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1.
J Med Virol ; 92(1): 11-16, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31436327

RESUMEN

The Zika virus (ZIKV) outbreak, which started in the year 2015, is considered the fastest and most widely spread outbreak reported for this flavivirus. The polymerase domain of the NS5 protein has been targeted in other viral infections and is recognized as a suitable target in ZIKV infection. Different novel modified compounds against ZIKV NS5 have been tested in silico. A few structures have been solved for ZIKV polymerase and deposited in the protein data bank website. Two of these solved structures (with a resolution of less than 1.9 A) are used in this study to test the binding of 74 novel compounds in silico. Molecular docking is used to quantify the binding affinities of ZIKV polymerase and compare it to the hepatitis C virus NS5B. A total of 19 novel compounds revealed results that are either similar to or better than the physiological molecule, guanosine triphosphate. Water molecules are found to facilitate the binding of the compounds to ZIKV RNA-dependent RNA polymerase (RdRp) structures. The presented 19 novel compounds represent good binders to ZIKV RdRp and could be suitable candidates for developing a new and effective anti-ZIKV polymerase nucleotide inhibitor.

2.
Virus Res ; 275: 197793, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31676367

RESUMEN

Zika virus (ZIKV) is an emergent flavivirus associated with severe neurological disorders. ZIKV NS3 protein is a viral protease that cleaves the ZIKV polyprotein precursor into individual viral proteins. In this study, we found that ZIKV NS3 by itself exhibited mitochondrial localization, which was quite different from its endoplasmic reticulum (ER) localization in ZIKV-infected cells. We screened viral proteins and identified NS2B as the bona fide recruiter of NS3 to the ER. The NS2B C-terminal tail interacted with NS3 protease domain to retain NS3 on the ER. ß-Sheet motifs that formed between NS2B and the NS3 protease domain played important roles in their interaction, while mutation in the ß-strand of NS2B attenuated NS2B-NS3 interaction and impaired the ability of NS3 protease to cleave the polyprotein precursor into multiple viral proteins. Consequently, NS2B mutations led to severe inhibition of ZIKV replication and production due to insufficient NS3 protease activity. In summary, our study reveals the critical role of NS2B in NS3 recruitment and protease function and provides mechanistic insight into ZIKV replication.

3.
Cytokine ; 125: 154864, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31577989

RESUMEN

Zika virus (ZIKV) is phylogenetically divided into two lineages comprising African (ZIKVAF) and Asian (ZIKVAS) genotypes. In the type-I interferon receptor deficient mouse model, ZIKVAF causes severe disease with all mice meeting humane endpoints with doses as low as 10 plaque-forming units (pfu) whereas a much milder infection is seen after challenge with ZIKVAS, including with doses as high as 106 pfu. Using this mouse model, the elucidation of cytokine, chemokine, growth factor and acute phase protein responses over the course of infection were studied to determine whether these analytes contributed to the stark difference in clinical outcome. Results demonstrated some significant differences, with the ZIKVAF infection being associated with increases in a higher number of biomarkers than ZIKVAS. When low (10 pfu) and high (106 pfu) challenge doses were compared, animals given the lower virus inoculum showed a wider range of responses, indicating a different disease progression compared to those challenged with high doses. These results aid with elucidating the different outcomes with the two lineages of ZIKV and with future work to assess pathogenicity of virus infection.

4.
Acta Trop ; 201: 105201, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31562846

RESUMEN

Zika virus (ZIKV) is a mosquito-borne flavivirus that has caused recent large outbreaks in the Americas. Given its association with severe congenital defects including microcephaly, distinguishing infections caused by ZIKV from those caused by dengue virus (DENV) is of primordial importance. The objectives of this study were to evaluate the recombinant proteins rEIII-ZIKV (Envelope protein domain III) and rNS1ß-leader-ZIKV (non-structural protein 1) for the serological diagnosis of ZIKV in the Mexican population. We also evaluated potential cross-reactivity in commercial enzyme-linked immunosorbent assays (ELISA) based on the ZIKV NS1 and DENV NS1 proteins. rEIII-ZIKV and rNS1ß-leader-ZIKV proteins were tested with sera from 30 PCR-confirmed ZIKV cases, 50 ZIKV-naive, DENV-exposed subjects with no acute febrile disease, (asymptomatic subjects, AS), and 50 ZIKV-naive and DENV naive AS. Commercial ELISA tests were evaluated with sera from 57 ZIKV and 20 DENV PCR-confirmed cases, and 50 ZIKV-naive, DENV-exposed AS. In-house ELISA assays showed that IgM antibody levels against rEIII-ZIKV and rNS1ß-ZIKV were higher in ZIKV naive, DENV-exposed AS than in acutely infected ZIKV individuals. IgG reactivity was highest for rEIII-ZIKV, and indistinguishable between acutely infected ZIKV cases and DENV exposed AS. Positivity for the Euroimmun Zika IgM assay at 7-10 days was considerably higher in DENV-naive ZIKV patients (86%) than in DENV-exposed ZIKV patients (33%), while 39% of the latter had false-negative anti-ZIKV IgG before 7 days of onset. DENV-exposed ZIKV patients presented lower anti-ZIKV IgM and higher IgG responses similar to a secondary dengue response. Forty-four percent of DENV- exposed acute ZIKV patients were DENV IgM positive with the Panbio Dengue assay, and two (15%) of the DENV-naive ZIKV patients presented false DENV IgG conversion. Given the extensive cross-reactivity to both the NS1 and EDIII proteins in current serological methods, the development of sensitive and specific serological tests to distinguish ZIKV from DENV infections is an urgent priority.

5.
Dev Comp Immunol ; 103: 103514, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31585195

RESUMEN

One of the defining features of mosquito vectors of arboviruses such as Dengue and Zika is their ability to tolerate high levels of virus proliferation without suffering significant pathology. This adaptation is central to vector competence and disease spread. The molecular mechanisms, pathways, cellular and metabolic adaptations responsible for mosquito disease tolerance are still largely unknown and may represent effective ways to control mosquito populations and prevent arboviral diseases. In this review article, we describe the key link between disease tolerance and pathogen transmission, and how vector control methods may benefit by focusing efforts on dissecting the mechanisms underlying mosquito tolerance of arboviral infections. We briefly review recent work investigating tolerance mechanisms in other insects, describe the state of the art regarding the mechanisms of disease tolerance in mosquitos, and highlight the emerging role of gut microbiota in mosquito immunity and disease tolerance.

7.
Methods Mol Biol ; 2097: 253-263, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31776931

RESUMEN

Developments in genetic engineering have allowed researchers and clinicians to begin harnessing viruses to target and kill cancer cells, either through direct lysis or through recruitment of antiviral immune responses. Two powerful viruses in the fight against cancer are the single-stranded RNA viruses vesicular stomatitis virus and Zika virus. Here, we describe methods to propagate and titer these two viruses. We also describe a simple cell-killing assay to begin testing modified viruses for increased potential killing of glioblastoma cells.

8.
Can J Microbiol ; 2019 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-31682478

RESUMEN

Zika virus (ZIKV) is a mosquito-borne virus which was first isolated from Zika forest, Uganda in 1947. Since of its inception, major and minor outbreaks have been documented from several parts of world. Aedes spp. mosquitoes are the primary vectors of ZIKV but the virus can also be transmitted through sexual practices, materno-fetal transmission and through blood transfusion. The clinical presentations of symptomatic ZIKV infections are similar to dengue and chikungunya, including fever, headache, arthralgia, retro-orbital pain, conjunctivitis and rash. ZIKV often causes mild illness in the majority of cases but in some instances it is linked with congenital microcephaly and autoimmune disorders like Guillain-Barré syndrome (GBS). The recent Indian ZIKV outbreak suggests that the virus is circulating in the South East Asian region and may cause new outbreaks in future. At present, no specific vaccines or antivirals are available to treat Zika virus and the management and control of ZIKV infections relies mostly on preventive measures.

9.
WMJ ; 118(3): 114-119, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31682746

RESUMEN

PROBLEM CONSIDERED: While travel during pregnancy is increasingly common, both the act of traveling and the destination itself may pose risks to pregnant women. Thus, it is relevant to ask pregnant women about travel for individual care and to assess how often pregnant women travel. Based upon our prior study, we hypothesized that domestic travel would be common, with approximately 30% of pregnant women traveling, and that international travel also would be common, with approximately 5% of the population traveling. We also hypothesized that maternal characteristics, such as socioeconomic status, country of birth, and parity, would affect domestic and international travel during pregnancy. METHODS: In order to study trends in travel by pregnant women, a survey was conducted among postpartum women at Meriter Hospital in Madison, Wisconsin, between October 17, 2016 and March 21, 2017. RESULTS: Of the 61 postpartum women surveyed, 75.4% had traveled domestically and 11.4% had traveled internationally while pregnant. Those who traveled domestically had a significantly higher level of education (P = 0.025) and higher annual income (P = 0.001) compared to women who did not travel domestically. There were no differences in these characteristics between those who did and did not travel internationally. Women traveling domestically were less likely to discuss their travel plans with their obstetrician when compared to women traveling internationally (67.4% v 85.7%, respectively). Out of 19 canceled trips, both domestic and international, 4 women opted to cancel their trips due to concerns about Zika virus (21.1%). CONCLUSION: This study allowed for an in-depth look at pregnant travelers and their reasons for traveling and for canceling their trips. When travel plans were discussed, in most instances (94.6%), the obstetrician initiated the conversation. As pregnant women travel both domestically and internationally at increasing rates, it is important to discuss risks associated with travel.

10.
Viruses ; 11(11)2019 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-31683628

RESUMEN

Zika virus (ZIKV) is transmitted by Aedes mosquitoes and exhibits genetic variation with African and Asian lineages. ZIKV Natal RGN strain, an Asian-lineage virus, has been identified in brain tissues from fetal autopsy cases with microcephaly and is suggested to be a neurotropic variant. However, ZIKV Natal RGN strain has not been isolated; its biological features are not yet illustrated. This study rescued and characterized recombinant, single-round infectious particles (SRIPs) of the ZIKV Natal RGN strain using reverse genetic and synthetic biology techniques. The DNA-launched replicon of ZIKV Natal RGN was constructed and contains the EGFP reporter, lacks prM-E genes, and replicates under CMV promoter control. The peak in the ZIKV Natal RGN SRIP titer reached 6.25 × 106 TCID50/mL in the supernatant of prM-E-expressing packaging cells 72 h post-transfection with a ZIKV Natal RGN replicon. The infectivity of ZIKV Natal RGN SRIPs has been demonstrated to correlate with the green florescence intensity of the EGFP reporter, the SRIP-induced cytopathic effect, and ZIKV's non-structural protein expression. Moreover, ZIKV Natal RGN SRIPs effectively self-replicated in rhabdomyosarcoma/muscle, glioblastoma/astrocytoma, and retinal pigmented epithelial cells, displaying unique cell susceptibility with differential attachment activity. Therefore, the recombinant ZIKV Natal RGN strain was rescued as SRIPs that could be used to elucidate the biological features of a neurotropic strain regarding cell tropism and pathogenic components, apply for antiviral agent screening, and develop vaccine candidates.

11.
Viruses ; 11(11)2019 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-31683742

RESUMEN

Flaviviruses, such as Zika virus (ZIKV), Japanese encephalitis virus (JEV), Dengue virus (DENV), and West Nile virus (WNV), are important arthropod-borne pathogens that present an immense global health problem. Their unpredictable disease severity, unusual clinical features, and severe neurological manifestations underscore an urgent need for antiviral interventions. Furin, a host proprotein convertase, is a key contender in processing flavivirus prM protein to M protein, turning the inert virus to an infectious particle. For this reason, the current study was planned to evaluate the antiviral activity of decanoyl-Arg-Val-Lys-Arg-chloromethylketone, a specific furin inhibitor, against flaviviruses, including ZIKV and JEV. Analysis of viral proteins revealed a significant increase in the prM/E index of ZIKV or JEV in dec-RVKR-cmk-treated Vero cells compared to DMSO-treated control cells, indicating dec-RVKR-cmk inhibits prM cleavage. Plaque assay, qRT-PCR, and immunofluorescence assay revealed a strong antiviral activity of dec-RVKR-cmk against ZIKV and JEV in terms of the reduction in virus progeny titer and in viral RNA and protein production in both mammalian cells and mosquito cells. Time-of-drug addition assay revealed that the maximum reduction of virus titer was observed in post-infection treatment. Furthermore, our results showed that dec-RVKR-cmk exerts its inhibitory action on the virus release and next round infectivity but not on viral RNA replication. Taken together, our study highlights an interesting antiviral activity of dec-RVKR-cmk against flaviviruses.

12.
Viruses ; 11(11)2019 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-31684080

RESUMEN

Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.

13.
BMJ Open ; 9(11): e032275, 2019 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-31685512

RESUMEN

OBJECTIVE: With the emergence of Zika virus (ZIKV) disease in Central and South America in the mid-2010s and recognition of the teratogenic effects of congenital exposure to ZIKV, there has been a substantial increase in new research published on ZIKV. Our objective is to synthesise the literature on health outcomes associated with ZIKV infection in humans. METHODS: We conducted a systematic review (SR) of SRs following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE, Embase, Cochrane and LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde) databases from inception to 22 July 2019, and included SRs that reported ZIKV-associated health outcomes. Three independent reviewers selected eligible studies, extracted data and assessed the quality of included SRs using the AMSTAR 2 (A MeaSurement Tool to Assess Systematic Reviews 2) tool. Conflicts were resolved by consensus or consultation with a third reviewer. RESULTS: The search yielded 1382 unique articles, of which 21 SRs met our inclusion criteria. The 21 SRs ranged from descriptive to quantitative data synthesis, including four meta-analyses. The most commonly reported ZIKV-associated manifestations and health outcomes were microcephaly, congenital abnormalities, brain abnormalities, neonatal death and Guillain-Barré syndrome. The included reviews were highly heterogeneous. The overall quality of the SRs was critically low with all studies having more than one critical weakness. CONCLUSION: The evolving nature of the literature on ZIKV-associated health outcomes, together with the critically low quality of existing SRs, demonstrates the need for high-quality SRs to guide patient care and inform policy decision making. PROSPERO REGISTRATION NUMBER: CRD42018091087.

14.
Viral Immunol ; 2019 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-31687902

RESUMEN

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that caused a public health emergency in the Americas when an outbreak in Brazil became linked to congenital microcephaly. Understanding how ZIKV could evade the innate immune defenses of the mother, placenta, and fetus has become central to determining how the virus can traffic into the fetal brain. ZIKV, like other flaviviruses, evades host innate immune responses by leveraging viral proteins and other processes that occur during viral replication to allow spread to the placenta. Within the placenta, there are diverse cell types with coreceptors for ZIKV entry, creating an opportunity for the virus to establish a reservoir for replication and infect the fetus. The fetal brain is vulnerable to ZIKV, particularly during the first trimester, when it is beginning a dynamic process, to form highly complex and specialized regions orchestrated by neuroprogenitor cells. In this review, we provide a conceptual framework to understand the different routes for viral trafficking into the fetal brain and the eye, which are most likely to occur early and later in pregnancy. Based on the injury profile in human and nonhuman primates, ZIKV entry into the fetal brain likely occurs across both the blood/cerebrospinal fluid barrier in the choroid plexus and the blood/brain barrier. ZIKV can also enter the eye by trafficking across the blood/retinal barrier. Ultimately, the efficient escape of innate immune defenses by ZIKV is a key factor leading to viral infection. However, the host immune response against ZIKV can lead to injury and perturbations in developmental programs that drive cellular division, migration, and brain growth. The combined effect of innate immune evasion to facilitate viral propagation and the maternal/placental/fetal immune response to control the infection will determine the extent to which ZIKV can injure the fetal brain.

15.
Clin J Sport Med ; 29(6): 523-526, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31688184

RESUMEN

OBJECTIVE: To evaluate the impact of Zika virus on preparation and management of the New Zealand (NZ) Olympic team. DESIGN: Descriptive manuscript. SETTING: New Zealand Olympic Health team preparation and management during the Rio de Janeiro Olympic Games, 2016. PATIENTS (OR PARTICIPANTS): New Zealand Olympic Team members. INTERVENTIONS (OR ASSESSMENT OF RISK FACTORS): This manuscript describes the approaches used by the NZ Olympic Health team to the minimization of risk from Zika virus. MAIN OUTCOME MEASURES: Although descriptive of approach forms most of the article, the results of Zika virus serology are presented. RESULTS: The NZ Olympic Health team took a proactive approach to risk mitigation, including extensive education, clothing changes, mosquito spray, mosquito nets, and voluntary postexposure testing. No positive serology was observed in those tested. CONCLUSIONS: The outbreak of Zika virus in Brazil, the associated complication of microcephaly, and the evolving understanding of virus transmission created significant uncertainty for NZ Olympic team members. The proactive approach taken by the health team to the mitigation of risk, combined with the anticipated low risk of arbovirus transmission over the period of the games, resulted in enhanced confidence from team members and no reports of positive serology.

16.
Viruses ; 11(11)2019 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-31717338

RESUMEN

RNA viruses are highly successful pathogens and are the causative agents for many important diseases. To fully understand the replication of these viruses it is necessary to address the roles of both positive-strand RNA ((+)RNA) and negative-strand RNA ((-)RNA), and their interplay with viral and host proteins. Here we used branched DNA (bDNA) fluorescence in situ hybridization (FISH) to stain both the abundant (+)RNA and the far less abundant (-)RNA in both hepatitis C virus (HCV)- and Zika virus-infected cells, and combined these analyses with visualization of viral proteins through confocal imaging. We were able to phenotypically examine HCV-infected cells in the presence of uninfected cells and revealed the effect of direct-acting antivirals on HCV (+)RNA, (-)RNA, and protein, within hours of commencing treatment. Herein, we demonstrate that bDNA FISH is a powerful tool for the study of RNA viruses that can provide insights into drug efficacy and mechanism of action.

17.
J Child Neurol ; : 883073819885724, 2019 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-31718421

RESUMEN

OBJECTIVE: To describe the 2-year neurodevelopmental outcome in children with cerebral palsy associated with congenital Zika (CZ) and explore variables associated with a more severe presentation. METHODS: Data on 69 children with cerebral palsy associated with CZ, followed in a neurorehabilitation hospital, who consecutively attended the neurodevelopmental assessment at 2 years of age, were collected. Bayley III Scales of Infant and Toddler Development, Hammersmith Infant Neurological Examination, and Gross Motor Function Classification System were used for the outcome evaluation. Descriptive and inferential statistical analysis were performed. RESULTS: The median age at follow-up was of 24.0 (23-32) months. Only 3 (4.3%) children were not microcephalic. The majority presented with bilateral (94.2%), spastic (100.0%), Gross Motor Function Classification System grade IV or V (92.8%) cerebral palsy, epilepsy (73.1%), extremely low performances on cognitive (94.2%), language (95.7%), and motor (95.7%) Bayley-III Scales of Infant and Toddler Development Test scores. The median Hammersmith Infant Neurological Examination score was of 21.0 (range 9-75). There was a correlation between birth head circumference with the cognitive (r = 0.3, P < .01), language (r = 0.3, P < .01), and motor (r = 0.3, P < .01) Bayley-III Scales of Infant and Toddler Development Test scores, as well as with the Hammersmith Infant Neurological Examination score (r = 0.2, P < .03). An association was observed between an inferior median Hammersmith Infant Neurological Examination score with congenital microcephaly (P = .04), arthrogryposis (P = .02), and epilepsy in the first year (P < .01). CONCLUSION: Cerebral palsy related to CZ presents with a severe global impairment at a 2-year follow-up. Birth head circumference, arthrogryposis, and early epilepsy are associated with a worse outcome and may be considered as prognostic markers. These findings are important for the neurorehabilitation planning, parents' guiding, and future prognostic studies.

19.
J Infect Dis ; 2019 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-31711190

RESUMEN

Next-generation sequencing technologies, exponential increases in the availability of virus genomic data, and ongoing advances in phylogenomic methods have made genomic epidemiology an increasingly powerful tool for public health response to a range of mosquito-borne virus outbreaks. In this review, we offer a brief primer on the scope and methods of phylogenomic analyses that can answer key epidemiological questions during mosquito-borne virus public health emergencies. We then focus on case examples of outbreaks, including those caused by dengue, Zika, yellow fever, West Nile, and chikungunya viruses, to demonstrate the utility of genomic epidemiology to support the prevention and control of mosquito-borne virus threats. We extend these case studies with operational perspectives on how to best incorporate genomic epidemiology into structured surveillance and response programs for mosquito-borne virus control. Many tools for genomic epidemiology already exist, but so do technical and nontechnical challenges to advancing their use. Frameworks to support the rapid sharing of multidimensional data and increased cross-sector partnerships, networks, and collaborations can support advancement on all scales, from research and development to implementation by public health agencies.

20.
Nat Rev Urol ; 2019 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-31712766
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