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1.
Antiviral Res ; : 105330, 2022 May 06.
Article in English | MEDLINE | ID: mdl-35533778

ABSTRACT

Despite substantial morbidity and mortality, no therapeutic agents exist for treatment of dengue or Zika, and the currently available dengue vaccine is only recommended for dengue virus (DENV)-immune individuals. Thus, development of therapeutic and/or preventive drugs is urgently needed. DENV and Zika virus (ZIKV) nonstructural protein 1 (NS1) can directly trigger endothelial barrier dysfunction and induce inflammatory responses, contributing to vascular leak in vivo. Here we evaluated the efficacy of the (1-6,1-3)-ß-D-glucan isolated from Agaricus subrufescens fruiting bodies (FR) and its sulfated derivative (FR-S) against DENV-2 and ZIKV infection and NS1-mediated pathogenesis. FR-S, but not FR, significantly inhibited DENV-2 and ZIKV replication in human monocytic cells (EC50 = 36.5 and 188.7 µg/mL, respectively) when added simultaneously with viral infection. No inhibitory effect was observed when FR or FR-S were added post-infection, suggesting inhibition of viral entry as a mechanism of action. In an in vitro model of endothelial permeability using human pulmonary microvascular endothelial cells (HPMECs), FR and FR-S (0.12 µg/mL) inhibited DENV-2 NS1- and ZIKV NS1-induced hyperpermeability by 50% and 100%, respectively, as measured by Trans-Endothelial Electrical Resistance. Treatment with 0.25 µg/mL of FR and FR-S inhibited DENV-2 NS1 binding to HPMECs. Further, FR-S significantly reduced intradermal hyperpermeability induced by DENV-2 NS1 in C57BL/6 mice and protected against DENV-induced morbidity and mortality in a murine model of dengue vascular leak syndrome. Thus, we demonstrate efficacy of FR-S against DENV and ZIKV infection and NS1-induced endothelial permeability in vitro and in vivo. These findings encourage further exploration of FR-S and other glycan candidates for flavivirus treatment alone or in combination with compounds with different mechanisms of action.

2.
Article in English | MEDLINE | ID: mdl-35507796

ABSTRACT

BACKGROUNDS: SARS-CoV-2 infection typically presents with fever and respiratory symptoms. Besides this, COVID-19 related central and peripheral nervous system manifestations are emerging. OBJECTIVES: This study summarises the demographics, clinical profile, laboratory findings, management strategies, and outcomes in a large number of patients with COVID-19 related GBS and its variants. We also compared its clinical profile with Zika and dengue virus-related GBS. METHODS: Authors carried out a literature search up to Dec 31, 2020, in MEDLINE, PubMed, SCOPUS, Cochrane database, and Google Scholar for all published articles. RESULTS: The study identified 54 different types of articles consisting of 70 cases from 17 countries worldwide. Maximum cases 15 (21.4%) were identified from Italy, followed by USA 12 (17.1%), Spain 11 (15.7%), and Iran 10 (14.3%). The age group more than 60 years had most cases with 32 (45.7%) cases followed by age group 40-60 with cases 25 (35.7%) with male and female ratio 2. Maximum cases were treated with IVIG infusion 58 (82.9%), followed by Plasma exchange 13 (18.6%) cases. Out of 70 cases, 7 (10%) cases were manifested as Miller-Fisher syndrome. The most predominant electrodiagnostic variant was demyelinating neuropathy in 41 (73.21%) cases. The outcome reported in 67 cases was survival in 63 (90%) cases and the death of 4 (5.7%) cases. CONCLUSION: Covid 19 related GBS were reported worldwide with a better outcome. Both postinfectious or parainfectious patterns were reported. Early recognition with prompt management of GBS can prevent further severe morbidity and mortality.

3.
FASEB J ; 36 Suppl 12022 May.
Article in English | MEDLINE | ID: mdl-35552299

ABSTRACT

Viral infections continue to be the bane of human medicine, often with minimal options for treatment. Of particular concern are arboviruses, or viruses transmitted by an arthropod vector, such as a mosquito. Recently, Zika virus (ZIKV), a mosquito borne arbovirus, has emerged as a major threat to public health in many parts of the world. It is unknown what protein(s) ZIKV uses to bind to and infect cells within its mosquito vector. The receptor used by ZIKV to bind to and infect human cells has been identified as the tyrosine kinase receptor family Axl. A homolog of the Axl gene is not present within the mosquito genome. However, genes for the Down-Syndrome Cell Adhesion Molecule family members (DSCAMs) found within multiple mosquito species share key functional modular ectodomains with the human Axl gene. Here, we extracted total RNA from Culex and Aedes species of mosquitos, reverse transcribed the RNA into cDNA and then cloned the mosquito DSCAM cDNA with the highest homology to human Axl into a eukaryotic expression vector. The vector will then be transfected into a mammalian cell line void of human DSCAM and human Axl expression to determine if the mosquito DSCAM molecule is expressed as a surface protein. Finally, we will determine if ZIKV is capable of binding to the mammalian cell line that now expresses the mosquito DSCAM protein. This project will allow us to learn if ZIKV is capable of binding to the mosquito DSCAM protein. In turn, this information could lead to the possibility that the mosquito DSCAM protein allows infection by ZIKV as well. Ultimately, this research could assist vaccine development for Zika, or lead to treatments that could block ZIKA from infecting its mosquito vector.

4.
Sci Rep ; 12(1): 7810, 2022 May 12.
Article in English | MEDLINE | ID: mdl-35552469

ABSTRACT

Zika fever is an infectious disease caused by the Zika virus (ZIKV). The disease is claiming millions of lives worldwide, primarily in developing countries. In addition to vector control strategies, the most effective way to prevent the spread of ZIKV infection is vaccination. There is no clinically approved vaccine to combat ZIKV infection and curb its pandemic. An epitope-based peptide vaccine (EBPV) is seen as a powerful alternative to conventional vaccinations because of its low production cost and short production time. Nonetheless, EBPVs have gotten less attention, despite the fact that they have a significant untapped potential for enhancing vaccine safety, immunogenicity, and cross-reactivity. Such a vaccine technology is based on target pathogen's selected antigenic peptides called T-cell epitopes (TCE), which are synthesized chemically based on their amino acid sequences. The identification of TCEs using wet-lab experimental approach is challenging, expensive, and time-consuming. Therefore in this study, we present computational model for the prediction of ZIKV TCEs. The model proposed is an ensemble of decision trees that utilizes the physicochemical properties of amino acids. In this way a large amount of time and efforts would be saved for quick vaccine development. The peptide sequences dataset for model training was retrieved from Virus Pathogen Database and Analysis Resource (ViPR) database. The sequences dataset consist of experimentally verified T-cell epitopes (TCEs) and non-TCEs. The model demonstrated promising results when evaluated on test dataset. The evaluation metrics namely, accuracy, AUC, sensitivity, specificity, Gini and Mathew's correlation coefficient (MCC) recorded values of 0.9789, 0.984, 0.981, 0.987, 0.974 and 0.948 respectively. The consistency and reliability of the model was assessed by carrying out the five (05)-fold cross-validation technique, and the mean accuracy of 0.97864 was reported. Finally, model was compared with standard machine learning (ML) algorithms and the proposed model outperformed all of them. The proposed model will aid in predicting novel and immunodominant TCEs of ZIKV. The predicted TCEs may have a high possibility of acting as prospective vaccine targets subjected to in-vivo and in-vitro scientific assessments, thereby saving lives worldwide, preventing future epidemic-scale outbreaks, and lowering the possibility of mutation escape.

5.
FASEB J ; 36 Suppl 12022 May.
Article in English | MEDLINE | ID: mdl-35552900

ABSTRACT

The ongoing Covid-19 pandemic, caused by the highly transmissible SARS-CoV-2 virus, constitutes the worst global public health crisis of the past century. Although effective vaccines have been developed, administration has been slow, new variants continue to emerge, and there remains a lack of effective antivirals to treat severe cases. Thus, there remains a significant need to understand the mechanisms of SARS-CoV-2 infection and replication to identify new potential therapeutic targets. To this end, we investigated whether SARS-CoV-2 might depend on the host cell chaperone system, particularly the essential cytosolic chaperonin, CCT, to fold or assemble any of its proteins. CCT has previously been shown to be required for the replication of several other viruses including reoviruses and zika virus. We screened likely candidates among the SARS-CoV-2 proteins for co-immunoprecipitation with CCT and identified an interaction with the RNA-dependent RNA polymerase, Nsp12. To confirm Nsp12 was a substrate, we depleted cells of CCT, then transfected with Nsp12 and observed a 40% decrease in Nsp12 expression in CCT-depleted cells compared to the control. This decrease is consistent with what we have observed for other known CCT substrates. Additionally, CCT-depleted cells infected with live SARS-CoV-2 produced a 50% decrease in viral titer compared to controls, indicating that CCT is important for viral replication. A preliminary cryo-EM structure of the Nsp12-CCT complex shows a very large mass identifiable as Nsp12 inside of CCT that extends from the equatorial domains up and out through one of the two folding cavities. The structure stands to both reveal an important step in SARS-CoV-2 replication and to answer a long-standing question regarding how CCT can accommodate very large substrates.

6.
Transbound Emerg Dis ; 2022 May 11.
Article in English | MEDLINE | ID: mdl-35544742

ABSTRACT

The emergence of Zika virus (ZIKV) infection, which is unexpectedly associated with congenital defects, has prompted the development of safe and effective vaccines. The gram-positive enhancer matrix-protein anchor (GEM-PA) display system has emerged as a versatile and highly effective platform for delivering target proteins in vaccines. In this study, we developed a bacterium-like particle vaccine, ZI-△-PA-GEM, based on the GEM-PA system. The fusion protein ZI-△-PA, which contains the prM-E-△TM protein of ZIKV (with a stem-transmembrane region deletion) and the protein anchor PA3, was expressed. The fusion protein was successfully displayed on the GEM surface to form ZI-△-PA-GEM. Moreover, the intramuscular immunization of BALB/c mice with ZI-△-PA-GEM combined with ISA 201 VG and poly(I:C) adjuvants induced durable ZIKV-specific IgG and protective neutralizing antibody responses. Potent B-cell/DC activation was also stimulated early after immunization. Notable, splenocyte proliferation, the secretion of multiple cytokines, T/B-cell activation and central memory T-cell responses were elicited. These data indicate that ZI-△-PA-GEM is a promising bacterium-like particle vaccine candidate for ZIKV. This article is protected by copyright. All rights reserved.

7.
J Virol ; : e0007122, 2022 May 16.
Article in English | MEDLINE | ID: mdl-35575481

ABSTRACT

Zika virus (ZIKV) is a global public health concern due to its ability to cause congenital Zika syndrome and lack of approved vaccine, therapeutic, or other control measures. We discovered eight novel rabbit monoclonal antibodies (MAbs) that bind to distinct ZIKV envelope protein epitopes. The majority of the MAbs were ZIKV specific and targeted the lateral ridge of the envelope (E) protein domain III, while the MAb with the highest neutralizing activity recognized a putative quaternary epitope spanning E protein domains I and III. One of the non-neutralizing MAbs specifically recognized ZIKV precursor membrane protein (prM). Somatic hypermutation of immunoglobulin variable regions increases antibody affinity maturation and triggers antibody class switching. Negative correlations were observed between the somatic hypermutation rate of the immunoglobulin heavy-chain variable region and antibody binding parameters such as equilibrium dissociation constant, dissociation constant, and half-maximal effective concentration value of MAb binding to ZIKV virus-like particles. Complementarity-determining regions recognize the antigen epitopes and are scaffolded by canonical framework regions. Reversion of framework region amino acids to the rabbit germ line sequence decreased anti-ZIKV MAb binding activity of some MAbs. Thus, antibody affinity maturation, including somatic hypermutation and framework region mutations, contributed to the binding and function of these anti-ZIKV MAbs. IMPORTANCE ZIKV is a global health concern against which no vaccine or therapeutics are available. We characterized eight novel rabbit monoclonal antibodies recognizing ZIKV envelope and prM proteins and studied the relationship between somatic hypermutation of complementarity-determining regions, framework regions, mutations, antibody specificity, binding, and neutralizing activity. The results contribute to understanding structural features and somatic mutation pathways by which potent Zika virus-neutralizing antibodies can evolve, including the role of antibody framework regions.

8.
Sci Rep ; 12(1): 7389, 2022 May 05.
Article in English | MEDLINE | ID: mdl-35513477

ABSTRACT

Hypsarrhythmia is a specific chaotic morphology, present in the interictal period of the electroencephalogram (EEG) signal in patients with West Syndrome (WS), a severe form of childhood epilepsy and that, recently, was also identified in the examinations of patients with Zika Virus Congenital Syndrome (ZVCS). This innovative work proposes the development of a computational methodology for analysis and differentiation, based on the time-frequency domain, between the chaotic pattern of WS and ZVCS hypsarrhythmia. The EEG signal time-frequency analysis is carried out from the Continuous Wavelet Transform (CWT). Four joint moments-joint mean-[Formula: see text], joint variance-[Formula: see text], joint skewness-[Formula: see text], and joint kurtosis-[Formula: see text]-and four entropy measurements-Shannon, Log Energy, Norm, and Sure-are obtained from the CWT to compose the representative feature vector of the EEG hypsarrhythmic signals under analysis. The performance of eight classical types of machine learning algorithms are verified in classification using the k-fold cross validation and leave-one-patient-out cross validation methods. Discrimination results provided 78.08% accuracy, 85.55% sensitivity, 73.21% specificity, and AUC = 0.89 for the ANN classifier.


Subject(s)
Spasms, Infantile , Zika Virus Infection , Zika Virus , Algorithms , Electroencephalography/methods , Entropy , Humans , Signal Processing, Computer-Assisted , Support Vector Machine , Syndrome , Wavelet Analysis , Zika Virus Infection/complications
9.
Disaster Med Public Health Prep ; : 1-8, 2022 Apr 11.
Article in English | MEDLINE | ID: mdl-35400356

ABSTRACT

OBJECTIVE: The aim of this study is to assess knowledge and attitudes toward Zika virus disease (ZVD) as well as mosquito prevention practices in Malaysia at a nationwide level. METHODS: Computer-assisted telephone interviews (CATI) were conducted between June 2019 and February 2020. RESULTS: There are gaps in knowledge about the symptoms, mode of transmission, and risk of microcephaly. The mean for the Zika-related knowledge score was 5.9 (SD ± 4.4) out of a possible score of 14. The majority perceived little or no risk of getting ZVD (75.0%) and 75.5% were a little or not at all worried about ZVD. A high proportion reported the use of insect sprays or mosquito coils to prevent mosquito bites; however, a relatively lower proportion of people reported fixing mosquito netting on doors and windows, and using mosquito bed nets. The mean for the mosquito prevention practices score was 11.9 (SD ± 4.7) out of a possible score of 27. Important factors influencing mosquito prevention practices include household income, environment factors, risk perception, and Zika-related knowledge. CONCLUSION: Zika prevention measures should be targeted in priority toward residents in lower socioeconomic neighborhoods. Campaigns should focus on messages highlighting the high risk of getting dengue.

10.
Arch Pharm Res ; 45(4): 280-293, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35441964

ABSTRACT

Zika virus (ZIKV), an arbovirus of the Flaviviridae family, has emerged as a significant public health concern owing to its association with congenital abnormalities and severe neurological sequelae. Thus, there is an urgent need to develop effective therapeutic approaches to efficiently treat ZIKV infections. This study used phenotypic screening to identify a series of 1,2,4-oxadiazole derivatives that possess antiviral activity against ZIKV infection. Subsequently, 28 new derivatives were designed, synthesized, and evaluated for this purpose. Among these compounds, 4-(5-phenyl-1,2,4-oxadiazol-3-yl)-N-(pyridin-3-ylmethyl)aniline (5d) had potent antiviral activity against ZIKV infections. Furthermore, a structure-activity relationship analysis indicated that a benzyl substitution on the aniline nitrogen of this compound improved potency while augmenting its drug-like properties. In addition, 5d exhibited antiviral activity against various viruses of Flaviviridae family of worldwide public health importance, such as dengue, Japanese encephalitis and classical swine fever viruses, indicating its potential as a lead compound for generating 1,2,4-oxadiazole derivatives with broad-spectrum anti-flaviviral properties.


Subject(s)
Classical Swine Fever Virus , Dengue , Encephalitis, Japanese , Zika Virus Infection , Zika Virus , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Dengue/drug therapy , Encephalitis, Japanese/drug therapy , Humans , Oxadiazoles/pharmacology , Oxadiazoles/therapeutic use , Virus Replication , Zika Virus Infection/drug therapy
11.
Rev Soc Bras Med Trop ; 55: e03062021, 2022.
Article in English | MEDLINE | ID: mdl-35416870

ABSTRACT

BACKGROUND: Guillian Barré syndrome (GBS) is an acute autoimmune polyradiculoneuropathy often associated with previous exposure to infectious agents. METHODS: A clinical cohort of 41 patients with GBS admitted to the Base Hospital Institute of the Federal District between May 2017 and April 2019 was followed up for 1 year. Serological tests for arbovirus detection and amplification of nucleic acids using polymerase chain reaction for zika virus (ZIKV), dengue virus (DENV), and chikungunya virus (CHIKV) were performed. RESULTS: The cohort consisted of 61% men with a median age of 40 years, and 83% had GBS-triggering events. A total of 54% had Grade 4 disability, 17% had Grade 3, 12% had Grade 2, 10% had Grade 5, and 7% had Grade 1. The classic form occurred in 83% of patients. Nerve conduction evaluations revealed acute demyelinating inflammatory polyneuropathy (51%), acute motor axonal neuropathy (17%), acute sensory-motor neuropathy (15%), and indeterminate forms (17%). Four patients were seropositive for DENV. There was no laboratory detection of ZIKV or CHIKV infection. Ninety percent of patients received human immunoglobulin. Intensive care unit admission occurred in 17.1% of the patients, and mechanical ventilation was used in 14.6%. One patient died of Bickerstaff's encephalitis. Most patients showed an improvement in disability at 10 weeks of follow-up. CONCLUSIONS: GBS in the Federal District showed a variable clinical spectrum, and it was possible to detect recent exposure to DENV.


Subject(s)
Arboviruses , Guillain-Barre Syndrome , Zika Virus Infection , Zika Virus , Adult , Female , Guillain-Barre Syndrome/complications , Guillain-Barre Syndrome/epidemiology , Guillain-Barre Syndrome/therapy , Humans , Male , Tertiary Care Centers , Zika Virus Infection/complications , Zika Virus Infection/diagnosis , Zika Virus Infection/epidemiology
12.
PLoS Pathog ; 18(4): e1010411, 2022 04.
Article in English | MEDLINE | ID: mdl-35377915

ABSTRACT

The recent global Zika epidemics have revealed the significant threat that mosquito-borne viruses pose. There are currently no effective vaccines or prophylactics to prevent Zika virus (ZIKV) infection. Limiting exposure to infected mosquitoes is the best way to reduce disease incidence. Recent studies have focused on targeting mosquito reproduction and immune responses to reduce transmission. Previous work has evaluated the effect of insulin signaling on antiviral JAK/STAT and RNAi in vector mosquitoes. Specifically, insulin-fed mosquitoes resulted in reduced virus replication in an RNAi-independent, ERK-mediated JAK/STAT-dependent mechanism. In this work, we demonstrate that targeting insulin signaling through the repurposing of small molecule drugs results in the activation of both RNAi and JAK/STAT antiviral pathways. ZIKV-infected Aedes aegypti were fed blood containing demethylasterriquinone B1 (DMAQ-B1), a potent insulin mimetic, in combination with AKT inhibitor VIII. Activation of this coordinated response additively reduced ZIKV levels in Aedes aegypti. This effect included a quantitatively greater reduction in salivary gland ZIKV levels up to 11 d post-bloodmeal ingestion, relative to single pathway activation. Together, our study indicates the potential for field delivery of these small molecules to substantially reduce virus transmission from mosquito to human. As infections like Zika virus are becoming more burdensome and prevalent, understanding how to control this family of viruses in the insect vector is an important issue in public health.


Subject(s)
Aedes , Zika Virus Infection , Zika Virus , Animals , Antiviral Agents/metabolism , Humans , Insect Vectors , Insulin/genetics , Insulin/metabolism , Mosquito Vectors , RNA Interference , Zika Virus/genetics
13.
Virulence ; 13(1): 670-683, 2022 12.
Article in English | MEDLINE | ID: mdl-35436420

ABSTRACT

Glycans are among the most important cell molecular components. However, given their structural diversity, their functions have not been fully explored. Glycosylation is a vital post-translational modification for various proteins. Many bacteria and viruses rely on N-linked and O-linked glycosylation to perform critical biological functions. The diverse functions of glycosylation on viral proteins during viral infections, including Dengue, Zika, influenza, and human immunodeficiency viruses as well as coronaviruses have been reported. N-linked glycosylation is the most common form of protein modification, and it modulates folding, transportation and receptor binding. Compared to N-linked glycosylation, the functions of O-linked viral protein glycosylation have not been comprehensively evaluated. In this review, we summarize findings on viral protein glycosylation, with particular attention to studies on N-linked glycosylation in viral life cycles. This review informs the development of virus-specific vaccines or inhibitors.


Subject(s)
Zika Virus Infection , Zika Virus , Glycosylation , Host Microbial Interactions , Humans , Protein Processing, Post-Translational , Viral Proteins/metabolism , Virulence , Zika Virus/metabolism
14.
Antiviral Res ; 202: 105325, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35460703

ABSTRACT

Epidemics caused by flaviviruses occur globally; however, no antiviral drugs treating flaviviruses infections have yet been developed. Nafamostat (NM) is a protease inhibitor approved for pancreatitis and anti-coagulation. The anti-flavivirus potential of NM has yet to be determined. Here, utilizing in vitro and in vivo infection assays, we present that NM effectively inhibits Zika virus (ZIKV) and other flaviviruses in vitro. NM inhibited the production of ZIKV viral RNA and proteins originating from Asia and African lineage in human-, mouse- and monkey-derived cell lines and the in vivo anti-ZIKV efficacy of NM was verified. Mode-of-action analysis using time-of-drug-addition assay, infectivity inhibition assay, surface plasmon resonance assay, and molecular docking revealed that NM interacted with viral particles and blocked the early stage of infection by targeting the domain III of ZIKV envelope protein. Analysing the anti-flavivirus effects of NM-related compounds suggested that the antiviral effect depended on the unique structure of NM. These findings suggest the potential use of NM as an anti-flavivirus candidate, and a novel drug design approach targeting the flavivirus envelope protein.

15.
Chaos ; 32(4): 041105, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35489839

ABSTRACT

Over the last decade, the release of Wolbachia-infected Aedes aegypti into the natural habitat of this mosquito species has become the most sustainable and long-lasting technique to prevent and control vector-borne diseases, such as dengue, zika, or chikungunya. However, the limited resources to generate such mosquitoes and their effective distribution in large areas dominated by the Aedes aegypti vector represent a challenge for policymakers. Here, we introduce a mathematical framework for the spread of dengue in which competition between wild and Wolbachia-infected mosquitoes, the cross-contagion patterns between humans and vectors, the heterogeneous distribution of the human population in different areas, and the mobility flows between them are combined. Our framework allows us to identify the most effective areas for the release of Wolbachia-infected mosquitoes to achieve a large decrease in the global dengue prevalence.


Subject(s)
Aedes/microbiology , Chikungunya Fever/prevention & control , Dengue/prevention & control , Mosquito Vectors/microbiology , Wolbachia/physiology , Zika Virus Infection/prevention & control , Animals , Chikungunya Fever/epidemiology , Chikungunya Fever/transmission , Dengue/epidemiology , Dengue/transmission , Humans , Mosquito Control/economics , Wolbachia/growth & development , Zika Virus Infection/epidemiology , Zika Virus Infection/transmission
16.
mBio ; : e0385721, 2022 Apr 26.
Article in English | MEDLINE | ID: mdl-35471083

ABSTRACT

Interferon lambda (IFN-λ) (type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here, we used mice lacking the IFN-λ receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I·C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling, specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αß (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages. IMPORTANCE Pregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-λ), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-λ can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-λ signaling occurs. Remarkably, both the protective and pathogenic effects of IFN-λ occurred through signaling exclusively in maternal immune cells rather than in fetal or placental tissues or in other maternal cell types, identifying a new role for IFN-λ at the maternal-fetal interface.

17.
J Med Chem ; 65(9): 6555-6572, 2022 May 12.
Article in English | MEDLINE | ID: mdl-35475620

ABSTRACT

Zika virus (ZIKV) is a human pathogenic arbovirus. So far, neither a specific treatment nor a vaccination against ZIKV infections has been approved. Starting from our previously described lead structure, a series of 29 new macrocyclic inhibitors of the Zika virus protease containing different linker motifs have been synthesized. By selecting hydrophobic d-amino acids as part of the linker, numerous inhibitors with Ki values < 5 nM were obtained. For 12 inhibitors, crystal structures in complex with the ZIKV protease up to 1.30 Å resolution were determined, which contribute to the understanding of the observed structure-activity relationship (SAR). In immunofluorescence assays, an antiviral effect was observed for compound 26 containing a d-homocyclohexylalanine residue in its linker segment. Due to its excellent selectivity profile and low cytotoxicity, this inhibitor scaffold could be a suitable starting point for the development of peptidic drugs against the Zika virus and related flaviviruses.

18.
Sex Reprod Healthc ; 32: 100722, 2022 Mar 31.
Article in English | MEDLINE | ID: mdl-35381437

ABSTRACT

BACKGROUND: In 2016, a Public Health Emergency of International Concern (PHEIC) was declared in response to the rise of microcephaly cases among newborns in Northeastern Brazil. A common reactionary measure by public health authorities was to recommend women postpone pregnancy to avoid the possible perinatal transmission of Zika virus (ZIKV). METHODS: The purpose of this study was to assess how women in Fortaleza, Brazil conceptualize pregnancy; experience facilitators and barriers to pregnancy avoidance; perceive the authorities' recommendation to postpone pregnancy due to the ZIKV outbreak; and recall their experiences during the ZIKV epidemic. Qualitative methods, specifically a Rapid Anthropological Assessment (RAA), were utilized in this study. Data collection included semi-structured interviews, triangulated with observations and informal interviews with community members. RESULTS: The sample included 35 women (18-39 years old) who exclusively utilized the national public health care system. Findings indicated that all participants perceived the ZIKV pregnancy-postponement recommendation to be counter-cultural to Brazilian social norms. Overall women's self-perceived agency to prevent pregnancy was low due to social expectations and lack of trust for contraceptives. ZIKV prevention was not seen as a reason to utilize contraceptives. Interestingly, only women who self-perceived as more affluent were willing to attempt pregnancy prevention for educational, occupational, or financial opportunity. CONCLUSION: Pregnancy postponement as a response to a ZIKV epidemic ignores gaps in reproductive agency and defies social norms, making it unrealistic and counter-cultural. Future ZIKV health recommendations must be culturally aligned with the population, and address barriers and motivators for family planning.

19.
Results Phys ; 37: 105481, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35433239

ABSTRACT

In co-infection models for two diseases, it is mostly claimed that, the dynamical behavior of the sub-models usually predict or drive the behavior of the complete models. However, under a certain assumption such as, allowing incident co-infection with both diseases, we have a different observation. In this paper, a new mathematical model for SARS-CoV-2 and Zika co-dynamics is presented which incorporates incident co-infection by susceptible individuals. It is worth mentioning that the assumption is missing in many existing co-infection models. We shall discuss the impact of this assumption on the dynamics of a co-infection model. The model also captures sexual transmission of Zika virus. The positivity and boundedness of solution of the proposed model are studied, in addition to the local asymptotic stability analysis. The model is shown to exhibit backward bifurcation caused by the disease-induced death rates and parameters associated with susceptibility to a second infection by those singly infected. Using Lyapunov functions, the disease free and endemic equilibria are shown to be globally asymptotically stable for R 0 1 , respectively. To manage the co-circulation of both infections effectively, under an endemic setting, time dependent controls in the form of SARS-CoV-2, Zika and co-infection prevention strategies are incorporated into the model. The simulations show that SARS-CoV-2 prevention could greatly reduce the burden of co-infections with Zika. Furthermore, it is also shown that prevention controls for Zika can significantly decrease the burden of co-infections with SARS-CoV-2.

20.
Virus Genes ; 58(3): 151-171, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35394596

ABSTRACT

Structural genomics involves the advent of three-dimensional structures of the genome encoded proteins through various techniques available. Numerous structural genomics research groups have been developed across the globe and they contribute enormously to the identification of three-dimensional structures of various proteins. In this review, we have discussed the applications of the structural genomics approach towards the discovery of potential lead-like molecules against the genomic drug targets of three vector-borne diseases, namely, Dengue, Chikungunya and Zika. Currently, all these three diseases are associated with the most important global public health problems and significant economic burden in tropical countries. Structural genomics has accelerated the identification of novel drug targets and inhibitors for the treatment of these diseases. We start with the current development status of the drug targets and antiviral drugs against these three diseases and conclude by describing challenges that need to be addressed to overcome the shortcomings in the process of drug discovery.


Subject(s)
Chikungunya Fever , Dengue Virus , Dengue , Zika Virus Infection , Zika Virus , Chikungunya Fever/drug therapy , Dengue/drug therapy , Dengue Virus/genetics , Drug Discovery , Genomics , Humans , Zika Virus/genetics , Zika Virus Infection/drug therapy
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