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1.
Proc Natl Acad Sci U S A ; 121(21): e2312755121, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38743628

RESUMO

Antigenic similarities between Zika virus (ZIKV) and other flaviviruses pose challenges to the development of virus-specific diagnostic tools and effective vaccines. Starting with a DNA-encoded one-bead-one-compound combinatorial library of 508,032 synthetic, non-natural oligomers, we selected and characterized small molecules that mimic ZIKV epitopes. High-throughput fluorescence-activated cell sorter-based bead screening was used to select molecules that bound IgG from ZIKV-immune but not from dengue-immune sera. Deep sequencing of the DNA from the "Zika-only" beads identified 40 candidate molecular structures. A lead candidate small molecule "CZV1-1" was selected that correctly identifies serum specimens from Zika-experienced patients with good sensitivity and specificity (85.3% and 98.4%, respectively). Binding competition studies of purified anti-CZV1-1 IgG against known ZIKV-specific monoclonal antibodies (mAbs) showed that CZV1-1 mimics a nonlinear, neutralizing conformational epitope in the domain III of the ZIKV envelope. Purified anti-CZV1-1 IgG neutralized infection of ZIKV in cell cultures with potencies comparable to highly specific ZIKV-neutralizing mAbs. This study demonstrates an innovative approach for identification of synthetic non-natural molecular mimics of conformational virus epitopes. Such molecular mimics may have value in the development of accurate diagnostic assays for Zika, as well as for other viruses.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Epitopos , Infecção por Zika virus , Zika virus , Zika virus/imunologia , Epitopos/imunologia , Humanos , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Imunoglobulina G/imunologia , Anticorpos Monoclonais/imunologia , Mimetismo Molecular/imunologia
2.
Sci Signal ; 17(837): eadi9844, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38771918

RESUMO

Oligoadenylate synthetase 3 (OAS3) and ribonuclease L (RNase L) are components of a pathway that combats viral infection in mammals. Upon detection of viral double-stranded RNA (dsRNA), OAS3 synthesizes 2'-5'-oligo(A), which activates the RNase domain of RNase L by promoting the homodimerization and oligomerization of RNase L monomers. Activated RNase L rapidly degrades all cellular mRNAs, shutting off several cellular processes. We sought to understand the molecular mechanisms underlying the rapid activation of RNase L in response to viral infection. Through superresolution microscopy and live-cell imaging, we showed that OAS3 and RNase L concentrated into higher-order cytoplasmic complexes known as dsRNA-induced foci (dRIF) in response to dsRNA or infection with dengue virus, Zika virus, or West Nile virus. The concentration of OAS3 and RNase L at dRIF corresponded with the activation of RNase L-mediated RNA decay. We showed that dimerized/oligomerized RNase L concentrated in a liquid-like shell surrounding a core OAS3-dRIF structure and dynamically exchanged with the cytosol. These data establish that the condensation of dsRNA, OAS3, and RNase L into dRIF is a molecular switch that promotes the rapid activation of RNase L upon detection of dsRNA in mammalian cells.


Assuntos
2',5'-Oligoadenilato Sintetase , Endorribonucleases , RNA de Cadeia Dupla , Zika virus , Endorribonucleases/metabolismo , Endorribonucleases/genética , Endorribonucleases/química , Humanos , 2',5'-Oligoadenilato Sintetase/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/química , RNA de Cadeia Dupla/metabolismo , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/genética , Zika virus/metabolismo , Animais , Vírus da Dengue/metabolismo , RNA Viral/metabolismo , RNA Viral/genética , Estabilidade de RNA , Vírus do Nilo Ocidental/metabolismo , Vírus do Nilo Ocidental/genética , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia , Ativação Enzimática , Células HeLa , Células HEK293
3.
PLoS One ; 19(5): e0302684, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722858

RESUMO

BACKGROUND: In most cases, Zika virus (ZIKV) causes a self-limited acute illness in adults, characterized by mild clinical symptoms that resolve within a few days. Immune responses, both innate and adaptive, play a central role in controlling and eliminating virus-infected cells during the early stages of infection. AIM: To test the hypothesis that circulating T cells exhibit phenotypic and functional activation characteristics during the viremic phase of ZIKV infection. METHODS: A comprehensive analysis using mass cytometry was performed on peripheral blood mononuclear cells obtained from patients with acute ZIKV infection (as confirmed by RT-PCR) and compared with that from healthy donors (HD). The frequency of IFN-γ-producing T cells in response to peptide pools covering immunogenic regions of structural and nonstructural ZIKV proteins was quantified using an ELISpot assay. RESULTS: Circulating CD4+ and CD8+ T lymphocytes from ZIKV-infected patients expressed higher levels of IFN-γ and pSTAT-5, as well as cell surface markers associated with proliferation (Ki-67), activation ((HLA-DR, CD38) or exhaustion (PD1 and CTLA-4), compared to those from HD. Activation of CD4+ and CD8+ memory T cell subsets, including Transitional Memory T Cells (TTM), Effector Memory T cells (TEM), and Effector Memory T cells Re-expressing CD45RA (TEMRA), was prominent among CD4+ T cell subset of ZIKV-infected patients and was associated with increased levels of IFN-γ, pSTAT-5, Ki-67, CTLA-4, and PD1, as compared to HD. Additionally, approximately 30% of ZIKV-infected patients exhibited a T cell response primarily directed against the ZIKV NS5 protein. CONCLUSION: Circulating T lymphocytes spontaneously produce IFN-γ and express elevated levels of pSTAT-5 during the early phase of ZIKV infection whereas recognition of ZIKV antigen results in the generation of virus-specific IFN-γ-producing T cells.


Assuntos
Linfócitos T CD8-Positivos , Interferon gama , Infecção por Zika virus , Zika virus , Humanos , Infecção por Zika virus/imunologia , Infecção por Zika virus/epidemiologia , Adulto , Zika virus/imunologia , Feminino , Masculino , Interferon gama/metabolismo , Interferon gama/imunologia , Brasil/epidemiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Pessoa de Meia-Idade , Adulto Jovem , Epidemias , Ativação Linfocitária/imunologia , Linfócitos T/imunologia
4.
PLoS One ; 19(5): e0281851, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38748732

RESUMO

Zika (ZIKV) and chikungunya (CHIKV) are arboviruses that cause infections in humans and can cause clinical complications, representing a worldwide public health problem. Aedes aegypti is the primary vector of these pathogens and Culex quinquefasciatus may be a potential ZIKV vector. This study aimed to evaluate fecundity, fertility, survival, longevity, and blood feeding activity in Ae. aegypti after exposure to ZIKV and CHIKV and, in Cx. quinquefasciatus exposed to ZIKV. Three colonies were evaluated: AeCamp (Ae. aegypti-field), RecL (Ae. aegypti-laboratory) and CqSLab (Cx. quinquefasciatus-laboratory). Seven to 10 days-old females from these colonies were exposed to artificial blood feeding with CHIKV or ZIKV. CHIKV caused reduction in fecundity and fertility in AeCamp and reduction in survival and fertility in RecL. ZIKV impacted survival in RecL, fertility in AeCamp and, fecundity and fertility in CqSLab. Both viruses had no effect on blood feeding activity. These results show that CHIKV produces a higher biological cost in Ae. aegypti, compared to ZIKV, and ZIKV differently alters the biological performance in colonies of Ae. aegypti and Cx. quinquefasciatus. These results provide a better understanding over the processes of virus-vector interaction and can shed light on the complexity of arbovirus transmission.


Assuntos
Aedes , Vírus Chikungunya , Culex , Fertilidade , Mosquitos Vetores , Infecção por Zika virus , Zika virus , Animais , Aedes/virologia , Aedes/fisiologia , Vírus Chikungunya/fisiologia , Vírus Chikungunya/patogenicidade , Zika virus/fisiologia , Zika virus/patogenicidade , Culex/virologia , Culex/fisiologia , Mosquitos Vetores/virologia , Mosquitos Vetores/fisiologia , Feminino , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Comportamento Alimentar/fisiologia , Humanos , Longevidade
5.
ACS Appl Bio Mater ; 7(5): 2862-2871, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38699864

RESUMO

Mosquito-borne viruses are a major worldwide health problem associated with high morbidity and mortality rates and significant impacts on national healthcare budgets. The development of antiviral drugs for both the treatment and prophylaxis of these diseases is thus of considerable importance. To address the need for therapeutics with antiviral activity, a library of heparan sulfate mimetic polymers was screened against dengue virus (DENV), Yellow fever virus (YFV), Zika virus (ZIKV), and Ross River virus (RRV). The polymers were prepared by RAFT polymerization of various acidic monomers with a target MW of 20 kDa (average Mn ∼ 27 kDa by GPC). Among the polymers, poly(SS), a homopolymer of sodium styrenesulfonate, was identified as a broad spectrum antiviral with activity against all the tested viruses and particularly potent inhibition of YFV (IC50 = 310 pM). Our results further uncovered that poly(SS) exhibited a robust inhibition of ZIKV infection in both mosquito and human cell lines, which points out the potential functions of poly(SS) in preventing mosquito-borne viruses associated diseases by blocking viral transmission in their mosquito vectors and mitigating viral infection in patients.


Assuntos
Antivirais , Heparitina Sulfato , Polímeros , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Animais , Humanos , Polímeros/química , Polímeros/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Culicidae/efeitos dos fármacos , Culicidae/virologia , Testes de Sensibilidade Microbiana , Teste de Materiais , Tamanho da Partícula , Linhagem Celular , Estrutura Molecular , Chlorocebus aethiops , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Zika virus/efeitos dos fármacos
6.
Sci Rep ; 14(1): 10003, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693192

RESUMO

Zika, a viral disease transmitted to humans by Aedes mosquitoes, emerged in the Americas in 2015, causing large-scale epidemics. Colombia alone reported over 72,000 Zika cases between 2015 and 2016. Using national surveillance data from 1121 municipalities over 70 weeks, we identified sociodemographic and environmental factors associated with Zika's emergence, re-emergence, persistence, and transmission intensity in Colombia. We fitted a zero-state Markov-switching model under the Bayesian framework, assuming Zika switched between periods of presence and absence according to spatially and temporally varying probabilities of emergence/re-emergence (from absence to presence) and persistence (from presence to presence). These probabilities were assumed to follow a series of mixed multiple logistic regressions. When Zika was present, assuming that the cases follow a negative binomial distribution, we estimated the transmission intensity rate. Our results indicate that Zika emerged/re-emerged sooner and that transmission was intensified in municipalities that were more densely populated, at lower altitudes and/or with less vegetation cover. Warmer temperatures and less weekly-accumulated rain were also associated with Zika emergence. Zika cases persisted for longer in more densely populated areas with more cases reported in the previous week. Overall, population density, elevation, and temperature were identified as the main contributors to the first Zika epidemic in Colombia. We also estimated the probability of Zika presence by municipality and week, and the results suggest that the disease circulated undetected by the surveillance system on many occasions. Our results offer insights into priority areas for public health interventions against emerging and re-emerging Aedes-borne diseases.


Assuntos
Aedes , Cadeias de Markov , Infecção por Zika virus , Zika virus , Infecção por Zika virus/transmissão , Infecção por Zika virus/epidemiologia , Colômbia/epidemiologia , Humanos , Animais , Aedes/virologia , Teorema de Bayes , Mosquitos Vetores/virologia , Surtos de Doenças
7.
Sci Rep ; 14(1): 10407, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710792

RESUMO

Glucose regulated protein 78 (GRP78) is a chaperone protein that is a central mediator of the unfolded protein response, a key cellular stress response pathway. GRP78 has been shown to be critically required for infection and replication of a number of flaviviruses, and to interact with both non-structural (NS) and structural flavivirus proteins. However, the nature of the specific interaction between GRP78 and viral proteins remains largely unknown. This study aimed to characterize the binding domain and critical amino acid residues that mediate the interaction of GRP78 to ZIKV E and NS1 proteins. Recombinant EGFP fused GRP78 and individual subdomains (the nucleotide binding domain (NBD) and the substrate binding domain (SBD)) were used as a bait protein and co-expressed with full length or truncated ZIKV E and NS1 proteins in HEK293T/17 cells. Protein-protein interactions were determined by a co-immunoprecipitation assay. From the results, both the NBD and the SBD of GRP78 were crucial for an effective interaction. Single amino acid substitutions in the SBD showed that R492E and T518A mutants significantly reduced the binding affinity of GRP78 to ZIKV E and NS1 proteins. Notably, the interaction of GRP78 with ZIKV E was stably maintained against various single amino acid substitutions on ZIKV E domain III and with all truncated ZIKV E and NS1 proteins. Collectively, the results suggest that the principal binding between GRP78 and viral proteins is mainly a classic canonical chaperone protein-client interaction. The blocking of GRP78 chaperone function effectively inhibited ZIKV infection and replication in neuronal progenitor cells. Our findings reveal that GRP78 is a potential host target for anti-ZIKV therapeutics.


Assuntos
Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico , Ligação Proteica , Proteínas não Estruturais Virais , Zika virus , Chaperona BiP do Retículo Endoplasmático/metabolismo , Zika virus/metabolismo , Zika virus/fisiologia , Humanos , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Células HEK293 , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/genética , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia , Replicação Viral
8.
J Chem Theory Comput ; 20(9): 3359-3378, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38703105

RESUMO

Despite the recent advancements by deep learning methods such as AlphaFold2, in silico protein structure prediction remains a challenging problem in biomedical research. With the rapid evolution of quantum computing, it is natural to ask whether quantum computers can offer some meaningful benefits for approaching this problem. Yet, identifying specific problem instances amenable to quantum advantage and estimating the quantum resources required are equally challenging tasks. Here, we share our perspective on how to create a framework for systematically selecting protein structure prediction problems that are amenable for quantum advantage, and estimate quantum resources for such problems on a utility-scale quantum computer. As a proof-of-concept, we validate our problem selection framework by accurately predicting the structure of a catalytic loop of the Zika Virus NS3 Helicase, on quantum hardware.


Assuntos
Teoria Quântica , Zika virus/química , Conformação Proteica , Proteínas/química , Proteínas não Estruturais Virais/química , RNA Helicases/química , RNA Helicases/metabolismo
9.
Euro Surveill ; 29(20)2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38757289

RESUMO

Aedes albopictus collected in 2023 in the greater Paris area (Île-de-France) were experimentally able to transmit five arboviruses: West Nile virus from 3 days post-infection (dpi), chikungunya virus and Usutu virus from 7 dpi, dengue virus and Zika virus from 21 dpi. Given the growing number of imported dengue cases reported in early 2024 in France, surveillance of Ae. albopictus should be reinforced during the Paris Olympic Games in July, when many international visitors including from endemic countries are expected.


Assuntos
Aedes , Vírus Chikungunya , Vírus da Dengue , Zika virus , Animais , Aedes/virologia , Humanos , Zika virus/isolamento & purificação , Vírus da Dengue/isolamento & purificação , Vírus Chikungunya/isolamento & purificação , Paris , Mosquitos Vetores/virologia , Vírus do Nilo Ocidental/isolamento & purificação , Arbovírus/isolamento & purificação , Infecções por Arbovirus/transmissão , Flavivirus/isolamento & purificação , França , Dengue/transmissão , Dengue/epidemiologia , Infecção por Zika virus/transmissão
10.
PLoS Negl Trop Dis ; 18(4): e0012053, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38557981

RESUMO

BACKGROUND: Mosquito-borne arboviruses are expanding their territory and elevating their infection prevalence due to the rapid climate change, urbanization, and increased international travel and global trade. Various significant arboviruses, including the dengue virus, Zika virus, Chikungunya virus, and yellow fever virus, are all reliant on the same primary vector, Aedes aegypti. Consequently, the occurrence of arbovirus coinfection in mosquitoes is anticipated. Arbovirus coinfection in mosquitoes has two patterns: simultaneous and sequential. Numerous studies have demonstrated that simultaneous coinfection of arboviruses in mosquitoes is unlikely to exert mutual developmental influence on these viruses. However, the viruses' interplay within a mosquito after the sequential coinfection seems intricated and not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We conducted experiments aimed at examining the phenomenon of arbovirus sequential coinfection in both mosquito cell line (C6/36) and A. aegypti, specifically focusing on dengue virus (DENV, serotype 2) and Zika virus (ZIKV). We firstly observed that DENV and ZIKV can sequentially infect mosquito C6/36 cell line, but the replication level of the subsequently infected ZIKV was significantly suppressed. Similarly, A. aegypti mosquitoes can be sequentially coinfected by these two arboviruses, regardless of the order of virus exposure. However, the replication, dissemination, and the transmission potential of the secondary virus were significantly inhibited. We preliminarily explored the underlying mechanisms, revealing that arbovirus-infected mosquitoes exhibited activated innate immunity, disrupted lipid metabolism, and enhanced RNAi pathway, leading to reduced susceptibility to the secondary arbovirus infections. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that, in contrast to simultaneous arbovirus coinfection in mosquitoes that can promote the transmission and co-circulation of these viruses, sequential coinfection appears to have limited influence on arbovirus transmission dynamics. However, it is important to note that more experimental investigations are needed to refine and expand upon this conclusion.


Assuntos
Aedes , Arbovírus , Coinfecção , Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Animais , Coinfecção/epidemiologia , Mosquitos Vetores , Dengue/epidemiologia
11.
Cells ; 13(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38607037

RESUMO

Zika virus (ZIKV) infection and pathogenesis are linked to the disruption of neurogenesis, congenital Zika syndrome and microcephaly by affecting neural progenitor cells. Nonstructural protein 5 (NS5) is the largest product encoded by ZIKV-RNA and is important for replication and immune evasion. Here, we studied the potential effects of NS5 on microtubules (MTs) and autophagy flux, together with the interplay of NS5 with histone deacetylase 6 (HDAC6). Fluorescence microscopy, biochemical cell-fractionation combined with the use of HDAC6 mutants, chemical inhibitors and RNA interference indicated that NS5 accumulates in nuclear structures and strongly promotes the acetylation of MTs that aberrantly reorganize in nested structures. Similarly, NS5 accumulates the p62 protein, an autophagic-flux marker. Therefore, NS5 alters events that are under the control of the autophagic tubulin-deacetylase HDAC6. HDAC6 appears to degrade NS5 by autophagy in a deacetylase- and BUZ domain-dependent manner and to control the cytoplasmic expression of NS5. Moreover, NS5 inhibits RNA-mediated RIG-I interferon (IFN) production, resulting in greater activity when autophagy is inhibited (i.e., effect correlated with NS5 stability). Therefore, it is conceivable that NS5 contributes to cell toxicity and pathogenesis, evading the IFN-immune response by overcoming HDAC6 functions. HDAC6 has emerged as an anti-ZIKV factor by targeting NS5.


Assuntos
Infecção por Zika virus , Zika virus , Humanos , Zika virus/fisiologia , Desacetilase 6 de Histona , Tubulina (Proteína) , Microtúbulos , RNA , Autofagia
12.
Curr Microbiol ; 81(5): 133, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592489

RESUMO

Zika virus (ZIKV) infections have been associated with severe clinical outcomes, which may include neurological manifestations, especially in newborns with intrauterine infection. However, licensed vaccines and specific antiviral agents are not yet available. Therefore, a safe and low-cost therapy is required, especially for pregnant women. In this regard, metformin, an FDA-approved drug used to treat gestational diabetes, has previously exhibited an anti-ZIKA effect in vitro in HUVEC cells by activating AMPK. In this study, we evaluated metformin treatment during ZIKV infection in vitro in a JEG3-permissive trophoblast cell line. Our results demonstrate that metformin affects viral replication and protein synthesis and reverses cytoskeletal changes promoted by ZIKV infection. In addition, it reduces lipid droplet formation, which is associated with lipogenic activation of infection. Taken together, our results indicate that metformin has potential as an antiviral agent against ZIKV infection in vitro in trophoblast cells.


Assuntos
Metformina , Infecção por Zika virus , Zika virus , Recém-Nascido , Gravidez , Feminino , Humanos , Infecção por Zika virus/tratamento farmacológico , Linhagem Celular Tumoral , Trofoblastos , Antivirais/farmacologia , Metformina/farmacologia
13.
Science ; 384(6693): 260, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38635700

RESUMO

Naturally occurring bacterium could offer an additional way to control mosquito-borne diseases.


Assuntos
Aedes , Vírus da Dengue , Dengue , Microbioma Gastrointestinal , Infecção por Zika virus , Zika virus , Animais , Humanos , Mosquitos Vetores
14.
Braz J Infect Dis ; 28(2): 103741, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38670165

RESUMO

Sickle Cell Disease (SCD) is a hereditary disease characterized by extravascular and intravascular hemolysis and clinical variability, from mild pain to potentially life-threatening. Arboviruses include mainly Zika (ZIKV), Chikungunya (CHKV), and Dengue (DENV) virus, and are considered a public and social health problem. The present cross-sectional observational study aimed to investigate the prevalence of arbovirus infection in SCD patients from two Brazilian cities, Salvador and Manaus located in Bahia and Amazonas states respectively. A total of 409 individuals with SCD were included in the study, and 307 (75.06 %) patients tested positive for DENV-IgG, 161 (39.36 %) for ZIKV-IgG, and 60 (14.67 %) for CHIKV-IgG. Only one individual was positive for DENV-NS1 and another for DENV-IgM, both from Salvador. No individuals had positive serology for ZIKV-IgM or CHIKV-IgM. Arbovirus positivity by IgG testing revealed that the SCD group presented high frequencies in both cities. Interestingly, these differences were only statistically significant for ZIKV-IgG (p = 0.023) and CHIKV-IgG (p = 0.005) among SCD patients from Manaus. The reshaping of arbovirus from its natural habitat by humans due to disorderly urban expansion and the ease of international Mobility has been responsible for facilitating the spread of vector-borne infectious diseases in humans. We found the need for further studies on arboviruses in this population to elucidate the real association and impact, especially in acute infection. We hope that this study will contribute to improvements in the personalized clinical follow-up of SCD patients, identifying the influence of arbovirus infection in severe disease manifestations.


Assuntos
Anemia Falciforme , Infecções por Arbovirus , Arbovírus , Humanos , Brasil/epidemiologia , Anemia Falciforme/epidemiologia , Anemia Falciforme/complicações , Estudos Transversais , Masculino , Feminino , Adulto , Prevalência , Infecções por Arbovirus/epidemiologia , Infecções por Arbovirus/virologia , Adulto Jovem , Adolescente , Arbovírus/isolamento & purificação , Imunoglobulina G/sangue , Criança , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/complicações , Anticorpos Antivirais/sangue , Pessoa de Meia-Idade , Dengue/epidemiologia , Imunoglobulina M/sangue , Vírus da Dengue/imunologia , Zika virus/imunologia , Zika virus/isolamento & purificação , Pré-Escolar , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/complicações
15.
J Virol ; 98(5): e0019424, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38567950

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10× Genomics Chromium single-cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human monocyte-derived dendritic cells infected with ZIKV at the single-cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN-dependent and -independent genes (the antiviral module). We modeled the ZIKV-specific antiviral state at the protein level, leveraging experimentally derived protein interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for evaluating the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per-cell basis with experimental protein interaction data. IMPORTANCE: Zika virus (ZIKV) remains a public health threat given its potential for re-emergence and the detrimental fetal outcomes associated with infection during pregnancy. Understanding the dynamics between ZIKV and its host is critical to understanding ZIKV pathogenesis. Through ZIKV-inclusive single-cell RNA sequencing (scRNA-seq), we demonstrate on the single-cell level the dynamic interplay between ZIKV and the host: the transcriptional program that restricts viral infection and ZIKV-mediated inhibition of that response. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool for gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.


Assuntos
Células Dendríticas , Análise de Célula Única , Infecção por Zika virus , Zika virus , Humanos , Zika virus/fisiologia , Infecção por Zika virus/virologia , Infecção por Zika virus/imunologia , Células Dendríticas/virologia , Células Dendríticas/imunologia , RNA Viral/metabolismo , RNA Viral/genética , Interferon Tipo I/metabolismo , Interações Hospedeiro-Patógeno , Análise de Sequência de RNA
16.
Viral Immunol ; 37(3): 167-175, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38574259

RESUMO

Zika virus (ZIKV) is an emerging flavivirus associated with several neurological diseases such as Guillain-Barré syndrome in adults and microcephaly in newborn children. Its distribution and mode of transmission (via Aedes aegypti and Aedes albopictus mosquitoes) collectively cause ZIKV to be a serious concern for global health. High genetic homology of flaviviruses and shared ecology is a hurdle for accurate detection. Distinguishing infections caused by different viruses based on serological recognition can be misleading as many anti-flavivirus monoclonal antibodies (mAbs) discovered to date are highly cross-reactive, especially those against the envelope (E) protein. To provide more specific research tools, we produced ZIKV E directed hybridoma cell lines and characterized two highly ZIKV-specific mAb clones (mAbs A11 and A42) against several members of the Flavivirus genus. Epitope mapping of mAb A11 revealed glycan loop specificity in Domain I of the ZIKV E protein. The development of two highly specific mAbs targeting the surface fusion protein of ZIKV presents a significant advancement in research capabilities as these can be employed as essential tools to enhance our understanding of ZIKV identification on infected cells ex vivo or in culture.


Assuntos
Aedes , Flavivirus , Infecção por Zika virus , Zika virus , Animais , Recém-Nascido , Humanos , Proteínas do Envelope Viral , Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais
17.
Viruses ; 16(4)2024 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-38675882

RESUMO

As a mosquito-borne flavivirus, Zika virus (ZIKV) has been identified as a global health threat. The virus has been linked to severe congenital disabilities, including microcephaly and other congenital malformations, resulting in fatal intrauterine death. Therefore, developing sensitive and specific methods for the early detection and accurate diagnosis of the ZIKV is essential for controlling its spread and mitigating its impact on public health. Herein, we set up a novel nucleic acid detection system based on Pyrococcus furiosus Argonaute (PfAgo)-mediated nucleic acid detection, targeting the non-structural protein 5 (NS5) region of the ZIKV genome (abbreviated ZIKV-PAND). Without preamplification with the polymerase chain reaction (PCR), the minimum detection concentration (MDC) of ZIKV-PAND was about 10 nM. When introducing an amplification step, the MDC can be dramatically decreased to the aM level (8.3 aM), which is comparable to qRT-PCR assay (1.6 aM). In addition, the diagnostic findings from the analysis of simulated clinical samples or Zika virus samples using ZIKV-PAND show a complete agreement of 100% with qRT-PCR assays. This correlation can aid in the implementation of molecular testing for clinical diagnoses and the investigation of ZIKV infection on an epidemiological scale.


Assuntos
Pyrococcus furiosus , Proteínas não Estruturais Virais , Infecção por Zika virus , Zika virus , Zika virus/genética , Zika virus/isolamento & purificação , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/virologia , Humanos , Proteínas não Estruturais Virais/genética , Pyrococcus furiosus/genética , Proteínas Argonautas/genética , Sensibilidade e Especificidade , RNA Viral/genética , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Genoma Viral
18.
Viruses ; 16(4)2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38675903

RESUMO

Gliomas account for approximately 75-80% of all malignant primary tumors in the central nervous system (CNS), with glioblastoma multiforme (GBM) considered the deadliest. Despite aggressive treatment involving a combination of chemotherapy, radiotherapy, and surgical intervention, patients with GBM have limited survival rates of 2 to 5 years, accompanied by a significant decline in their quality of life. In recent years, novel management strategies have emerged, such as immunotherapy, which includes the development of vaccines or T cells with chimeric antigen receptors, and oncolytic virotherapy (OVT), wherein wild type (WT) or genetically modified viruses are utilized to selectively lyse tumor cells. In vitro and in vivo studies have shown that the Zika virus (ZIKV) can infect glioma cells and induce a robust oncolytic activity. Consequently, interest in exploring this virus as a potential oncolytic virus (OV) for high-grade gliomas has surged. Given that ZIKV actively circulates in Colombia, evaluating its neurotropic and oncolytic capabilities holds considerable national and international importance, as it may emerge as an alternative for treating highly complex gliomas. Therefore, this literature review outlines the generalities of GBM, the factors determining ZIKV's specific tropism for nervous tissue, and its oncolytic capacity. Additionally, we briefly present the progress in preclinical studies supporting the use of ZIKV as an OVT for gliomas.


Assuntos
Neoplasias Encefálicas , Glioma , Terapia Viral Oncolítica , Vírus Oncolíticos , Infecção por Zika virus , Zika virus , Terapia Viral Oncolítica/métodos , Humanos , Zika virus/fisiologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologia , Glioma/terapia , Glioma/virologia , Animais , Infecção por Zika virus/terapia , Infecção por Zika virus/virologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/virologia , Glioblastoma/terapia , Glioblastoma/virologia
19.
Viruses ; 16(4)2024 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-38675911

RESUMO

Zika virus (ZIKV) remains a public health concern, with epidemics in endemic regions and sporadic outbreaks in new areas posing significant threats. Several mosquito-borne flaviviruses that can cause human illness, including West Nile, Usutu, and St. Louis encephalitis, have associations with birds. However, the susceptibility of chickens to ZIKV and their role in viral epidemiology is not currently known. We investigated the susceptibility of chickens to experimental ZIKV infection using chickens ranging from 1-day-old chicks to 6-week-old birds. ZIKV caused no clinical signs in chickens of all age groups tested. Viral RNA was detected in the blood and tissues during the first 5 days post-inoculation in 1-day and 4-day-old chicks inoculated with a high viral dose, but ZIKV was undetectable in 6-week-old birds at all timepoints. Minimal antibody responses were observed in 6-week-old birds, and while present in younger chicks, they waned by 28 days post-infection. Innate immune responses varied significantly between age groups. Robust type I interferon and inflammasome responses were measured in older chickens, while limited innate immune activation was observed in younger chicks. Signal transducer and activator of transcription 2 (STAT2) is a major driver of host restriction to ZIKV, and chicken STAT2 is distinct from human STAT2, potentially contributing to the observed resistance to ZIKV infection. The rapid clearance of the virus in older chickens coincided with an effective innate immune response, highlighting age-dependent susceptibility. Our study indicates that chickens are not susceptible to productive ZIKV infection and are unlikely to play a role in the ZIKV epidemiology.


Assuntos
Galinhas , Imunidade Inata , Doenças das Aves Domésticas , Infecção por Zika virus , Zika virus , Animais , Galinhas/virologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/imunologia , Suscetibilidade a Doenças , Doenças das Aves Domésticas/virologia , Doenças das Aves Domésticas/imunologia , Fatores Etários , Anticorpos Antivirais/sangue , RNA Viral/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-38594795

RESUMO

Abstract: Timor-Leste is a mountainous, half-island nation with a population of 1.3 million, which shares a land border with Indonesia and is 550 km from Darwin, Australia. Since independence in 2002, Timor-Leste has achieved significant development; however, high levels of poverty remain. Chikungunya virus (CHIKV) is endemic in over 100 countries in Africa, Asia, Europe and in the Americas. It is transmitted by the bite of infected Aedes aegypti or Ae. albopictus mosquitoes, which are present in Timor-Leste and which contribute to annual rainy-season dengue virus (DENV) outbreaks. Symptomatic people typically suffer from acute onset of fever, usually accompanied by severe arthritis or arthralgia. Joint pain can be debilitating for several days, and may sometimes last for weeks, months or years. Unlike DENV infection which has significant mortality, most people recover completely. Between 2002 and 2023, there were 26 cases of CHIKV notified in Australia who acquired their infection in Timor-Leste; however, laboratory testing capability for CHIKV in Timor-Leste only became available in 2021 using polymerase chain reaction (PCR). The first locally diagnosed case was notified in November 2023. In January 2024, an outbreak of CHIKV was recognised in Timor-Leste for the first time, with 195 outbreak cases reported during 1-31 January 2024; all were PCR positive. There were no cases hospitalised, and no deaths. The median age of cases was 17 years (range 1-76 years); 51% were males. Cases were reported across the country; most (88/195) were from Dili, although the highest incidence was seen in the neighbouring municipality of Ermera (monthly incidence rate of 58.8 cases per 100,000 population). This first reported outbreak of CHIKV in Timor-Leste highlights the need for improved mosquito-borne illness control and response strategies, including minimising breeding sites and promoting early presentation for treatment and differential diagnosis from DENV, and consideration of the deployment of Wolbachia-infected mosquitoes, particularly as they have shown to reduce the transmission of CHIKV, DENV and Zika virus, all of which pose threats in Timor-Leste.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Infecção por Zika virus , Zika virus , Masculino , Animais , Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Feminino , Febre de Chikungunya/epidemiologia , Timor-Leste/epidemiologia , Austrália/epidemiologia , Vírus Chikungunya/genética , Surtos de Doenças , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/prevenção & controle
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