogenicidade da Vacina , Nicarágua/epidemiologia , Risco , Sorogrupo
12.
Trends Biotechnol ; 38(9): 943-947, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32600777

RESUMO

Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.


Assuntos
Infecções por Coronavirus/prevenção & controle , Aprovação de Drogas/organização & administração , Doença pelo Vírus Ebola/prevenção & controle , Influenza Humana/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/biossíntese , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/biossíntese , Ebolavirus/efeitos dos fármacos , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Europa (Continente)/epidemiologia , Saúde Global/tendências , Regulamentação Governamental , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/biossíntese , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Estados Unidos/epidemiologia , Vacinas Virais/administração & dosagem , Zika virus/efeitos dos fármacos , Zika virus/imunologia , Zika virus/patogenicidade , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia
13.
Nat Commun ; 11(1): 2967, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528049

RESUMO

The recent outbreak of Zika virus (ZIKV) was associated with birth defects and pregnancy loss when maternal infection occurs in early pregnancy, but specific mechanisms driving placental insufficiency and subsequent ZIKV-mediated pathogenesis remain unclear. Here we show, using large scale metabolomics, that ZIKV infection reprograms placental lipidome by impairing the lipogenesis pathways. ZIKV-induced metabolic alterations provide building blocks for lipid droplet biogenesis and intracellular membrane rearrangements to support viral replication. Furthermore, lipidome reprogramming by ZIKV is paralleled by the mitochondrial dysfunction and inflammatory immune imbalance, which contribute to placental damage. In addition, we demonstrate the efficacy of a commercially available inhibitor in limiting ZIKV infection, provides a proof-of-concept for blocking congenital infection by targeting metabolic pathways. Collectively, our study provides mechanistic insights on how ZIKV targets essential hubs of the lipid metabolism that may lead to placental dysfunction and loss of barrier function.


Assuntos
Placenta/virologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/metabolismo , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa , Lipidômica/métodos , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/metabolismo , Zika virus/imunologia , Zika virus/patogenicidade
14.
PLoS Negl Trop Dis ; 14(6): e0008335, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511241

RESUMO

Zika virus (ZIKV), a neglected tropical disease until its re-emergence in 2007, causes microcephaly in infants and Guillain-Barré syndrome in adults. Its re-emergence and spread to more than 80 countries led the World Health Organization in 2016 to declare a Public Health Emergency. ZIKV is mainly transmitted by mosquitos, but can persist in infected human male semen for prolonged periods and may be sexually transmitted. Testicular Sertoli cells support ZIKV replication and may be a reservoir for persistent ZIKV infection. Electrical impedance analyses indicated ZIKV infection rapidly disrupted Vero cell monolayers but had little effect upon human Sertoli cells (HSerC). We determined ZIKV-induced proteomic changes in HSerC using an aptamer-based multiplexed technique (SOMAscan) targeting >1300 human proteins. ZIKV infection caused differential expression of 299 proteins during three different time points, including 5 days after infection. Dysregulated proteins are involved in different bio-functions, including cell death and survival, cell cycle, maintenance of cellular function, cell signaling, cellular assembly, morphology, movement, molecular transport, and immune response. Many signaling pathways important for maintenance of HSerC function and spermatogenesis were highly dysregulated. These included IL-6, IGF1, EGF, NF-κB, PPAR, ERK/MAPK, and growth hormone signaling. Down-regulation of the PPAR signaling pathway might impact cellular energy supplies. Upstream molecule analysis also indicated microRNAs involved in germ cell development were downregulated by infection. Overall, this study leads to a better understanding of Sertoli cellular mechanisms used by ZIKV during persistent infection and possible ZIKV impacts on spermatogenesis.


Assuntos
Células de Sertoli/imunologia , Espermatogênese , Junções Íntimas/imunologia , Infecção por Zika virus/imunologia , Animais , Chlorocebus aethiops , Humanos , Masculino , Proteômica , Sêmen/virologia , Células de Sertoli/virologia , Transdução de Sinais , Junções Íntimas/virologia , Células Vero , Replicação Viral , Zika virus
15.
An Acad Bras Cienc ; 92(1): e20190883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32491129

RESUMO

Zika virus appeared in South America in 2015, generating alarm worldwide as it causes microcephaly and autoimmunity. This study aims to determine the serological footprint of the incoming epidemic in a student community and to characterize the memory functional cell response during post convalescence. In a cross-sectional study, Zika-specific IgG using LIA immunoassay was found in 328 university students (CI=95%), while in the second phase, the functional cellular memory response for IFN-γ and IL-2 was quantified using post-stimulus ELISpot with inactivated virus, starting with individuals seropositive for Zika and control individuals (seropositive only for Dengue and seronegative for Zika-Dengue). Depending on the antigen used, memory humoral response (IgG) against Zika Virus was observed in >60% of the population; seropositivity for NS1 was 21.1% higher than E antigen with high intensity. The analysis of cell functionality in 22 individuals seropositive for Zika virus revealed either IFN-γ+ or IL-2+ cells in 86.3% of cases (Th1 profile), presenting multifunctionality in 50% (11 individuals), 64% of which presented> 6 SFC/104 PBMCs (>600 SFC/106 PBMC), reflecting memory circulating cells. A good agreement (Kappa= 0.754) was observed between the coexistence of both cellular and humoral responses but not in their intensity.


Assuntos
Anticorpos Antivirais/sangue , Memória Imunológica/imunologia , Infecção por Zika virus/virologia , Zika virus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Colômbia , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudantes , Universidades , Adulto Jovem , Infecção por Zika virus/imunologia
16.
Nat Commun ; 11(1): 2421, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415086

RESUMO

Zika virus (ZIKV) is a mosquito-borne pathogen with increasing public health significance. To characterize immune responses to ZIKV, here we examine transcriptional signatures of CD4 T, CD8 T, B, and NK cells, monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs) from three individuals with ZIKV infection. While gene expression patterns from most cell subsets display signs of impaired antiviral immune activity, pDCs from infected host have distinct transcriptional response associated with activation of innate immune recognition and type I interferon signaling pathways, but downregulation of key host factors known to support ZIKV replication steps; meanwhile, pDCs exhibit a unique expression pattern of gene modules that are correlated with alternative cell populations, suggesting collaborative interactions between pDCs and other immune cells, particularly B cells. Together, these results point towards a discrete but integrative function of pDCs in the human immune responses to ZIKV infection.


Assuntos
Células Dendríticas/imunologia , Infecção por Zika virus/imunologia , Adulto , Animais , Linfócitos B/virologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Culicidae , Células Dendríticas/virologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Células Matadoras Naturais/virologia , Leucócitos Mononucleares/virologia , Monócitos/metabolismo , Monócitos/virologia , Células Mieloides/virologia , Transcrição Genética , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/virologia
18.
PLoS Negl Trop Dis ; 14(5): e0008285, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463814

RESUMO

Little is known about the contribution of virus-specific and cross-reacting antibodies (Abs) or the cellular immune response generated by a primary dengue (DENV) infection on the course of a secondary zika (ZIKV) infection in vivo. Here we show that the length of time between DENV/ZIKV infections has a qualitative impact on controlling early ZIKV replication. Depletion of DENV2-specific Abs in sera confirmed that those type-specific Abs do not contribute to ZIKV control. We show that the magnitude and durability of the neutralizing antibodies (nAbs) induced by a secondary ZIKV infection is modest compared to the response induced after a secondary heterologous DENV infection. Our in vivo results are showing a complex interplay between the cellular and innate immune responses characterized by a high frequency of plasmacytoid dendritic cells (pDC) correlating with an increase in the frequency of DENV antigen specific T cells and a significant control of ZIKV replication which is time dependent. Taken together, our results suggest that early after ZIKV infection other mechanisms such as the innate and cellular immune responses may play a predominant role in controlling ZIKV replication. Regardless of the time elapsed between infections there was no evidence of in vivo antibody-dependent enhancement (ADE) of ZIKV by DENV immunity. These findings have pivotal implications while interpreting ZIKV pathogenesis in flavivirus-experimented populations, diagnostic results interpretation and vaccine designs and schedules among others.


Assuntos
Dengue/imunologia , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Células Dendríticas/imunologia , Fatores Imunológicos , Macaca mulatta , Masculino , Linfócitos T/imunologia , Fatores de Tempo
19.
Proc Natl Acad Sci U S A ; 117(18): 9865-9875, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32321830

RESUMO

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.


Assuntos
Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/imunologia , Proteínas do Envelope Viral/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Epitopos/imunologia , Células Germinativas/imunologia , Humanos , Recém-Nascido , Domínios Proteicos/imunologia , Vacinas Virais/imunologia , Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/patogenicidade , Vírus da Febre Amarela/imunologia , Vírus da Febre Amarela/patogenicidade , Zika virus/isolamento & purificação , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/virologia
20.
PLoS One ; 15(4): e0230692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32243482

RESUMO

BACKGROUND: Zika virus caused thousands of congenital anomalies during a recent epidemic. Because Zika emerged in areas endemic for dengue and these related flaviviruses elicit cross-reactive antibodies, it is challenging to serologically monitor pregnant women for Zika infection. METHODS: A prospective cohort of 253 pregnant women was established in León, Nicaragua. Women were followed during prenatal care through delivery. Serologic specimens were obtained at each visit, and birth outcome was recorded. Established flavivirus serologic methods were adapted to determine Zika seroprevalence, and a stepwise testing algorithm estimated timing of Zika infection in relation to pregnancy. RESULTS: Zika seroprevalence was approximately 59% among women tested. Neutralization testing was highly concordant with Zika NS1 BOB results. Per study algorithm, 21% (40/187) of women were classified as experiencing Incident ZIKV infection during pregnancy. Importantly, the Incident ZIKV group included mostly women pregnant during the 2016 Zika epidemic peak and the only 3 subjects in the cohort with RT-PCR-confirmed infections. Approximately 17% of births had complications; 1.5% (3/194) manifesting clinical criteria of congenital Zika syndrome, one was RT-PCR-confirmed as a case of congenital Zika syndrome. Adverse birth outcome did not correlate with timing of Zika infection. CONCLUSIONS: By leveraging prenatal care systems, we developed a simple algorithm for identifying women who were likely infected by Zika during pregnancy.


Assuntos
Epidemias , Monitoramento Epidemiológico , Mães , Testes Sorológicos , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/imunologia , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Nicarágua/epidemiologia , Gravidez , Estudos Prospectivos , Fatores de Tempo , Adulto Jovem
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