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1.
Sci Rep ; 13(1): 308, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609450

RESUMO

The increasing trend of mosquito-borne pathogens demands more accurate global estimations of infection and transmission risks between mosquitoes. Here, we systematically review field and laboratory studies to assess the natural field infection and experimental laboratory transmission risk in Culex mosquitoes. We studied four worldwide flaviviruses: West Nile, Usutu, Japanese encephalitis, and St. Louis encephalitis, belonging to the Japanese encephalitis Serocomplex (JES). The PRISMA statement was carried out for both approaches. The Transmission-Infection Risk of the diverse mosquito species for the different viruses was estimated through seven variables. We considered 130 and 95 articles for field and experimental approach, respectively. We identified 30 species naturally infected, and 23 species capable to transmit some of the four flaviviruses. For the JES, the highest Transmission-Infection Risk estimate was recorded in Culex quinquefasciatus (North America). The maximum Infection-Transmission Risk values for West Nile was Culex restuans, for Usutu it was Culex pipiens (Europe), for St. Louis encephalitis Culex quinquefasciatus (North America), and for Japanese encephalitis Culex gelidus (Oceania). We conclude that on a worldwide scale, a combination of field and experimental data offers a better way of understanding natural infection and transmission risks between mosquito populations.


Assuntos
Culex , Culicidae , Vírus da Encefalite Japonesa (Subgrupo) , Encefalite Japonesa , Encefalite de St. Louis , Flavivirus , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Animais , Mosquitos Vetores , Encefalite de St. Louis/epidemiologia , Encefalite Japonesa/epidemiologia
2.
Arch Virol ; 168(2): 47, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609616

RESUMO

Brazil has experienced an increase in outbreaks caused by flaviviruses. The high incidence of dengue fever, the morbidity of Zika in children, and the high mortality of yellow fever have affected millions in recent years. Deciphering host-virus interactions is important for treating viral infections, and the mitogen-activated protein kinases (MAPK) are an interesting target because of their role in flavivirus replication. In particular, mitogen-activated protein kinase kinase (MEK), which targets extracellular-signal-regulated kinase (ERK), is necessary for dengue and yellow fever infections. In this study, we evaluated the role of the MEK/ERK pathway and the effect of the MEK inhibitor trametinib on the Asian ZIKV strain PE243 and the prototype African ZIKV strain MR766, addressing genome replication, morphogenesis, and viral release. ZIKV infection stimulated ERK phosphorylation in Vero cells at 12 and 18 hours postinfection (hpi). Trametinib showed sustained antiviral activity, inhibiting both ZIKV strains for at least four days, and electron microscopy showed probable inhibition of ZIKV morphogenesis. ZIKV PE243 can complete one cycle in Vero cells in 14 hours; genome replication was detected around 8 hpi, intracellular viral particles at 12 hpi, and extracellular progeny at 14 hpi. Treatments at 6-hour intervals showed that trametinib inhibited late stages of viral replication, and the titration of intra- or extracellular virions showed that the treatment especially affected viral morphogenesis and release. Thus, ZIKV stimulated ERK phosphorylation during viral morphogenesis and release, which correlated with trametinib inhibiting both the signaling pathway and viral replication.


Assuntos
Flavivirus , Febre Amarela , Infecção por Zika virus , Zika virus , Animais , Chlorocebus aethiops , Criança , Humanos , Zika virus/genética , Células Vero , Febre Amarela/genética , MAP Quinases Reguladas por Sinal Extracelular , Quinases de Proteína Quinase Ativadas por Mitógeno , Replicação Viral/fisiologia
3.
Viruses ; 15(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36680184

RESUMO

Zika virus (ZIKV) is an RNA-enveloped virus that belongs to the Flavivirus genus, and ZIKV infections potentially induce severe neurodegenerative diseases and impair male fertility. Palmitoylation is an important post-translational modification of proteins that is mediated by a series of DHHC-palmitoyl transferases, which are implicated in various biological processes and viral infections. However, it remains to be investigated whether palmitoylation regulates ZIKV infections. In this study, we initially observed that the inhibition of palmitoylation by 2-bromopalmitate (2-BP) enhanced ZIKV infections, and determined that the envelope protein of ZIKV is palmitoylated at Cys308. ZDHHC11 was identified as the predominant enzyme that interacts with the ZIKV envelope protein and catalyzes its palmitoylation. Notably, ZDHHC11 suppressed ZIKV infections in an enzymatic activity-dependent manner and ZDHHC11 knockdown promoted ZIKV infection. In conclusion, we proposed that the envelope protein of ZIKV undergoes a novel post-translational modification and identified a distinct mechanism in which ZDHHC11 suppresses ZIKV infections via palmitoylation of the ZIKV envelope protein.


Assuntos
Flavivirus , Infecção por Zika virus , Zika virus , Masculino , Humanos , Zika virus/fisiologia , Proteínas do Envelope Viral/metabolismo , Flavivirus/metabolismo , Proteínas/metabolismo , Anticorpos Antivirais/metabolismo
4.
Viruses ; 15(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36680235

RESUMO

Ilheus virus (ILHV) is a mosquito-borne flavivirus circulating throughout Central and South America and the Caribbean. It has been detected in several mosquito genera including Aedes and Culex, and birds are thought to be its primary amplifying and reservoir host. Here, we describe the genomic and morphologic characterization of ten ILHV strains. Our analyses revealed a high conservation of both the 5'- and 3'-untranslated regions but considerable divergence within the open reading frame. We also showed that ILHV displays a typical flavivirus structural and genomic organization. Our work lays the foundation for subsequent ILHV studies to better understand its transmission cycles, pathogenicity, and emergence potential.


Assuntos
Aedes , Culex , Flavivirus , Animais , Flavivirus/genética , América do Sul , Região do Caribe , Filogenia
5.
Antiviral Res ; 210: 105517, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592668

RESUMO

Flaviviruses are vector-borne pathogens capable of causing devastating human diseases. The re-emergence of Zika in 2016 notoriously led to a widescale epidemic in the Americas. New daunting evidence suggests that a single mutation in Zika virus genome may increase transmission and pathogenesis, further highlighting the need to be prepared for flavivirus outbreaks. Dengue, in particular infects about 400 million people each year, leading to reoccurring local outbreaks. Public health efforts to mitigate flavivirus transmission is largely dependent on vector control strategies, as only a limited number of flavivirus vaccines have been developed thus far. There are currently no commercially available antivirals for flaviviruses, leaving supportive care as the primary treatment option. In this review, we will briefly paint a broad picture of the flavivirus landscape in terms of therapeutics, with particular focus on viral targets, promising novel compounds entering the drug discovery pipeline, as well as model systems for evaluating drug efficacy.


Assuntos
Infecções por Flavivirus , Flavivirus , Vacinas Virais , Infecção por Zika virus , Zika virus , Humanos , Flavivirus/genética , Zika virus/genética , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/prevenção & controle
6.
J Cell Biochem ; 124(1): 127-145, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36502494

RESUMO

Numerous pathogens affecting human is present in the flavivirus family namely west nile, dengue, yellow fever, and zika which involves in development of global burden and distressing the environment economically. Till date, no approved drugs are available for targeting these viruses. The threat which urged the identification of small molecules for the inhibition of these viruses is the spreading of serious viral diseases. The recent outbreak of zika and dengue infections postured a solemn risk to worldwide public well-being. RNA-dependent RNA polymerase (RdRp) is the supreme adaptable enzymes of all the RNA viruses which is responsible for the replication and transcription of genome among the structural and nonstructural proteins of flaviviruses. It is understood that the RdRp of the flaviviruses are similar stating that the japanese encephalitis and west nile shares 70% identity with zika whereas the dengue serotype 2 and 3 shares the identity of 76% and 81%, respectively. In this study, we investigated the binding site of four flaviviral RdRp and provided insights into various interaction of the molecules using the computational approach. Our study helps in recognizing the potent compounds that could inhibit the viral protein as a common inhibitor. Additionally, with the conformational stability analysis, we proposed the possible mechanism of inhibition of the identified common small molecule toward RdRp of flavivirus. Finally, this study could be an initiative for the identification of common inhibitors and can be explored further for understanding the mechanism of action through in vitro studies for the study on efficacy.


Assuntos
Dengue , Flavivirus , Infecção por Zika virus , Zika virus , Humanos , Flavivirus/genética , Flavivirus/metabolismo , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Reposicionamento de Medicamentos , Proteínas Virais/metabolismo
7.
Emerg Microbes Infect ; 12(1): 2156815, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36495563

RESUMO

Usutu (USUV) and West Nile (WNV) viruses are two closely related Flavivirus belonging to Japanese encephalitis virus serogroup. Evidence of increased circulation of these two arboviruses now exist in Europe. Neurological disorders are reported in humans mainly for WNV, despite the fact that the interaction and effects of viral infections on the neurovasculature are poorly described, notably for USUV. Using a human in vitro blood-brain barrier (BBB) and a mouse model, this study characterizes and compares the cerebral endothelial cell permissiveness, innate immunity and inflammatory responses and immune cell recruitment during infection by USUV and WNV. Both viruses are able to infect and cross the human BBB but with different consequences. We observed that WNV infects BBB cells resulting in significant endothelium impairment, potent neuroinflammation and immune cell recruitment, in agreement with previous studies. USUV, despite being able to infect BBB cells with higher replication rate than WNV, does not strongly affect endothelium integrity. Importantly, USUV also induces neuroinflammation, immune cell recruitment such as T lymphocytes, monocytes and dendritic cells (DCs) and was able to infect dendritic cells (DCs) more efficiently compared to WNV, with greater propensity for BBB recruitment. DCs may have differential roles for neuroinvasion of the two related viruses.


Assuntos
Flavivirus , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Animais , Camundongos , Humanos , Doenças Neuroinflamatórias , Barreira Hematoencefálica
8.
Emerg Infect Dis ; 29(1): 164-169, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36573591

RESUMO

We collected >40,000 mosquitoes from 5 provinces in South Africa during 2011-2018 and screened for zoonotic flaviviruses. We detected West Nile virus in mosquitoes from conservation and periurban sites and potential new mosquito vectors; Banzi virus was rare. Our results suggest flavivirus transmission risks are increasing in South Africa.


Assuntos
Culex , Culicidae , Flavivirus , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Animais , África do Sul/epidemiologia , Flavivirus/genética , Vírus do Nilo Ocidental/genética , Mosquitos Vetores
9.
Vet Microbiol ; 277: 109636, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36580873

RESUMO

West Nile virus (WNV) and Usutu virus (USUV), two antigenically related flaviviruses co-circulating in Europe, can cause severe neurological disease in animals and humans. The immune response against USUV and WNV and their immunopathogenesis are still poorly investigated. Here we present results upon sequential infections of adult immunocompetent CD-1 and BALB/c mice primed with two different doses (high dose, HD or low dose, LD) of an USUV isolate and challenged with HD or LD of three different WNV isolates. CD-1 and BALB/c LD USUV-primed mice, regardless of the dose, are largely protected from lethal WNV challenges despite showing no detectable neutralizing antibodies. Furthermore, mice immunized with a chimeric virus harboring the E protein of USUV within the WNV backbone (WNVE-USUV) are protected against a lethal challenge with WNV. We believe these findings could contribute to understanding the dynamics of the interaction during sequential infection of these two flaviviruses.


Assuntos
Infecções por Flavivirus , Flavivirus , Doenças dos Roedores , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Humanos , Animais , Camundongos , Febre do Nilo Ocidental/prevenção & controle , Febre do Nilo Ocidental/veterinária , Infecções por Flavivirus/prevenção & controle , Infecções por Flavivirus/veterinária , Imunização/veterinária , Anticorpos Antivirais
10.
Antiviral Res ; 210: 105512, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36572192

RESUMO

The Zika virus (ZIKV) epidemic outbreak in Americas in 2016 attracted global attention because of the association of the virus infection with severe birth defects such as microcephaly, mediated through transplacental virus transmission during pregnancy. Less well-known, but also reported is the increasing evidence that prenatal vertical transmission can be caused by other flaviviruses such as dengue virus (DENV). Currently, the mechanism(s) that cause the vertical transmission of flaviviruses is understudied. Here we review the published reports of clinical evidence of intrauterine transmission of ZIKV and other flaviviruses. We also discuss the animal models for flavivirus infection during pregnancy that have been developed to study the mechanisms underlying the transplacental transmission of flaviviruses in order to develop potential countermeasures for its prevention.


Assuntos
Vírus da Dengue , Dengue , Infecções por Flavivirus , Flavivirus , Infecção por Zika virus , Zika virus , Gravidez , Animais , Feminino
11.
Antiviral Res ; 210: 105516, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36586467

RESUMO

Flaviviruses are important human pathogens and include dengue (DENV), West Nile (WNV), Yellow fever virus (YFV), Japanese encephalitis (JEV) and Zika virus (ZIKV). DENV, transmitted by mosquitoes, causes diseases ranging in severity from mild dengue fever with non-specific flu-like symptoms to fatal dengue hemorrhagic fever and dengue shock syndrome. DENV infections are caused by four serotypes, DENV1-4, which interact differently with antibodies in blood serum. The incidence of DENV infection has increased dramatically in recent decades and the CDC estimates 400 million dengue infections occur each year, resulting in ∼25,000 deaths mostly among children and elderly people. Similarly, ZIKV infections are caused by infected mosquito bites to humans, can be transmitted sexually and through blood transfusions. If a pregnant woman is infected, the virus can cross the placental barrier and can spread to her fetus, causing severe brain malformations in the child including microcephaly and other birth defects. It is noteworthy that the neurological manifestations of ZIKV were also observed in DENV endemic regions, suggesting that pre-existing antibody response to DENV could augment ZIKV infection. WNV, previously unknown in the US (and known to cause only mild disease in Middle East), first arrived in New York city in 1999 (NY99) and spread throughout the US and Canada by Culex mosquitoes and birds. WNV is now endemic in North America. Thus, emerging and re-emerging flaviviruses are significant threat to human health. However, vaccines are available for only a limited number of flaviviruses, and antiviral therapies are not available for any flavivirus. Hence, there is an urgent need to develop therapeutics that interfere with essential enzymatic steps, such as protease in the flavivirus lifecycle as these viruses possess significant threat to future pandemics. In this review, we focus on our E. coli expression of NS2B hydrophilic domain (NS2BH) covalently linked to NS3 protease domain (NS3Pro) in their natural context which is processed by the combined action of both subunits of the NS2B-NS3Pro precursor. Biochemical activities of the viral protease such as solubility and autoproteolysis of NS2BH-NS3Pro linkage depended on the C-terminal portion of NS2BH linked to the NS3Pro domain. Since 2008, we also focus on the use of the recombinant protease in high throughput screens and characterization of small molecular compounds identified in these screens.


Assuntos
Infecções por Flavivirus , Flavivirus , Peptídeo Hidrolases , Animais , Feminino , Humanos , Gravidez , Dengue/prevenção & controle , Vírus da Dengue , Flavivirus/enzimologia , Pandemias , Placenta , Zika virus , Infecção por Zika virus/prevenção & controle , Infecções por Flavivirus/prevenção & controle
12.
J Mol Biol ; 434(6): 167277, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-34599939

RESUMO

Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions induced by IFN. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent manner, opening new perspectives to target weakness points in the life cycle of these viruses.


Assuntos
Flavivirus , Interferons , Replicação Viral , Apolipoproteínas L/genética , Apolipoproteínas L/metabolismo , Flavivirus/fisiologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Interferons/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , SARS-CoV-2/fisiologia , Zika virus/fisiologia
13.
Nat Commun ; 13(1): 7780, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526630

RESUMO

Zoonotic viruses circulate in the natural reservoir and sporadically spill over into human populations, resulting in endemics or pandemics. We previously found that the Chaoyang virus (CYV), an insect-specific flavivirus (ISF), is replication-defective in vertebrate cells. Here, we develope a proof-of-concept mosquito-delivered vaccine to control the Zika virus (ZIKV) within inaccessible wildlife hosts using CYV as the vector. The vaccine is constructed by replacing the pre-membrane and envelope (prME) proteins of CYV with those of ZIKV, assigned as CYV-ZIKV. CYV-ZIKV replicates efficiently in Aedes mosquitoes and disseminates to the saliva, with no venereal or transovarial transmission observed. To reduce the risk of CYV-ZIKV leaking into the environment, mosquitoes are X-ray irradiated to ensure 100% infertility, which does not affect the titer of CYV-ZIKV in the saliva. Immunization of mice via CYV-ZIKV-carrying mosquito bites elicites robust and persistent ZIKV-specific immune responses and confers complete protection against ZIKV challenge. Correspondingly, the immunized mice could no longer transmit the challenged ZIKV to naïve mosquitoes. Therefore, immunization with an ISF-vectored vaccine via mosquito bites is feasible to induce herd immunity in wildlife hosts of ZIKV. Our study provides a future avenue for developing a mosquito-delivered vaccine to eliminate zoonotic viruses in the sylvatic cycle.


Assuntos
Aedes , Flavivirus , Mordeduras e Picadas de Insetos , Vacinas , Infecção por Zika virus , Zika virus , Humanos , Camundongos , Animais , Mosquitos Vetores , Animais Selvagens , Vacinas/metabolismo
14.
Sci Rep ; 12(1): 21548, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513793

RESUMO

The non-structural protein-1 (NS1) of dengue virus (DENV) contributes to several functions related to dengue disease pathogenesis as well as diagnostic applications. Antibodies against DENV NS1 can cross-react with other co-circulating flaviviruses, which may lead to incorrect diagnosis. Herein, five anti-DENV NS1 monoclonal antibodies (mAbs) were investigated. Four of them (1F11, 2E3, 1B2, and 4D2) cross-react with NS1 of all four DENV serotypes (pan-DENV mAbs), whereas the other (2E11) also reacts with NS1 of other flaviviruses (flavi-cross-reactive mAb). The binding epitopes recognized by these mAbs were found to overlap a region located on the disordered loop of the NS1 wing domain (amino acid residues 104 to 123). Fine epitope mapping employing phage display technology and alanine-substituted DENV2 NS1 mutants indicates the critical binding residues W115, K116, and K120 for the 2E11 mAb, which are conserved among flaviviruses. In contrast, the critical binding residues of four pan-DENV mAbs include both flavi-conserved residues (W115 to G119) and DENV-conserved flanking residues (K112, Y113, S114 and A121, K122). Our results highlight DENV-conserved residues in cross-reactive epitopes that distinguish pan-DENV antibodies from the flavi-cross-reactive antibody. These antibodies can be potentially applied to differential diagnosis of DENV from other flavivirus infections.


Assuntos
Vírus da Dengue , Dengue , Flavivirus , Humanos , Anticorpos Antivirais , Proteínas não Estruturais Virais/genética , Reações Cruzadas , Epitopos , Anticorpos Monoclonais
15.
Front Cell Infect Microbiol ; 12: 1042735, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389173

RESUMO

Infection by flaviviruses leads to dramatic remodeling of the endoplasmic reticulum (ER). Viral replication occurs within virus-induced vesicular invaginations in the ER membrane. A hallmark of flavivirus infection is expansion of the ER membrane which can be observed at specific time points post infection. However, this process has not been effectively visualized in living cells throughout the course of infection at the single cell resolution. In this study, we developed a plasmid-based reporter system to monitor flavivirus infection and simultaneous virus-induced manipulation of single cells throughout the course of infection in real-time. This system requires viral protease cleavage to release an ER-anchored fluorescent protein infection reporter that is fused to a nuclear localization signal (NLS). This proteolytic cleavage allows for the translocation of the infection reporter signal to the nucleus while an ER-specific fluorescent marker remains localized in the lumen. Thus, the construct allows for the visualization of virus-dependent changes to the ER throughout the course of infection. In this study, we show that our reporter was efficiently cleaved upon the expression of multiple flavivirus proteases, including dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV). We also found that the DENV protease-dependent cleavage of our ER-anchored reporter exhibited more stringent cleavage sequence specificity than what has previously been shown with biochemical assays. Using this system for long term time-lapse imaging of living cells infected with DENV, we observed nuclear translocation of the reporter signal beginning approximately 8 hours post-infection, which continued to increase throughout the time course. Interestingly, we found that increased reporter signal translocation correlated with increased ER signal intensity, suggesting a positive association between DENV infection and ER expansion in a time-dependent manner. Overall, this report demonstrates that the FlavER platform provides a useful tool for monitoring flavivirus infection and simultaneously observing virus-dependent changes to the host cell ER, allowing for study of the temporal nature of virus-host interactions.


Assuntos
Vírus da Dengue , Infecções por Flavivirus , Flavivirus , Infecção por Zika virus , Zika virus , Humanos , Vírus da Dengue/genética , Retículo Endoplasmático
16.
Vaccine ; 40(49): 7022-7031, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36319490

RESUMO

Historically, virulent variola virus infection caused hundreds of millions of deaths. The smallpox pandemic in human beings has spread for centuries until the advent of the attenuated vaccinia virus (VV) vaccine, which played a crucial role in eradicating the deadly contagious disease. Decades of exploration and utilization have validated the attenuated VV as a promising vaccine vehicle against various lethal viruses. In this review, we focus on the advances in VV-based vaccine vector studies, including construction approaches of recombinant VV, the impact of VV-specific pre-existing immunity on subsequent VV-based vaccines, and antigen-specific immune responses. More specifically, the recombinant VV-based flaviviruses are intensively discussed. Based on the publication data, this review aims to provide valuable insights and guidance for future VV-based vaccine development.


Assuntos
Flavivirus , Vacina Antivariólica , Vacinas , Vaccinia , Humanos , Vírus Vaccinia , Flavivirus/genética , Desenvolvimento de Vacinas , Vetores Genéticos
17.
Viruses ; 14(11)2022 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-36366557

RESUMO

Infections with arboviruses are reported worldwide. Saint Louis encephalitis (SLEV) and West Nile (WNV) viruses are closely related flaviviruses affecting humans and animals. SLEV has been sporadically detected in humans, and corresponding antibodies have been frequently detected in horses throughout Brazil. WNV was first reported in western Brazil over a decade ago, has been associated with neurological disorders in humans and equines and its prevalence is increasing nationwide. Herein, we investigated by molecular and serological methods the presence of SLEV and WNV in equines from Rio de Janeiro. A total of 435 serum samples were collected from healthy horses and tested for specific neutralizing antibodies by plaque reduction neutralization test (PRNT90). Additionally, samples (serum, cerebrospinal fluid, central nervous system tissue) from 72 horses, including horses with neurological disorders resulting in a fatal outcome or horses which had contact with them, were tested by real-time reverse transcription-polymerase chain reaction (RT-qPCR) for both viruses. Adopting the criterion of four-fold antibody titer difference, 165 horses (38%) presented neutralizing antibodies for flaviviruses, 89 (20.4%) for SLEV and five (1.1%) for WNV. No evidence of SLEV and WNV infection was detected by RT-qPCR and, thus, such infection could not be confirmed in the additional samples. Our findings indicate horses of Rio de Janeiro were exposed to SLEV and WNV, contributing to the current knowledge on the distribution of these viruses in Brazil.


Assuntos
Encefalite de St. Louis , Flavivirus , Doenças dos Cavalos , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Animais , Humanos , Cavalos , Vírus do Nilo Ocidental/genética , Encefalite de St. Louis/epidemiologia , Encefalite de St. Louis/veterinária , Brasil/epidemiologia , Anticorpos Antivirais , Febre do Nilo Ocidental/epidemiologia , Febre do Nilo Ocidental/veterinária , Anticorpos Neutralizantes , Doenças dos Cavalos/epidemiologia
18.
Antiviral Res ; 208: 105460, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36334638

RESUMO

Usutu virus (USUV), is a mosquito-borne flavivirus currently spreading outside the African continent producing substantial avian mortality. In contrast, infected humans could exhibit mild neurological symptoms or remain asymptomatic. As in other flaviviruses, the capped USUV genome encodes three structural and seven non-structural (NS) proteins. Among the NS proteins, NS5 plays crucial roles in virus replication, harbouring the capping and methyltransferase (MTase) activities in its N-terminal domain and the RNA-dependent RNA polymerase (RdRP) activity at the C-terminus. In this work, we present the first structural and functional characterization of the USUV MTase domain. The first structure of the USUV MTase has been determined in complex with its natural ligands (S-adenosyl-L-methionine [SAM]) and S-adenosyl-L-homocysteine [SAH]) at 2.2 Å resolution, showing a molecular dimer in the crystal asymmetric unit. One molecule is bound to the methyl donor SAM while the second is bound to the reaction by-product SAH. Both molecules are almost identical and also show a high structural similarity to the MTase domains of other flaviviruses. The structure of the USUV MTase bound to the inhibitor sinefungin at 1.8 Å resolution is also described. Careful comparisons of the interactions in the SAM-binding cavity prompt us to hypothesize about the strength and weakness of the structure-based design of antivirals directed to the SAM/SAH binding site that could be effective to deal with this threat.


Assuntos
Flavivirus , Metiltransferases , Flavivirus/genética , Flavivirus/metabolismo , Metiltransferases/química , RNA Polimerase Dependente de RNA/genética , S-Adenosilmetionina/metabolismo , Proteínas não Estruturais Virais/química
19.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293480

RESUMO

Flaviviruses (the genus Flavivirus of the Flaviviridae family) include many arthropod-borne viruses, often causing life-threatening diseases in humans, such as hemorrhaging and encephalitis. Although the flaviviruses have a significant clinical impact, it has become apparent that flavivirus replication is restricted by cellular factors induced by the interferon (IFN) response, which are called IFN-stimulated genes (ISGs). SHFL (shiftless antiviral inhibitor of ribosomal frameshifting) is a novel ISG that inhibits dengue virus (DENV), West Nile virus (WNV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV) infections. Interestingly, SHFL functions as a broad-spectrum antiviral factor exhibiting suppressive activity against various types of RNA and DNA viruses. In this review, we summarize the current understanding of the molecular mechanisms by which SHFL inhibits flavivirus infection and discuss the molecular basis of the inhibitory mechanism using a predicted tertiary structure of SHFL generated by the program AlphaFold2.


Assuntos
Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa , Flavivirus , Infecção por Zika virus , Zika virus , Humanos , Flavivirus/fisiologia , Interferons/farmacologia , Antivirais/farmacologia , RNA , Replicação Viral
20.
Front Cell Infect Microbiol ; 12: 976843, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36310869

RESUMO

The genus Flavivirus of the Flaviviridae family includes important viruses, such as Dengue, Zika, West Nile, Japanese encephalitis, Murray Valley encephalitis, tick-borne encephalitis, Yellow fever, Saint Louis encephalitis, and Usutu viruses. They are transmitted by mosquitoes or ticks, and they can infect humans, causing fever, encephalitis, or haemorrhagic fever. The treatment resources for these diseases and the number of vaccines available are limited. It has been discovered that eukaryotic cells synthesize small RNA molecules that can bind specifically to sequences present in messenger RNAs to inhibit the translation process, thus regulating gene expression. These small RNAs have been named microRNAs, and they have an important impact on viral infections. In this review, we compiled the available information on miRNAs that can interact with the 3' untranslated region (3'UTR) of the flavivirus genome, a conserved region that is important for viral replication and translation.


Assuntos
Encefalite Japonesa , Flavivirus , MicroRNAs , Infecção por Zika virus , Zika virus , Animais , Humanos , Regiões 3' não Traduzidas , MicroRNAs/genética , Biologia Computacional , Flavivirus/genética , Encefalite Japonesa/genética , Zika virus/genética
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