Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 716
Filtrar
1.
PLoS Negl Trop Dis ; 15(3): e0009259, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33705409

RESUMO

Dengue, Zika and chikungunya are diseases of global health significance caused by arboviruses and transmitted by the mosquito Aedes aegypti, which is of worldwide circulation. The arrival of the Zika and chikungunya viruses to South America increased the complexity of transmission and morbidity caused by these viruses co-circulating in the same vector mosquito species. Here we present an integrated analysis of the reported arbovirus cases between 2007 and 2017 and local climate and socio-economic profiles of three distinct Colombian municipalities (Bello, Cúcuta and Moniquirá). These locations were confirmed as three different ecosystems given their contrasted geographic, climatic and socio-economic profiles. Correlational analyses were conducted with both generalised linear models and generalised additive models for the geographical data. Average temperature, minimum temperature and wind speed were strongly correlated with disease incidence. The transmission of Zika during the 2016 epidemic appeared to decrease circulation of dengue in Cúcuta, an area of sustained high incidence of dengue. Socio-economic factors such as barriers to health and childhood services, inadequate sanitation and poor water supply suggested an unfavourable impact on the transmission of dengue, Zika and chikungunya in all three ecosystems. Socio-demographic influencers were also discussed including the influx of people to Cúcuta, fleeing political and economic instability from neighbouring Venezuela. Aedes aegypti is expanding its range and increasing the global threat of these diseases. It is therefore vital that we learn from the epidemiology of these arboviruses and translate it into an actionable local knowledge base. This is even more acute given the recent historical high of dengue cases in the Americas in 2019, preceding the COVID-19 pandemic, which is itself hampering mosquito control efforts.


Assuntos
Febre de Chikungunya/epidemiologia , Dengue/epidemiologia , Infecção por Zika virus/epidemiologia , Aedes/fisiologia , Aedes/virologia , Animais , Febre de Chikungunya/economia , Febre de Chikungunya/virologia , Vírus Chikungunya/fisiologia , Clima , Colômbia/epidemiologia , Dengue/economia , Dengue/virologia , Vírus da Dengue/fisiologia , Ecossistema , Humanos , Mosquitos Vetores/fisiologia , Mosquitos Vetores/virologia , América do Sul , Temperatura , Zika virus/fisiologia , Infecção por Zika virus/economia , Infecção por Zika virus/virologia
2.
BMC Med Res Methodol ; 21(1): 50, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33706715

RESUMO

BACKGROUND: Outbreaks of infectious diseases generate outbreaks of scientific evidence. In 2016 epidemics of Zika virus emerged, and in 2020, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of coronavirus disease 2019 (COVID-19). We compared patterns of scientific publications for the two infections to analyse the evolution of the evidence. METHODS: We annotated publications on Zika virus and SARS-CoV-2 that we collected using living evidence databases according to study design. We used descriptive statistics to categorise and compare study designs over time. RESULTS: We found 2286 publications about Zika virus in 2016 and 21,990 about SARS-CoV-2 up to 24 May 2020, of which we analysed a random sample of 5294 (24%). For both infections, there were more epidemiological than laboratory science studies. Amongst epidemiological studies for both infections, case reports, case series and cross-sectional studies emerged first, cohort and case-control studies were published later. Trials were the last to emerge. The number of preprints was much higher for SARS-CoV-2 than for Zika virus. CONCLUSIONS: Similarities in the overall pattern of publications might be generalizable, whereas differences are compatible with differences in the characteristics of a disease. Understanding how evidence accumulates during disease outbreaks helps us understand which types of public health questions we can answer and when.


Assuntos
/prevenção & controle , Publicações/estatística & dados numéricos , Publicações/tendências , Infecção por Zika virus/prevenção & controle , Zika virus/isolamento & purificação , /epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Surtos de Doenças , Humanos , Pandemias , Publicações Periódicas como Assunto/estatística & dados numéricos , Publicações Periódicas como Assunto/tendências , Zika virus/fisiologia , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/virologia
3.
Nat Commun ; 12(1): 916, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568638

RESUMO

The global emergence of Zika virus (ZIKV) revealed the unprecedented ability for a mosquito-borne virus to cause congenital birth defects. A puzzling aspect of ZIKV emergence is that all human outbreaks and birth defects to date have been exclusively associated with the Asian ZIKV lineage, despite a growing body of laboratory evidence pointing towards higher transmissibility and pathogenicity of the African ZIKV lineage. Whether this apparent paradox reflects the use of relatively old African ZIKV strains in most laboratory studies is unclear. Here, we experimentally compare seven low-passage ZIKV strains representing the recently circulating viral genetic diversity. We find that recent African ZIKV strains display higher transmissibility in mosquitoes and higher lethality in both adult and fetal mice than their Asian counterparts. We emphasize the high epidemic potential of African ZIKV strains and suggest that they could more easily go unnoticed by public health surveillance systems than Asian strains due to their propensity to cause fetal loss rather than birth defects.


Assuntos
Infecção por Zika virus/mortalidade , Infecção por Zika virus/virologia , Zika virus/fisiologia , Zika virus/patogenicidade , Aedes/fisiologia , Aedes/virologia , África , Animais , Ásia , Feminino , Humanos , Masculino , Camundongos , Filogenia , Virulência , Zika virus/classificação , Zika virus/genética , Infecção por Zika virus/transmissão
4.
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
5.
Viruses ; 13(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440758

RESUMO

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination-which is critical for saltatory conduction and neuronal function-has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.


Assuntos
Axônios/virologia , Doenças Desmielinizantes/etiologia , Infecção por Zika virus/complicações , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Biomarcadores , Traumatismos dos Nervos Cranianos/etiologia , Traumatismos dos Nervos Cranianos/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Ratos , Transcriptoma
6.
Cell ; 184(1): 133-148.e20, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33338421

RESUMO

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.


Assuntos
Infecções por Flavivirus/genética , Flavivirus/fisiologia , Proteínas de Membrana/metabolismo , Animais , Grupo com Ancestrais do Continente Asiático/genética , Autofagia , /metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/metabolismo , Infecções por Flavivirus/virologia , Técnicas de Inativação de Genes , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Replicação Viral , Vírus da Febre Amarela/fisiologia , Zika virus/fisiologia
7.
Viruses ; 12(12)2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371476

RESUMO

Flaviviruses bear class II fusion proteins as their envelope (E) proteins. Here, we describe the development of an in vitro quantitative mosquito-cell-based membrane-fusion assay for the E protein using dual split proteins (DSPs). The assay does not involve the use of live viruses and allows the analysis of a membrane-fusion step independent of other events in the viral lifecycle, such as endocytosis. The progress of membrane fusion can be monitored continuously by measuring the activities of Renilla luciferase derived from the reassociation of DSPs during cell fusion. We optimized the assay to screen an FDA-approved drug library for a potential membrane fusion inhibitor using the E protein of Zika virus. Screening results identified atovaquone, which was previously described as an antimalarial agent. Atovaquone potently blocked the in vitro Zika virus infection of mammalian cells with an IC90 of 2.1 µM. Furthermore, four distinct serotypes of dengue virus were also inhibited by atovaquone with IC90 values of 1.6-2.5 µM, which is a range below the average blood concentration of atovaquone after its oral administration in humans. These findings make atovaquone a likely candidate drug to treat illnesses caused by Zika as well as dengue viruses. Additionally, the DSP assay is useful to study the mechanism of membrane fusion in Flaviviruses.


Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Dengue/virologia , Fusão de Membrana/efeitos dos fármacos , Proteínas do Envelope Viral/metabolismo , Infecção por Zika virus/virologia , Zika virus/efeitos dos fármacos , Animais , Linhagem Celular , Culicidae , Dengue/tratamento farmacológico , Vírus da Dengue/fisiologia , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , Internalização do Vírus/efeitos dos fármacos , Zika virus/fisiologia , Infecção por Zika virus/tratamento farmacológico
8.
BMC Med ; 18(1): 399, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33327961

RESUMO

BACKGROUND: Zika virus (ZIKV) emerged as a global epidemic in 2015-2016 from Latin America with its true geographical extent remaining unclear due to widely presumed underreporting. The identification of locations with potential and unknown spread of ZIKV is a key yet understudied component for outbreak preparedness. Here, we aim to identify locations at a high risk of cryptic ZIKV spread during 2015-2016 to further the understanding of the global ZIKV epidemiology, which is critical for the mitigation of the risk of future epidemics. METHODS: We developed an importation simulation model to estimate the weekly number of ZIKV infections imported in each susceptible spatial unit (i.e. location that did not report any autochthonous Zika cases during 2015-2016), integrating epidemiological, demographic, and travel data as model inputs. Thereafter, a global risk model was applied to estimate the weekly ZIKV transmissibility during 2015-2016 for each location. Finally, we assessed the risk of onward ZIKV spread following importation in each susceptible spatial unit to identify locations with a high potential for cryptic ZIKV spread during 2015-2016. RESULTS: We have found 24 susceptible spatial units that were likely to have experienced cryptic ZIKV spread during 2015-2016, of which 10 continue to have a high risk estimate within a highly conservative scenario, namely, Luanda in Angola, Banten in Indonesia, Maharashtra in India, Lagos in Nigeria, Taiwan and Guangdong in China, Dakar in Senegal, Maputo in Mozambique, Kinshasa in Congo DRC, and Pool in Congo. Notably, among the 24 susceptible spatial units identified, some have reported their first ZIKV outbreaks since 2017, thus adding to the credibility of our results (derived using 2015-2016 data only). CONCLUSION: Our study has provided valuable insights into the potentially high-risk locations for cryptic ZIKV circulation during the 2015-2016 pandemic and has also laid a foundation for future studies that attempt to further narrow this key knowledge gap. Our modelling framework can be adapted to identify areas with likely unknown spread of other emerging vector-borne diseases, which has important implications for public health readiness especially in resource-limited settings.


Assuntos
Mapeamento Geográfico , Infecção por Zika virus/epidemiologia , Aedes/fisiologia , Aedes/virologia , Animais , Surtos de Doenças/história , Ecologia , Epidemias , Geografia , História do Século XXI , Humanos , Viagem/estatística & dados numéricos , Zika virus/fisiologia , Infecção por Zika virus/história
9.
BMC Bioinformatics ; 21(Suppl 18): 578, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33375933

RESUMO

BACKGROUND: As the number of RNA-seq datasets that become available to explore transcriptome diversity increases, so does the need for easy-to-use comprehensive computational workflows. Many available tools facilitate analyses of one of the two major mechanisms of transcriptome diversity, namely, differential expression of isoforms due to alternative splicing, while the second major mechanism-RNA editing due to post-transcriptional changes of individual nucleotides-remains under-appreciated. Both these mechanisms play an essential role in physiological and diseases processes, including cancer and neurological disorders. However, elucidation of RNA editing events at transcriptome-wide level requires increasingly complex computational tools, in turn resulting in a steep entrance barrier for labs who are interested in high-throughput variant calling applications on a large scale but lack the manpower and/or computational expertise. RESULTS: Here we present an easy-to-use, fully automated, computational pipeline (Automated Isoform Diversity Detector, AIDD) that contains open source tools for various tasks needed to map transcriptome diversity, including RNA editing events. To facilitate reproducibility and avoid system dependencies, the pipeline is contained within a pre-configured VirtualBox environment. The analytical tasks and format conversions are accomplished via a set of automated scripts that enable the user to go from a set of raw data, such as fastq files, to publication-ready results and figures in one step. A publicly available dataset of Zika virus-infected neural progenitor cells is used to illustrate AIDD's capabilities. CONCLUSIONS: AIDD pipeline offers a user-friendly interface for comprehensive and reproducible RNA-seq analyses. Among unique features of AIDD are its ability to infer RNA editing patterns, including ADAR editing, and inclusion of Guttman scale patterns for time series analysis of such editing landscapes. AIDD-based results show importance of diversity of ADAR isoforms, key RNA editing enzymes linked with the innate immune system and viral infections. These findings offer insights into the potential role of ADAR editing dysregulation in the disease mechanisms, including those of congenital Zika syndrome. Because of its automated all-inclusive features, AIDD pipeline enables even a novice user to easily explore common mechanisms of transcriptome diversity, including RNA editing landscapes.


Assuntos
Software , Transcriptoma , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Expressão Gênica , Ontologia Genética , Humanos , Análise de Componente Principal , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Edição de RNA , RNA-Seq , Células-Tronco/citologia , Células-Tronco/metabolismo , Células-Tronco/virologia , Zika virus/fisiologia
10.
PLoS Negl Trop Dis ; 14(12): e0008971, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33338046

RESUMO

Aedes aegypti is a vector of dengue, chikungunya, and Zika viruses. Current vector control strategies such as community engagement, source reduction, and insecticides have not been sufficient to prevent viral outbreaks. Thus, interest in novel strategies involving genetic engineering is growing. Female mosquitoes rely on flight to mate with males and obtain a bloodmeal from a host. We hypothesized that knockout of genes specifically expressed in female mosquitoes associated with the indirect flight muscles would result in a flightless female mosquito. Using CRISPR-Cas9 we generated loss-of-function mutations in several genes hypothesized to control flight in mosquitoes, including actin (AeAct-4) and myosin (myo-fem) genes expressed specifically in the female flight muscle. Genetic knockout of these genes resulted in 100% flightless females, with homozygous males able to fly, mate, and produce offspring, albeit at a reduced rate when compared to wild type males. Interestingly, we found that while AeAct-4 was haplosufficient, with most heterozygous individuals capable of flight, this was not the case for myo-fem, where about half of individuals carrying only one intact copy could not fly. These findings lay the groundwork for developing novel mechanisms of controlling Ae. aegypti populations, and our results suggest that this mechanism could be applicable to other vector species of mosquito.


Assuntos
Aedes/genética , Sistemas CRISPR-Cas , Inseticidas/farmacologia , Controle de Mosquitos , Mosquitos Vetores/genética , Infecção por Zika virus/prevenção & controle , Zika virus/fisiologia , Aedes/fisiologia , Aedes/virologia , Animais , Feminino , Voo Animal , Técnicas de Inativação de Genes , Humanos , Masculino , Mosquitos Vetores/fisiologia , Mosquitos Vetores/virologia , Fenótipo , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
11.
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
12.
Viruses ; 13(1)2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374816

RESUMO

Zika virus (ZIKV) became a worldwide public health emergency after its introduction in the Americas. Brazil was implicated as central in the ZIKV dispersion, however, a better understanding of the pathways the virus took to arrive in Brazil and the dispersion within the country is needed. An updated genome dataset was assembled with publicly available data. Bayesian phylogeography methods were applied to reconstruct the spatiotemporal history of ZIKV in the Americas and with more detail inside Brazil. Our analyses reconstructed the Brazilian state of Pernambuco as the likely point of introduction of ZIKV in Brazil, possibly during the 2013 Confederations Cup. Pernambuco played an important role in spreading the virus to other Brazilian states. Our results also underscore the long cryptic circulation of ZIKV in all analyzed locations in Brazil. Conclusions: This study brings new insights about the early moments of ZIKV in the Americas, especially regarding the Brazil-Haiti cluster at the base of the American clade and describing for the first time migration patterns within Brazil.


Assuntos
Infecção por Zika virus/epidemiologia , Infecção por Zika virus/virologia , Zika virus/fisiologia , América/epidemiologia , Brasil/epidemiologia , Surtos de Doenças , Genoma Viral , Humanos , Filogenia , Filogeografia , Vigilância em Saúde Pública , Análise Espaço-Temporal , Zika virus/classificação
13.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375140

RESUMO

Zika virus (ZIKV) acquired a special relevance due to the pandemic that occurred in the Americas in 2015, when an important number of fetal microcephaly cases occurred. Since then, numerous studies have tried to elucidate the pathogenic mechanisms and the potential therapeutic approaches to combat the virus. Cellular and animal models have proved to be a basic resource for this research, with the more recent addition of organoids as a more realistic and physiological 3D culture for the study of ZIKV. Nanotechnology can also offer a promising therapeutic tool, as the nanoparticles developed by this field can penetrate cells and deliver a wide array of drugs in a very specific and controlled way inside the cells. These two state-of-the-art scientific tools clearly provide a very relevant resource for the study of ZIKV, and will help researchers find an effective treatment or vaccine against the virus.


Assuntos
Antivirais/farmacologia , Nanotecnologia/métodos , Técnicas de Cultura de Órgãos/métodos , Organoides/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico , Zika virus/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Nanomedicina/métodos , Organoides/virologia , Zika virus/fisiologia , Infecção por Zika virus/virologia
14.
Cells ; 9(11)2020 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-33171736

RESUMO

Viruses exhibit an elegant simplicity, as they are so basic, but so frightening. Although only a few are life threatening, they have substantial implications for human health and the economy, as exemplified by the ongoing coronavirus pandemic. Viruses are rather small infectious agents found in all types of life forms, from animals and plants to prokaryotes and archaebacteria. They are obligate intracellular parasites, and as such, subvert many molecular and cellular processes of the host cell to ensure their own replication, amplification, and subsequent spread. This special issue addresses the cell biology of viral infections based on a collection of original research articles, communications, opinions, and reviews on various aspects of virus-host cell interactions. Together, these articles not only provide a glance into the latest research on the cell biology of viral infections, but also include novel technological developments.


Assuntos
Viroses/patologia , Animais , Betacoronavirus/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Transdução de Sinais , Viroses/metabolismo , Viroses/virologia , Zika virus/fisiologia
15.
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
16.
Nat Commun ; 11(1): 4953, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009400

RESUMO

Zika virus (ZIKV) is an emerging mosquito borne flavivirus and a major public health concern causing severe disease. Due to the presence of a lipid membrane and structural heterogeneity, attaining an atomic resolution structure is challenging, but important to understand virus assembly and life cycle mechanisms that offer distinct targets for therapeutic intervention. We here use subvolume refinement to achieve a 3.4 Å resolution structure and identify two distinct lipid moieties. The first arises from the inner leaflet and is coordinated by hydrophobic residues of the M and E transmembrane helices that form a binding pocket not previously characterized. The second lipid arises from the outer leaflet coordinate between two E protein helices. Structure-based mutagenesis identifies critical hydrophobic interactions and their effect on the virus life cycle. Results show that lipids play an essential role in the ZIKV assembly pathway revealing a potential target of lipid based antiviral drug development.


Assuntos
Montagem de Vírus/fisiologia , Zika virus/fisiologia , Animais , Chlorocebus aethiops , Células HEK293 , Humanos , Células Vero , Vírion/ultraestrutura , Zika virus/isolamento & purificação , Zika virus/ultraestrutura
17.
PLoS One ; 15(10): e0235877, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33091010

RESUMO

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.


Assuntos
Transtornos da Audição/patologia , Malformações do Sistema Nervoso/patologia , Complicações Infecciosas na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Transtornos da Visão/patologia , Infecção por Zika virus/complicações , Zika virus/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Transtornos da Audição/etiologia , Macaca mulatta , Malformações do Sistema Nervoso/etiologia , Gravidez , Complicações Infecciosas na Gravidez/etiologia , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Transtornos da Visão/etiologia , Infecção por Zika virus/virologia
18.
Chem Biol Interact ; 331: 109218, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916141

RESUMO

Flavonoids are natural products widely recognized for their plurality of applications such as antiviral, antiproliferative, antitumor activities and, antioxidant properties. The flavanone naringenin is presented in citrus fruits and has been studied to combat recurrent diseases that still lack effective treatment. Research groups have been investing efforts to the development of new, safe and active candidates to combat these agents or conditions and despite good results recently reported against the Zika virus (ZIKV) and tumor cells, the use of citrus naringenin is limited due to its low bioavailability. Structural exchanges through functionalization, for example, attaching lipophilic groups instead of hydroxyl groups, can further enhance biological properties. Here, the synthesis and characterization of regioselective naringenin mono-7-O-ethers and both mono and di-fatty acid esters, structurally lipophilic ones were demonstrated. Finally, in vitro studies of anti-ZIKV action and antiproliferative activities against melanoma (B16-F10) and breast carcinoma (4T1) cells showed the ether derivatives were actives, with IC50 ranging from 6.76, 18.5 and 22.6 µM to 28.53, 45.1 and 32.3 µM referring to ZIKV, B16-F10 and 4T1 cell lines, respectively. The lipophilic ethers present the ability to inhibit selectively ZIKV-replication in human cells and inhibitions. This class of modifications in flavonoid molecules could be further explore in the future development of specific anti-ZIKV compounds.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antivirais/farmacologia , Citrus/química , Flavanonas/química , Zika virus/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/química , Antivirais/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citrus/metabolismo , Flavanonas/farmacologia , Humanos , Camundongos , Replicação Viral/efeitos dos fármacos , Zika virus/fisiologia
19.
PLoS One ; 15(9): e0239238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941515

RESUMO

Zika virus (ZIKV) is a single-stranded RNA virus belonging to the family Flaviviridae. ZIKV predominantly enters cells using the TAM-family protein tyrosine kinase receptor AXL, which is expressed on a range of cell types, including neural progenitor cells, keratinocytes, dendritic cells, and osteoblasts. ZIKV infections have been associated with fetal brain damage, which prompted the World Health Organization to declare a public health emergency in 2016. ZIKV infection has also been linked to birth defects in other organs. Several studies have reported congenital heart defects (CHD) in ZIKV infected infants and cardiovascular complications in adults infected with ZIKV. To develop a better understanding of potential causes for these pathologies at a cellular level, we characterized ZIKV infection of human fetal cardiac mesenchymal stromal cells (fcMSCs), a cell type that is known to contribute to both embryological development as well as adult cardiac physiology. Total RNA, supernatants, and/or cells were collected at various time points post-infection to evaluate ZIKV replication, cell death, and antiviral responses. We found that ZIKV productively infected fcMSCs with peak (~70%) viral mRNA detected at 48 h. Use of an antibody blocking the AXL receptor decreased ZIKV infection (by ~50%), indicating that the receptor is responsible to a large extent for viral entry into the cell. ZIKV also altered protein expression of several mesenchymal cell markers, which suggests that ZIKV could affect fcMSCs' differentiation process. Gene expression analysis of fcMSCs exposed to ZIKV at 6, 12, and 24 h post-infection revealed up-regulation of genes/pathways associated with interferon-stimulated antiviral responses. Stimulation of TLR3 (using poly I:C) or TLR7 (using Imiquimod) prior to ZIKV infection suppressed viral replication in a dose-dependent manner. Overall, fcMSCs can be a target for ZIKV infection, potentially resulting in CHD during embryological development and/or cardiovascular issues in ZIKV infected adults.


Assuntos
Células-Tronco Embrionárias Humanas/virologia , Células-Tronco Mesenquimais/virologia , Miócitos Cardíacos/virologia , Replicação Viral , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Morte Celular , Células Cultivadas , Chlorocebus aethiops , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Interferons/genética , Interferons/metabolismo , Células-Tronco Mesenquimais/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Células Vero , Zika virus/patogenicidade , Infecção por Zika virus/metabolismo
20.
Nat Commun ; 11(1): 3896, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753727

RESUMO

The outbreak of Zika virus (ZIKV) in 2016 created worldwide health emergency which demand urgent research efforts on understanding the virus biology and developing therapeutic strategies. Here, we present a time-resolved chemical proteomic strategy to track the early-stage entry of ZIKV into host cells. ZIKV was labeled on its surface with a chemical probe, which carries a photocrosslinker to covalently link virus-interacting proteins in living cells on UV exposure at different time points, and a biotin tag for subsequent enrichment and mass spectrometric identification of the receptor or other host proteins critical for virus internalization. We identified Neural Cell Adhesion Molecule (NCAM1) as a potential ZIKV receptor and further validated it through overexpression, knockout, and inhibition of NCAM1 in Vero cells and human glioblastoma cells U-251 MG. Collectively, the strategy can serve as a universal tool to map virus entry pathways and uncover key interacting proteins.


Assuntos
Moléculas de Adesão de Célula Nervosa/metabolismo , Proteômica , Receptores Virais/metabolismo , Internalização do Vírus , Replicação Viral/fisiologia , Zika virus/fisiologia , Animais , Antígeno CD56/genética , Antígeno CD56/metabolismo , Linhagem Celular Tumoral , Chlorocebus aethiops , Técnicas de Inativação de Genes , Glioblastoma , Células HEK293 , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Moléculas de Adesão de Célula Nervosa/genética , Células Vero , Proteínas Virais/metabolismo , Ligação Viral , Infecção por Zika virus/virologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...