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Zika is a flavivirus that is transmitted to humans either through the bites of infected Aedes mosquitoes or through sexual transmission. Zika has been associated with congenital anomalies, like microcephalus. We developed and analyzed the fractional‐order Zika virus model in this paper, considering the vector transmission route with human influence. The model consists of four compartments: susceptible individuals are x1(t), infected individuals are x2(t), x3(t) shows susceptible mosquitos, and x4(t) shows the infected mosquitos. The fractional parameter is used to develop the system of complex nonlinear differential equations by using Caputo and Atangana–Baleanu derivative. The stability analysis as well as qualitative analysis of the fractional‐order model has been made and verify the non‐negative unique solution. Finally, numerical simulations of the model with Caputo and Atangana Baleanu are discussed to present the graphical results for different fractional‐order values as well as for the classical model. A comparison has been made to check the accuracy and effectiveness of the developed technique for our obtained results. This investigative research leads to the latest information sector included in the evolution of the Zika virus with the application of fractional analysis in population dynamics. [ABSTRACT FROM AUTHOR]

In this paper, we are interested in propagation dynamics of a nonlocal dispersal Zika transmission model with general incidence. When the threshold R$$ \mathcal{R} $$ is greater than one, we prove that there is a wave speed c∗>0$$ {c}^{\ast }>0 $$ such that the model has a traveling wave solution with speed c>c∗$$ c>{c}^{\ast } $$, and there is no traveling wave solution with speed less than c∗$$ {c}^{\ast } $$. When the threshold R$$ \mathcal{R} $$ is less than or equal to one, we show that there is no nontrivial traveling wave solution. The approaches we use here are Schauder's fixed point theorem with an explicit construction of a pair of upper and lower solutions, the contradictory approach, and the two‐sided Laplace transform. [ABSTRACT FROM AUTHOR]

Background: Early pregnancy Zika virus (ZIKV) infection is associated with major brain damage in fetuses, leading to microcephaly in 0.6–5.0% of cases, but the underlying mechanisms remain largely unknown. Methods: To understand the kinetics of ZIKV infection during fetal development in a nonhuman primate model, four cynomolgus macaque fetuses were exposed in utero through echo-guided intramuscular inoculation with 103 PFU of ZIKV at 70–80 days of gestation, 2 controls were mock inoculated. Clinical, immuno-virological and ultrasound imaging follow-ups of the mother/fetus pairs were performed until autopsy after cesarean section 1 or 2 months after exposure (n = 3 per group). Results: ZIKV was transmitted from the fetus to the mother and then replicate in the peripheral blood of the mother from week 1 to 4 postexposure. Infected fetal brains tended to be smaller than those of controls, but not the femur lengths. High level of viral RNA ws found after the first month in brain tissues and placenta. Thereafter, there was partial control of the virus in the fetus, resulting in a decreased number of infected tissue sections and a decreased viral load. Immune cellular and humoral responses were effectively induced. Conclusions: ZIKV infection during the second trimester of gestation induces short-term brain injury, and although viral genomes persist in tissues, most of the virus is cleared before delivery. [ABSTRACT FROM AUTHOR]

The Zika virus (ZIKV) is a serious global public health crisis. A major control challenge is its multiple transmission modes. This paper aims to simulate the transmission patterns of ZIKV using a dynamic process-based epidemiological model written in ordinary differential equations, which incorporates the human-to-mosquito infection by bites and sewage, mosquito-to-human infection by bites, and human-to-human infection by sex. Mathematical analyses are carried out to calculate the basic reproduction number and backward bifurcation, and prove the existence and stability of the equilibria. The model is validated with infection data by applying it to the 2015–2016 ZIKV epidemic in Brazil. The results indicate that the reproduction number is estimated to be 2.13, in which the contributions by mosquito bite, sex and sewage account for 85.7%, 3.5% and 10.8%, respectively. This number and the morbidity rate are most sensitive to parameters related to mosquito ecology, rather than asymptomatic or human-to-human transmission. Multiple transmission routes and suitable temperature exacerbate ZIKV infection in Brazil, and the vast majority of human infection cases were prevented by the intervention implemented. These findings may provide new insights to improve the risk assessment of ZIKV infection. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), a mosquito‐borne Flavivirus of international concern, causes congenital microcephaly in newborns and Guillain–Barré syndrome in adults. ZIKV capsid (C) protein, one of three key structural proteins, is essential for viral assembly and encapsidation. In dengue virus, a closely related flavivirus, the homologous C protein interacts with host lipid systems, namely intracellular lipid droplets, for successful viral replication. Here, we investigate ZIKV C interaction with host lipid systems, showing that it binds host lipid droplets but, contrary to expected, in an unspecific manner. Contrasting with other flaviviruses, ZIKV C also does not bind very‐low density‐lipoproteins. Comparing with other Flavivirus, capsid proteins show that ZIKV C structure is particularly thermostable and seems to be locked into an auto‐inhibitory conformation due to a disordered N‐terminal, hence blocking specific interactions and supporting the experimental differences observed. Such distinct structural features must be considered when targeting capsid proteins in drug development. [ABSTRACT FROM AUTHOR]

Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. We determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-β and 2′C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers, and all primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-β inhibited replication of all arboviruses, while 2′C-methyl-cytidine reduced only USUV and ZIKV titers. Collectively, USUV can infect human brain tissue, showing similarities in tropism and neurovirulence as WNV and ZIKV. These data suggest that a blockade to infection of the human brain may not be the explanation for the low clinical incidence of USUV-associated neurological disease. However, USUV replicated more slowly and to lower titers than WNV, which could help to explain the reduced severity of neurological disease resulting from USUV infection. [ABSTRACT FROM AUTHOR]

At the start of the Zika virus (ZIKV) epidemic in 2015, ZIKV spread across South and Central America, and reached parts of the southern United States placing pregnant women at risk for fetal microcephaly, fetal loss, and other adverse pregnancy outcomes associated with congenital ZIKA syndrome (CZS). For this reason, testing of a safe and efficacious ZIKV vaccine remains a global health priority. Here we report that a single immunization with Ad26.M.Env ZIKV vaccine, when administered prior to conception, fully protects pregnant rhesus macaques from ZIKV viral RNA in blood and tissues with no adverse effects in dams and fetuses. Furthermore, vaccination prevents ZIKV distribution to fetal tissues including the brain. ZIKV associated neuropathology was absent in offspring of Ad26.M.Env vaccinated dams, although pathology was limited in fetuses from non-immunized, challenged dams. Vaccine efficacy is associated with induction of ZIKV neutralizing antibodies in pregnant rhesus macaques. These data suggest the feasibility of vaccine prevention of CZS in humans. [ABSTRACT FROM AUTHOR]

Mosquito-borne Zika virus (ZIKV) from sub-Saharan Africa has recently gained attention due to its epidemic potential and its capacity to be highly teratogenic. To improve our knowledge on currently circulating strains of African ZIKV, we conducted protein sequence alignment and identified contemporary West Africa NS1 (NS1CWA) protein as a highly conserved viral protein. Comparison of NS1CWA with the NS1 of the historical African ZIKV strain MR766 (NS1MR766), revealed seven amino acid substitutions. The effects of NS1 mutations on protein expression, virus replication, and innate immune activation were assessed in human cells using recombinant NS1 proteins and a chimeric viral clone MR766 with NS1CWA replacing NS1MR766. Our data indicated higher secretion efficiency of NS1CWA compared to NS1MR766 associated with a change in subcellular distribution. A chimeric MR766 virus with NS1CWA instead of authentic protein displayed a greater viral replication efficiency, leading to more pronounced cell death compared to parental virus. Enhanced viral growth was associated with reduced activation of innate immunity. Our data raise questions of the importance of NS1 protein in the pathogenicity of contemporary ZIKV from sub-Saharan Africa and point to differences within viral strains of African lineage. Author summary: Mosquito-borne Zika virus (ZIKV) of African lineage has the potential to cause epidemics alongside a high risk of fetal pathogenicity. Improved surveillance has enabled a deeper understanding of the molecular characteristics of currently circulating viral strains from sub-Saharan Africa. A remarkable conservation of ZIKV NS1 protein has been identified between recently isolated viral strains from West Africa, with data indicating that contemporary African NS1 is secreted efficiently from human cells. The protein has been shown to enhance viral replication, associated with a reduced activation of innate immune responses. The NS1 protein might therefore play a major role in the pathogenicity of contemporary ZIKV from sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Flaviviridae is a family of positive-stranded RNA viruses, including human pathogens, such as Japanese encephalitis virus (JEV), dengue virus (DENV), Zika virus (ZIKV), and West Nile virus (WNV). Nuclear localization of the viral core protein is conserved among Flaviviridae, and this feature may be targeted for developing broad-ranging anti-flavivirus drugs. However, the mechanism of core protein translocation to the nucleus and the importance of nuclear translocation in the viral life cycle remain unknown. We aimed to identify the molecular mechanism underlying core protein nuclear translocation. We identified importin-7 (IPO7), an importin-β family protein, as a nuclear carrier for Flaviviridae core proteins. Nuclear import assays revealed that core protein was transported into the nucleus via IPO7, whereas IPO7 deletion by CRISPR/Cas9 impaired their nuclear translocation. To understand the importance of core protein nuclear translocation, we evaluated the production of infectious virus or single-round-infectious-particles in wild-type or IPO7-deficient cells; both processes were significantly impaired in IPO7-deficient cells, whereas intracellular infectious virus levels were equivalent in wild-type and IPO7-deficient cells. These results suggest that IPO7-mediated nuclear translocation of core proteins is involved in the release of infectious virus particles of flaviviruses. Author summary: The Flaviviridae family, which includes Japanese encephalitis virus (JEV), dengue virus (DENV), Zika virus (ZIKV), and West Nile virus (WNV), possesses a single-stranded positive-sense RNA and conducts viral RNA replication, translation, and particle formation in the endoplasmic reticulum. The core proteins of flaviviruses, which form viral capsid, have been recognized to localize in not only the cytoplasm but also the nucleus, particularly in the nucleolus. Although this nuclear translocation of the core proteins is conserved within the Flaviviridae family, the underlying molecular mechanisms and their contribution to the viral life cycle remain largely unknown. Our in vitro biochemical assay and mass spectrometry analysis identified IPO7 as a nuclear carrier for Flaviviridae core proteins, such as those in JEV, DENV, ZIKV, and WNV. Moreover, we found that IPO7-mediated nuclear translocation of core proteins is important for the release of infectious viral particles. Our data suggest that the Flaviviridae family evolved to use the IPO7-mediated translocation of core proteins for efficient viral production. Therefore, IPO7 might be a target for the development of antiviral drugs against a broad range of Flaviviruses. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy plays a crucial role in inhibiting viral replication and regulating the host’s immune response. The autophagy receptor SQSTM1/p62 (sequestosome 1) restricts viral replication by directing specific viral proteins to phagophores for degradation. In this study, we investigate the reciprocal relationship between Zika virus (ZIKV) and selective autophagy mediated by SQSTM1/p62. We show that NS2B3 protease encoded by ZIKV cleaves human SQSTM1/p62 at arginine 265 (R265). This cleavage also occurs with endogenous SQSTM1 in ZIKV-infected cells. Furthermore, overexpression of SQSTM1 inhibits ZIKV replication in A549 cells, while its absence increases viral titer. We have also shown that SQSTM1 impedes ZIKV replication by interacting with NS3 and NS5 and directing them to autophagic degradation, and that NS2B3-mediated cleavage could potentially alter this antiviral function of SQSTM1. Taken together, our study highlights the role of SQSTM1-mediated selective autophagy in the host’s antiviral defense against ZIKV and uncovers potential viral evasion strategies that exploit the host’s autophagic machinery to ensure successful infection.Abbreviation: Cas9: CRISPR-associated protein 9; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DENV: dengue virus; GFP: green fluorescent protein; IFA: indirect immunofluorescence assay; KIR: KEAP1-interacting region; KO: knockout; LIR: MAP1LC3/LC3-interacting region; mAb: monoclonal antibody; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; pAb: polyclonal antibody; PB1: Phox/BEM1 domain; R265A, a SQSTM1 construct with the arginine (R) residue at position 265 replaced with glutamic acid (A); SQSTM1: sequestosome 1; SQSTM1-C, C-terminal fragment of SQSTM1; SQSTM1-N, N-terminal fragment of SQSTM1; SVV: Seneca Valley virus; TAX1BP1: Tax1 binding protein 1; TBD: TRAF6-binding domain; TCID50: 50% tissue culture infective dose; UBA: ubiquitin-associated domain; Ub: ubiquitin; WT: wild type; ZIKV: Zika virus; ZZ: ZZ-type zinc finger domain. [ABSTRACT FROM AUTHOR]

The microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection. Elizabethkingia anophelis, originally isolated from the midgut of Anopheles gambiae possess a broad-spectrum antiviral phenotype, yet a gap in knowledge regarding the mechanistic basis of its interaction with viruses exists. The current study aims to identify pathways and genetic factors linked to E. anophelis antiviral activity. The understanding of E. anophelis antiviral mechanism could lead to novel transmission barrier tools to prevent arboviral outbreaks. We utilized a non-targeted multi-omics approach, analyzing extracellular lipids, proteins, metabolites of culture supernatants coinfected with ZIKV and E. anophelis. We observed a significant decrease in arginine and phenylalanine levels, metabolites that are essential for viral replication and progression of viral infection. This study provides insights into the molecular basis of E. anophelis antiviral phenotype. The findings lay a foundation for in-depth mechanistic studies. [ABSTRACT FROM AUTHOR]

Microcephaly, Guillain-Barré syndrome, and potential sexual transmission stand as prominent complications associated with Zika virus (ZIKV) infection. The absence of FDA-approved drugs or vaccines presents a substantial obstacle in combatting the virus. Furthermore, the inclusion of pregnancy in the pharmacological screening process complicates and extends the endeavor to ensure molecular safety and minimal toxicity. Given its pivotal role in viral assembly and maturation, the NS2B-NS3 viral protease emerges as a promising therapeutic target against ZIKV. In this context, a dipeptide inhibitor was specifically chosen as a control against 200 compounds for docking analysis. Subsequent molecular dynamics simulations extending over 200 ns were conducted to ascertain the stability of the docked complex and confirm the binding of the inhibitor at the protein's active site. The simulation outcomes exhibited conformity to acceptable thresholds, encompassing parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), ligand-protein interaction analysis, ligand characterization, and surface area analysis. Notably, analysis of ligand angles bolstered the identification of prospective ligands capable of inhibiting viral protein activity and impeding virus dissemination. In this study, the integration of molecular docking and dynamics simulations has pinpointed the dipeptide inhibitor as a potential candidate ligand against ZIKV protease, thereby offering promise for therapeutic intervention against the virus. [ABSTRACT FROM AUTHOR]

This study presents a computational investigation of a stochastic Zika virus along with optimal control model using the Legendre spectral collocation method (LSCM). By accumulation of stochasticity into the model through the proposed stochastic differential equations, we appropriating the random fluctuations essential in the progression and disease transmission. The stability, convergence and accuracy properties of the LSCM are conscientiously analyzed and also demonstrating its strength for solving the complex epidemiological models. Moreover, the study evaluates the various control strategies, such as treatment, prevention and treatment pesticide control, and identifies optimal combinations that the intervention costs and also minimize the proposed infection rates. The basic properties of the given model, such as the reproduction number, were determined with and without the presence of the control strategies. For R 0 < 0 , the model satisfies the disease-free equilibrium, in this case the disease die out after some time, while for R 0 > 1 , then endemic equilibrium is satisfied, in this case the disease spread in the population at higher scale. The fundamental findings acknowledge the significant impact of stochastic phonemes on the robustness and effectiveness of control strategies that accelerating the need for cost-effective and multi-faceted approaches. In last the results provide the valuable insights for public health department to enabling more impressive mitigation of Zika virus outbreaks and management in real-world scenarios. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment. [ABSTRACT FROM AUTHOR]

Zika virus, a mosquito-borne arbovirus, has repeatedly caused large pandemics with symptoms worsening from mild and self-limiting diseases to Guillain–Barré syndrome in adults and fetal microcephaly in newborns. In recent years, Zika virus diseases have posed a serious threat to human health. The shortage of susceptible small animal models makes it difficult to study pathogenic mechanisms and evaluate potential therapies for Zika virus infection. Therefore, we chose immunocompromised mice (AG129 mice) deficient in IFN-α/β and IFN-γ receptors, which can abolish the innate immune system that prevents Zika virus infection early. AG129 mice were infected with the Zika virus, and this mouse model exhibited replication dynamics, tissue tropism, pathological lesion and immune activation of the Zika virus. Our results suggest that the inoculum dose of Zika virus can affect the viral replication dynamics, cytokine responses and survival rate in AG129 mice. By testing the potential antiviral drug favipiravir, several critical indicators, including replication dynamics and survival rates, were identified in AG129 mice after Zika virus infection. It is suggested that the model is reliable for drug evaluation. In brief, this model provides a potential platform for studies of the infectivity, virulence, and pathogenesis of the Zika virus. Moreover, the development of an accessible mouse model of Zika virus infection will expedite the research and deployment of therapeutics and vaccines. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) impacts the developing brain. Here, a technique was applied to define, in 3D, developmental changes in the brains of ZIKV-infected mice. Postnatal day 1 mice were uninfected or ZIKV-infected, then analysed by iodine staining and micro-CT scanning (diffusible iodine contrast-enhanced micro-CT; diceCT) at 3-, 6-, and 10-days post-infection (dpi). Multiple brain regions were visualised using diceCT: the olfactory bulb, cerebrum, hippocampus, midbrain, interbrain, and cerebellum, along with the lens and retina of the eye. Brain regions were computationally segmented and quantitated, with increased brain volumes and developmental time in uninfected mice. Conversely, in ZIKV-infected mice, no quantitative differences were seen at 3 or 6 dpi when there were no clinical signs, but qualitatively, diverse visual defects were identified at 6–10 dpi. By 10 dpi, ZIKV-infected mice had significantly lower body weight and reduced volume of brain regions compared to 10 dpi-uninfected or 6 dpi ZIKV-infected mice. Nissl and immunofluorescent Iba1 staining on post-diceCT tissue were successful, but RNA extraction was not. Thus, diceCT shows utility for detecting both 3D qualitative and quantitative changes in the developing brain of ZIKV-infected mice, with the benefit, post-diceCT, of retaining the ability to apply traditional histology and immunofluorescent analysis to tissue. [ABSTRACT FROM AUTHOR]

Zika virus infection is a mosquito-borne viral disease that has become a global health concern recently. Zika virus belongs to the Flavivirus genus and is primarily transmitted by Aedes mosquitoes. Prevention of Zika virus infection involves avoiding mosquito bites by using repellent, wearing protective clothing, and staying in screened areas, especially for pregnant women. Treatment focuses on managing symptoms with rest, fluids, and acetaminophen, with close monitoring for pregnant women. Currently, there is no specific antiviral treatment or vaccine for the Zika virus, highlighting the importance of prevention strategies to control its spread. Therefore, in this study, the Zika virus non-structural protein NS3 was targeted to inhibit Zika infection by identifying the novel inhibitor through an in silico approach. Here, 2864 natural compounds were screened using a machine learning-based QSAR model, and later docking was performed to select the potential target. Subsequently, Tanimoto similarity and clustering were performed to obtain the potential target. The three most potential compounds were obtained: (a) 5297, (b) 432449, and (c) 85137543. The protein–ligand complex's stability and flexibility were then investigated by dynamic modelling. The 300 ns simulation showed that 5297 exhibited the steadiest deviation and constant creation of hydrogen bonds. Compared to the other compounds, 5297 demonstrated a superior binding free energy (ΔG = −20.81 kcal/mol) with the protein when the MM/GBSA technique was used. The study determined that 5297 showed significant therapeutic potential and justifies further experimental investigation as a possible inhibitor of the NS2B-NS3 protease target implicated in Zika virus infection. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) can cause permanent neurological damage and death, yet no approved drugs exist for these infections. Rhodiola crenulate, an herb used in traditional Chinese medicine for its antioxidation and antifatigue properties, was studied for its antiviral activity against ZIKV and JEV in vitro. The cytotoxicity of Rhodiola crenulata extract (RCE) was evaluated using the CCK-8 reagent. Antiviral effects of RCE were assessed in ZIKV-infected or JEV-infected Vero cells via quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, fluorescent focus assay (FFA), and immunofluorescence assay (IFA). The cell-free antiviral effects of RCE were evaluated using an inactivation assay. To determine the stage of the viral life cycle affected by RCE, time-of-addition, binding, and entry assays were conducted. Three bioactive constituents of RCE (salidroside, tyrosol, and gallic acid) were tested for antiviral activity. RCE exhibited dose-dependent anti-ZIKV and anti-JEV activities at non-cytotoxic concentrations, which were likely achieved by disrupting viral binding and stability. Gallic acid exhibited antiviral activity against ZIKV and JEV. Our findings indicate that RCE disrupts viral binding and stability, presenting a potential strategy to treat ZIKV and JEV infections. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that has been associated with congenital neurological defects in fetuses born to infected mothers. At present, no vaccine or antiviral therapy is available to combat this devastating disease. Repurposing drugs that target essential host factors exploited by viruses is an attractive therapeutic approach. Here, we screened a panel of clinically approved small-molecule kinase inhibitors for their antiviral effects against a clinical isolate of ZIKV and thoroughly characterized their mechanisms of action. We found that the Raf kinase inhibitors Dabrafenib and Regorafenib potently impair the replication of ZIKV, but not that of its close relative dengue virus. Time-of-addition experiments showed that both inhibitors target ZIKV infection at post-entry steps. We found that Dabrafenib, but not Regorafenib, interfered with ZIKV genome replication by impairing both negative- and positive-strand RNA synthesis. Regorafenib, on the other hand, altered steady-state viral protein levels, viral egress, and blocked NS1 secretion. We also observed Regorafenibinduced ER fragmentation in ZIKV-infected cells, which might contribute to its antiviral effects. Because these inhibitors target different steps of the ZIKV infection cycle, their use in combination therapy may amplify their antiviral effects which could be further explored for future therapeutic strategies against ZIKV and possibly other flaviviruses. IMPORTANCE There is an urgent need to develop effective therapeutics against re-emerging arboviruses associated with neurological disorders like Zika virus (ZIKV). We identified two FDA-approved kinase inhibitors, Dabrafenib and Regorafenib, as potent inhibitors of contemporary ZIKV strains at distinct stages of infection despite overlapping host targets. Both inhibitors reduced viral titers by ~1 to 2 log10 (~10-fold to 100-fold) with minimal cytotoxicity. Furthermore, we show that Dabrafenib inhibits ZIKV RNA replication whereas Regorafenib inhibits ZIKV translation and egress. Regorafenib has the added benefit of limiting NS1 secretion, which contributes to the pathogenesis and disease progression of several flaviviruses. Because these inhibitors affect distinct post-entry steps of ZIKV infection, their therapeutic potential may be amplified by combination therapy and likely does not require prophylactic administration. This study provides further insight into ZIKV-host interactions and has implications for the development of novel antivirals against ZIKV and possibly other flaviviruses. [ABSTRACT FROM AUTHOR]

Tick‐borne encephalitis (TBE) virus is the most prevalent tick‐transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA‐based detection of specific antibodies in the patient serum. However, cross‐reactivity between orthoflaviviruses complicates the diagnosis. Specificity issues may be mitigated by serum neutralization assays (SNT), although the handling of clinically relevant orthoflaviviruses requires biosafety level (BSL) 3 conditions and they have highly divergent viral kinetics and cell tropisms. In the present study, we established a reporter virus particle (RVP)‐based SNT in which the infectivity is measured by luminescence and that can be performed under BSL‐2 conditions. The RVP‐based SNT for TBEV exhibited a highly significant correlation with the traditional virus‐based SNT (R2 = 0.8637, p < 0.0001). The RVP‐based assay demonstrated a sensitivity of 92.3% (95% CI: 79.7%–97.4%) and specificity of 100% (95% CI: 81.6%–100%). We also tested the cross‐reactivity of serum samples in RVP‐based assays against other orthoflaviviruses (yellow fever virus, dengue virus type 2, Zika virus, West Nile virus and Japanese encephalitis virus). Interestingly, all serum samples which had tested TBEV‐positive by ELISA but negative by RVP‐based SNT were reactive for antibodies against other orthoflaviviruses. Thus, the RVP‐based seroneutralization assay provides an added value in clinical diagnostics as well as in epidemiological studies. [ABSTRACT FROM AUTHOR]

Introduction: Human Erythrovirus (parvovirus) B19 infection can produce symptoms similar to those produced by Dengue, Chikungunya, and Zika viruses, making clinical diagnosis difficult. The importance of erythrovirus B19 in human pathology has been increased and reported in numerous studies published globally. Methods: The B19V infection was investigated by real-time PCR in sera samples from patients with signs and symptoms related to classic arboviral symptoms. This study was conducted to provide information on the genetic diversity of Human Erythrovirus B19 (B19V) circulating in the state of Mato Grosso do Sul, Midwest region of Brazil, from 2017 to 2022. A total of 773 sera samples of patients with negative diagnostic results for Dengue, Chikungunya, and Zika, during the study period were analyzed. Results: Erythrovirus DNA was found in 10.6% (82/773) of patients, among them 10 were pregnant women. Four samples were completely sequenced, and the other five partially, to genotype by phylogenetic reconstruction. All samples belong to worldwide dispersed genotype 1, subgenotype 1a. Discussion: The findings of the study demonstrate the importance of including B19V in differential laboratory diagnosis for epidemiological purposes and appropriate patient management. The diagnosis for B19V should be performed, particularly among pregnant women, immunocompromised patients, and individuals with hemolytic diseases, given that the infection is more severe in these cases. [ABSTRACT FROM AUTHOR]

Flaviviruses, including dengue (DENV), Zika (ZIKV), West Nile (WNV), Japanese encephalitis (JEV), yellow fever (YFV), and tick-borne encephalitis (TBEV) viruses, pose a significant global emerging threat. With their potential to cause widespread outbreaks and severe health complications, the development of effective vaccines and antiviral therapeutics is imperative. The flaviviral non-structural protein 5 (NS5) is a highly conserved and multifunctional protein that is crucial for viral replication, and the NS5 protein of many flaviviruses has been shown to be a potent inhibitor of interferon (IFN) signalling. In this review, we discuss the functions of NS5, diverse NS5-mediated strategies adopted by flaviviruses to evade the host antiviral response, and how NS5 can be a target for the development of vaccines and antiviral therapeutics. [ABSTRACT FROM AUTHOR]

Orthoflaviviruses cause a major threat to global public health, and no antiviral treatment is available yet. Zika virus (ZIKV) entry, together with many other viruses, is known to be enhanced by phosphatidylserine (PS) receptors such as T-cell immunoglobulin mucin domain protein 1 (TIM-1). In this study, we demonstrate for the first time, using cell-based electrical impedance (CEI) biosensing, that ZIKV entry is also enhanced by expression of CD300a, another PS receptor. Furthermore, inhibiting CD300a in immature monocyte-derived dendritic cells partially but significantly inhibits ZIKV replication. As we have previously demonstrated that CEI is a useful tool to study Orthoflavivirus infection in real time, we now use this technology to determine how these PS receptors influence the kinetics of in vitro ZIKV infection. Results show that ZIKV entry is highly sensitive to minor changes in TIM-1 expression, both after overexpression of TIM-1 in infection-resistant HEK293T cells, as well as after partial knockout of TIM-1 in susceptible A549 cells. These results are confirmed by quantification of viral copy number and viral infectivity, demonstrating that CEI is highly suited to study and compare virus-host interactions. Overall, the results presented here demonstrate the potential of targeting this universal viral entry pathway. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death. Synopsis: ZIKV exhibits a high neurotropism and poses significant risks to the developing nervous system. We show that inhibition of the host TRPC4 channel or CaMKII impedes ZIKV propagation in human brain organoids and improves survival in a neonatal mouse model of ZIKV infection. ZIKV upregulates the expression of TRPC4 in host cells through the NS3-CaMKII-CREB pathway. Inhibition of the TRPC4 channel effectively disrupts the replication stage of the ZIKV life cycle. TRPC4 and CaMKII inhibitors successfully block proliferation and spread of ZIKV in human induced pluripotent stem cell (iPSC)-derived brain organoids. Treatment with TRPC4 and CaMKII inhibitors reduces seizures and improves survival rates in newborn mice infected with ZIKV. Thus, targeting TRPC4 holds promise as a potential approach for developing anti-ZIKV drugs, offering new treatment strategies for neurological dysfunction caused by ZIKV virus infection. ZIKV exhibits a high neurotropism and poses significant risks to the developing nervous system. We show that inhibition of the host TRPC4 channel or CaMKII impedes ZIKV propagation in human brain organoids and improves survival in a neonatal mouse model of ZIKV infection. [ABSTRACT FROM AUTHOR]

The mosquito, Aedes aegypti, is the principal vector for several arboviruses. The mosquito midgut is the initial tissue that gets infected with an arbovirus acquired along with a blood meal from a vertebrate host. Blood meal ingestion leads to midgut tissue distention thereby increasing the pore size of the surrounding basal lamina. This allows newly synthesized virions to exit the midgut by traversing the distended basal lamina to infect secondary tissues of the mosquito. We conducted a quantitative label‐free proteomic time course analysis with saline meal‐fed Ae. aegypti females to identify host factors involved in midgut tissue distention. Around 2000 proteins were detected during each of the seven sampling time points and 164 of those were uniquely expressed. Forty‐five of 97 differentially expressed proteins were upregulated during the 96‐h time course and most of those were involved in cytoskeleton modulation, metabolic activity, and vesicle/vacuole formation. The F‐actin‐modulating Ae. aegypti (Aa)‐gelsolin was selected for further functional studies. Stable knockout of Aa‐gelsolin resulted in a mosquito line, which showed distorted actin filaments in midgut‐associated tissues likely due to diminished F‐actin processing by gelsolin. Zika virus dissemination from the midgut of these mosquitoes was diminished and delayed. The loss of Aa‐gelsolin function was associated with an increased induction of apoptosis in midgut tissue indicating an involvement of Aa‐gelsolin in apoptotic signaling in mosquitoes. Here, we used proteomics to discover a novel host factor, Aa‐gelsolin, which affects the midgut escape barrier for arboviruses in mosquitoes and apoptotic signaling in the midgut. [ABSTRACT FROM AUTHOR]

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS. Author summary: Zika virus (ZIKV) infection in pregnant women can lead to the development of Congenital Zika Syndrome (CZS) in infants, resulting in complications such as microcephaly, intrauterine growth restriction (IUGR), and miscarriages. Although the mechanisms of apoptosis and inflammatory responses in ZIKV-induced CZS are not fully understood, our study investigated the role of c-FLIP, a critical regulator of apoptosis and inflammation during ZIKV infection and its associated CZS. In both human trophoblast cells and murine-derived macrophages, we observed that c-FLIP facilitated ZIKV infection by modulating caspase-8/3-mediated apoptosis. Mice deficient in c-FLIP exhibited reduced ZIKV replication and a decrease in inflammatory cytokine production. Importantly, c-FLIP deficiency demonstrated an inhibitory effect on CZS in ZIKV-infected pregnant mice. Additionally, c-FLIP displayed a parental influence on ZIKV replication in the fetal head by triggering caspase-3 activation. This research emphasizes the significance of c-FLIP in regulating caspase-8/3 and its profound impact on ZIKV-induced CZS, providing valuable insights into the role of apoptosis in ZIKV vertical transmission and fetal development. [ABSTRACT FROM AUTHOR]

Point-of-care (POC) diagnostics have emerged as a crucial technology for emerging pathogen detections to enable rapid and on-site detection of infectious diseases. However, current POC devices often suffer from limited sensitivity with poor reliability to provide quantitative readouts. In this paper, we present a self-powered digital loop-mediated isothermal amplification (dLAMP) microfluidic chip (SP-dChip) for the rapid and quantitative detection of nucleic acids. The SP-dChip utilizes a vacuum lung design to passively digitize samples into individual nanoliter wells for high-throughput analysis. The superior digitization scheme is further combined with reverse transcription loop-mediated isothermal amplification (RT-LAMP) to demonstrate dLAMP detection of Zika virus (ZIKV). Firstly, the LAMP assay is loaded into the chip and passively digitized into individual wells. Mineral oil is then pipetted through the chip to differentiate each well as an individual reactor. The chip did not require any external pumping or power input for rapid and reliable results to detect ZIKA RNA as low as 100 copies per μL within one hour. As such, this SP-dChip offers a new class of solutions for truly affordable, portable, and quantitative POC detections for emerging viruses. [ABSTRACT FROM AUTHOR]

The Zika virus (ZIKV) is an emerging virus associated with the Flaviviridae family that mainly causes infection in pregnant women and leads to several abnormalities during pregnancy. This virus has unique properties that may lead to pathological diseases. As the virus has the ability to evade immune response, a crucial effort is required to deal with ZIKV. Vaccines are a safe means to control different pathogenic infectious diseases. In the current research, a multiepitope-based vaccination against ZIKV is being designed using in silico methods. For the epitope prediction and prioritization phase, ZIKV polyprotein (YP_002790881.1) and flavivirus polyprotein (>YP_009428568.1) were targeted. The predicted B-cell epitopes were used for MHC-I and MHC-II epitope prediction. Afterward, several immunoinformatics filters were applied and nine (REDLWCGSL, MQDLWLLRR, YKKSGITEV, TYTDRRWCF, RDAFPDSNS, KPSLGLINR, ELIGRARVS, AITQGKREE, and EARRSRRAV) epitopes were found to be probably antigenic in nature, non-allergenic, non-toxic, and water soluble without any toxins. Selected epitopes were joined using a particular GPGPG linker to create the base vaccination for epitopes, and an extra EAAAK linker was used to link the adjuvant. A total of 312 amino acids with a molecular weight (MW) of 31.62762 and an instability value of 34.06 were computed in the physicochemical characteristic analysis, indicating that the vaccine design is stable. The molecular docking analysis predicted a binding energy of -329.46 (kcal/mol) for TLR-3 and -358.54 (kcal/mol) for TLR-2. Moreover, the molecular dynamics simulation analysis predicted that the vaccine and receptor molecules have stable binding interactions in a dynamic environment. The C-immune simulation analysis predicted that the vaccine has the ability to generate both humoral and cellular immune responses. Based on the design, the vaccine construct has the best efficacy to evoke immune response in theory, but experimental analysis is required to validate the in silico base approach and ensure its safety. [ABSTRACT FROM AUTHOR]

Introduction: Mayaro Fever (MF) is a tropical disease caused by the Mayaro virus (MAYV), with outbreaks documented in Latin America. Methods: A hospital-based fever surveillance in Leticia, Colombian Amazon, collected sera from 1,460 patients aged 5-89 between December 2020 and April 2023. Results: Dengue and malaria were the main diagnoses (19.4 and 5.8%, respectively), leaving 71.4% of cases unidentified after testing. Metagenomic sequencing and real-time RT-qPCR testing identified MAYV in two patients (25-year-old male and an 80-year-old female) exhibiting typical symptoms, of MF including rash, joint pain, and fever. Phylogenetics analysis of these two viruses revealed a close relationship to Peruvian strains within the MAYV D genotype. Discussion: The study of AFI in Leticia, Colombia, identified dengue as prevalent, with malaria, COVID-19, Influenza, and Zika viruses also detected. Despite extensive testing, most cases remained unexplained until metagenomic sequencing revealed MAYV, previously unseen in Colombia but known in neighboring countries. Conclusion: This study presents the first near full-length genomes of MAYV in Colombia, highlighting the need for further seroprevalence studies and enhanced surveillance to understand and control the spread of the virus in the region. [ABSTRACT FROM AUTHOR]

Pathogenic microorganisms play a crucial role in the global disease burden due to their ability to cause various diseases and spread through multiple transmission routes. Immunity tests identify antigens related to these pathogens, thereby confirming past infections and monitoring the host's immune response. Traditional pathogen detection methods, including enzyme-linked immunosorbent assays (ELISAs) and chemiluminescent immunoassays (CLIAs), are often labor-intensive, slow, and reliant on sophisticated equipment and skilled personnel, which can be limiting in resource-poor settings. In contrast, the development of microfluidic technologies presents a promising alternative, offering automation, miniaturization, and cost efficiency. These advanced methods are poised to replace traditional assays by streamlining processes and enabling rapid, high-throughput immunity testing for pathogens. This review highlights the latest advancements in microfluidic systems designed for rapid and high-throughput immunity testing, incorporating immunosensors, single molecule arrays (Simoas), a lateral flow assay (LFA), and smartphone integration. It focuses on key pathogenic microorganisms such as SARS-CoV-2, influenza, and the ZIKA virus (ZIKV). Additionally, the review discusses the challenges, commercialization prospects, and future directions to advance microfluidic systems for infectious disease detection. [ABSTRACT FROM AUTHOR]

Zika Virus (ZIKV) is a positive-strand RNA virus that can lead to Guillain-Barré syndrome or encephalitis in some individuals and hence presents a serious public health risk. Since the first outbreak of ZIKV in Brazil in 2015, no effective clinical inhibitors have been developed, making the development of effective ZIKV drugs an urgent issue that needs to be addressed. ZIKV belongs to the Flaviviridae family, and its structure includes three structural proteins, namely, capsular (C), premembrane (prM), and envelope (E) proteins, as well as seven nonstructural proteins, namely, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. To provide a reference for the development of future ZIKV drugs, this paper reviews the structure of the ZIKV based on recent literature reports, analyzes the potential therapeutic targets of various proteins, and proposes feasible drug design strategies. Additionally, this paper reviews and classifies the latest research progress on several protease inhibitors, such as E protein inhibitors, NS2BNS3 inhibitors, and NS5 inhibitors, so that researchers can quickly understand the current status of development and the interconnections among these inhibitors. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) has become a global health problem over the past decade due to the extension of the geographic distribution of the Asian/American genotype. Recent epidemics of Asian/American ZIKV have been associated with developmental disorders in humans. There is mounting evidence that African ZIKV may be associated with increased fetal pathogenicity necessitating to pay a greater attention towards currently circulating viral strains in sub-Saharan Africa. Here, we generated an infectious molecular clone GUINEA-18 of a recently transmitted human ZIKV isolate from West Africa, ZIKV-15555. The available infectious molecular clone MR766MC of historical African ZIKV strain MR766-NIID was used for a molecular clone-based comparative study. Viral clones GUINEA-18 and MR766MC were compared for their ability to replicate in VeroE6, A549 and HCM3 cell lines. There was a lower replication rate for GUINEA-18 associated with weaker cytotoxicity and reduced innate immune system activation compared with MR766MC. Analysis of chimeric viruses between viral clones stressed the importance of NS1 to NS4B proteins, with a particular focus of NS4B on GUINEA-18 replicative properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. GUINEA-18 was greatly efficient in inhibiting stress granule assembly in A549 cells subjected to a physiological stressor, with NS1 to NS4B proteins also being critical in this process. The impact of these GUINEA-18 proteins on viral replicative abilities and host-cell responses to viral infection raises the question of the role of nonstructural proteins in the pathogenicity of currently circulating ZIKV in sub-Saharan Africa. Author summary: Most studies with the objective to understand the biology of Zika virus (ZIKV) were carried out using the epidemic Asian genotype of this pathogen. It is currently being discussed whether ZIKV of African genotype may have epidemic potential associated a high risk of fetal pathogenicity. It is thus urgent to improve our knowledge on recently isolated ZIKV strains from West Africa. In this study, we used the sequence of a viral strain from an individual infected by ZIKV in Guinea in 2018 to generate an infectious molecular clone. Analysis of this viral clone highlighted the preponderant role of NS1 to NS4B proteins in virus replication and cell interactions with a particular focus on ZIKV-specific stress granule formation blocking activity. We believe that our data will improve our understanding of the biology of contemporary West Africa ZIKV, opening perspectives towards a better understanding of the pathogenicity of African viral strains. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion In Brazil, urban arboviruses, such as dengue virus (DENV), Zika virus (ZIKV) and chikungunya virus (CHIKV), constitute a major public health problem, and due to their endemicity and asymptomatic cases, they pose a potential threat to blood donations. Rio de Janeiro (RJ), Brazil, has been impacted by extensive DENV epidemics over the last 30 years and, after 2015, by CHIKV and ZIKV.Urban arboviruses DENV, ZIKV and CHIKV were investigated in blood donations (n = 778) at the State Institute of Hematology, HEMORIO (RJ) from 2019 to 2022 by serological and molecular methods.An overall arbovirus exposure was observed in 26.1% of the blood donations. Anti‐DENV IgM was detected in 4.0% of samples and two donations were DENV NS1 positive. Positive anti‐CHIKV IgM was observed in 4.7% of the donations. Co‐detection of anti‐CHIKV IgM and anti‐DENV IgM was observed in 1.0% of donors, and CHIKV prevalence was 21.3%. All blood donations tested were negative for the DENV, ZIKV and CHIKV RNA.IgM seroprevalence to the arboviruses analyzed here is an indicator of recent infection in asymptomatic donors, showing that the population of blood donors can be a vehicle for new infections, especially during epidemic periods. [ABSTRACT FROM AUTHOR]

In response to the 2015 Zika virus (ZIKV) epidemic that occurred in Brazil, numerous commercial serological assays have been developed for clinical and research applications. Diagnosis of recent infection in pregnant women remains challenging. Having standardized, comparative studies of ZIKV tests is important for implementing optimal diagnostic testing and disease surveillance. This is especially important for serology tests used to detect ZIKV infection given that antibodies against ZIKV can cross-react with other arboviruses in the same virus family, such as dengue virus (DENV), yellow fever virus (YFV) and West Nile virus (WNV). We looked at the sensitivity and specificity of tests detecting ZIKV antibodies (IgM, IgG) from multiple manufacturers using panels of samples previously collected with known exposure to ZIKV and other arboviruses. We found that performance of the IgM tests was highly variable, with only one test (Inbios 2.0 IgM capture ELISA) having both high sensitivity and specificity. All IgG tests showed good sensitivity; however, specificity was highly variable, with some assays giving false-positive results on samples infected by another flavivirus. Overall, the results confirmed that accurate ZIKV antibody testing is challenging, especially in specimens from regions endemic for multiple other flaviviruses, and highlight the importance of available and suitable reference samples to evaluate ZIKV diagnostics. [ABSTRACT FROM AUTHOR]

Little is known about the frequency of Zika virus (ZIKV) infections in Sudan. The aim of this study was to obtain data on the prevalence of ZIKV infections and the immunity of the population in the country. To this end, 198 sera obtained between December 2012 and January 2013 in different regions in Sudan were examined for neutralizing antibodies against ZIKV, dengue virus (DENV), and yellow fever virus (YFV). The sera were non-randomly selected. The neutralization titers were compared with each other and with the WHO 1st International Standard for anti-Asian lineage Zika virus antibody. Twenty-six sera neutralized ZIKV. One-third of these sera had higher neutralization titers against ZIKV than against DENV-2 and -3. Two sera showed higher neutralization titers than the WHO standard for ZIKV antibodies. These data suggest occasional ZIKV infections in Sudan. The low percentage of sera in this cohort that neutralized ZIKV indicates that, in the study period, the population was susceptible to ZIKV infection. [ABSTRACT FROM AUTHOR]

Background and Aim: Some Culex mosquitoes are competent vectors for Japanese encephalitis virus (JEV) and Zika virus (ZIKV), which cause public health problems worldwide, especially in South-east Asia. Xenosurveillance of Culex mosquitoes remains limited compared with other common mosquito-borne diseases. This study aimed to identify JEV and ZIKV in field-caught Culex mosquitoes collected from Ubon Ratchathani province. Materials and Methods: We investigated the presence of JEV and ZIKV in Culex mosquitoes from two districts in Ubon Ratchathani province, Thailand, and examined their role in viral interepidemic circulation. Female Culex mosquitoes (5,587) were collected using a mechanical aspirator from indoors and outdoors. The consensus sequences of the E and NS1 genes of JEV and the E gene of ZIKV were identified using real-time reverse transcription-polymerase chain reaction. Results: From 335 sample pools that contain a total of 5587 adult female Culex mosquitoes collected from Don Yung, Mueang district (4,406) and Phon Duan, Det Udom district (1,181), none of the collected mosquitoes tested positive for either JEV or ZIKV. Conclusion: This study did not find JEV and ZIKV in Culex mosquitoes collected from the area of collection, which may be due to the low circulating amount of the virus in the vectors in the area, making it undetectable, or it may be because Culex mosquitoes are not suitable vector for the virus being tested. However, further xenosurveillance study of JEV and ZIKV in mosquito is suggested to prepare for the next outbreak. [ABSTRACT FROM AUTHOR]

The Indonesian government wanted to determine the transmission of the Omicron virus via immigrants and foreign tourists in Indonesia. Hence, the Omicron transmission Susceptible-Infectious-Recovered model, with parameters of foreign travelers and immigrants was constructed. Then, using the next-generation matrix method, it was discovered that when the number of foreign travelers and immigrants who entered Indonesia (a) is constant and the number of foreign travelers who leave Indonesia (c) varies, the basic reproductive number is R0 = 5.6. Conversely, when the number of foreign travelers and immigrants entering Indonesia (a) varies and the number of foreign travelers leaving Indonesia (c) is constant, the basic reproductive number is R0 = 6.7. [ABSTRACT FROM AUTHOR]

Live-attenuated flavivirus vaccines confer long-term protection against disease, but the design of attenuated flaviviruses does not follow a general approach. The non-coding, subgenomic flavivirus RNA (sfRNA) is produced by all flaviviruses and is an essential factor in viral pathogenesis and transmission. We argue that modulating sfRNA expression is a promising, universal strategy to finetune flavivirus attenuation for developing effective flavivirus vaccines of the future. [ABSTRACT FROM AUTHOR]

The diagnosis of a congenital infection leads to feeling of anxiety and fear not only the pregnant woman but also in the medical practitioner caring for the woman. This is not surprising given that these conditions are rare events and so each clinician may only see a handful in their career. This article gives practical advice for when to suspect congenital infection, and to provide a framework for investigation, counselling and management of seven important congenital infections: toxoplasmosis, cytomegalovirus (CMV), zika virus, parvovirus B19, rubella, syphilis, and varicella zoster. [ABSTRACT FROM AUTHOR]

In order to study the impact of seasonality on Zika virus dynamics, we analyzed a non-autonomous mathematical model for the Zika virus (ZIKV) transmission where we considered time-dependent parameters. We proved that the system admitted a unique bounded positive solution and a global attractor set. The basic reproduction number, R0, was defined using the next generation matrix method for the case of fixed environment and as the spectral radius of a linear integral operator for the case of seasonal environment. We proved that if R0 was smaller than the unity, then a disease-free periodic solution was globally asymptotically stable, while if R0 was greater than the unity, then the disease persisted. We validated the theoretical findings using several numerical examples. [ABSTRACT FROM AUTHOR]

Over the years, research regarding the Zika virus has been steadily increasing. Early immunization for ZIKV is a priority for preventing complications such as microencephaly and Guillain–Barré syndrome (GBS). Unlike traditional vaccination approaches, oral dissolving films (ODFs) or mucoadhesive film technology is an emerging, exciting concept that can be used in the field of pharmaceuticals for vaccine design and formulation development. This attractive and novel method can help patients who suffer from dysphagia as a complication of a disease or syndrome. In this study, we investigated a microparticulate Zika vaccine administered via the buccal route with the help of thin films or oral dissolving films (ODFs) with a prime dose and two booster doses two weeks apart. In vitro, the ODFs displayed excellent physiochemical properties, indicating that the films were good carriers for vaccine microparticles and biocompatible with the buccal mucosa. In vivo results revealed robust humoral (IgG, subtypes IgG1 and IgG2a) and T-cell responses (CD4+/CD8+) for ZIKV-specific immunity. Both the Zika MP vaccine and the adjuvanted Zika MP vaccine affected memory (CD45R/CD27) and intracellular cytokine (TNF-α and IL-6) expression. In this study, ZIKV vaccination via the buccal route with the aid of ODFs demonstrated great promise for the development of pain-free vaccines for infectious diseases. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), a mosquito-borne flavivirus, is prominently associated with microcephaly in babies born to infected mothers as well as Guillain-Barré Syndrome in adults. Each cell type infected by ZIKV—neuronal cells (radial glial cells, neuronal progenitor cells, astrocytes, microglia cells, and glioblastoma stem cells) and non-neuronal cells (primary fibroblasts, epidermal keratinocytes, dendritic cells, monocytes, macrophages, and Sertoli cells)—displays its own characteristic changes to their cell physiology and has various impacts on disease. Here, we provide an in-depth review of the ZIKV life cycle and its cellular targets, and discuss the current knowledge of how infections cause neuropathologies, as well as what approaches researchers are currently taking to further advance such knowledge. A key aspect of ZIKV neuropathogenesis is virus-induced neuronal apoptosis via numerous mechanisms including cell cycle dysregulation, mitochondrial fragmentation, ER stress, and the unfolded protein response. These, in turn, result in the activation of p53-mediated intrinsic cell death pathways. A full spectrum of infection models including stem cells and co-cultures, transwells to simulate blood–tissue barriers, brain-region-specific organoids, and animal models have been developed for ZIKV research. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), a re-emerging flavivirus, is associated with devasting developmental and neurological disease outcomes particularly in infants infected in utero. Towards understanding the molecular underpinnings of the unique ZIKV disease pathologies, numerous transcriptome-wide studies have been undertaken. Notably, these studies have overlooked the assimilation of RNA-seq analysis from ZIKV-infected patients with cell culture model systems. In this study we find that ZIKV-infection of human lung adenocarcinoma A549 cells, mirrored both the transcriptional and alternative splicing profiles from previously published RNA-seq data of peripheral blood mononuclear cells collected from pediatric patients during early acute, late acute, and convalescent phases of ZIKV infection. Our analyses show that ZIKV infection in cultured cells correlates with transcriptional changes in patients, while the overlap in alternative splicing profiles was not as extensive. Overall, our data indicate that cell culture model systems support dissection of select molecular changes detected in patients and establishes the groundwork for future studies elucidating the biological implications of alternative splicing during ZIKV infection. [ABSTRACT FROM AUTHOR]

We previously reported the first-in-human assessment of three doses (2, 5, and 10 µg) of purified inactivated Zika virus vaccine (PIZV or TAK-426) in the Phase 1 ZIK-101 study (NCT03343626). Here, we report dose selection based on extended safety and immunogenicity data (6 months post-vaccination) and discuss considerations (e.g., immunological, historic, flavivirus immunological cross-reactions) for selecting a Zika virus (ZIKV) vaccine dose formulation. TAK-426 dose selection was conducted at the first interim analysis, and was based on cumulative safety data from both flavivirus-naïve (up to ≥28 days post-dose PD2) and flavivirus-primed participants (up to ≥28 days PD1), and on immunogenicity data from flavivirus-naïve participants only (at 28 days PD1 and 28 days PD2). The safety profile from TAK-426 recipients was compared to placebo recipients. Immunogenicity was assessed by geometric mean titer ratios of neutralizing anti-ZIKV antibodies and differences in seroconversion rates. There was no significant difference in safety between the three TAK-426 doses. The 10 μg dose provided the earliest and strongest immune response (with close to 100% seroconversion and higher antibody titers PD1 in flavivirus-naïve participants), and was well tolerated with acceptable safety profiles in both flavivirus-naïve and flavivirus-primed participants; this dose was selected for further development. [ABSTRACT FROM AUTHOR]

Abstract Background Early pregnancy Zika virus (ZIKV) infection is associated with major brain damage in fetuses, leading to microcephaly in 0.6–5.0% of cases, but the underlying mechanisms remain largely unknown. Methods To understand the kinetics of ZIKV infection during fetal development in a nonhuman primate model, four cynomolgus macaque fetuses were exposed in utero through echo-guided intramuscular inoculation with 103 PFU of ZIKV at 70–80 days of gestation, 2 controls were mock inoculated. Clinical, immuno-virological and ultrasound imaging follow-ups of the mother/fetus pairs were performed until autopsy after cesarean section 1 or 2 months after exposure (n = 3 per group). Results ZIKV was transmitted from the fetus to the mother and then replicate in the peripheral blood of the mother from week 1 to 4 postexposure. Infected fetal brains tended to be smaller than those of controls, but not the femur lengths. High level of viral RNA ws found after the first month in brain tissues and placenta. Thereafter, there was partial control of the virus in the fetus, resulting in a decreased number of infected tissue sections and a decreased viral load. Immune cellular and humoral responses were effectively induced. Conclusions ZIKV infection during the second trimester of gestation induces short-term brain injury, and although viral genomes persist in tissues, most of the virus is cleared before delivery.

Abstract Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. We determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-β and 2′C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers, and all primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-β inhibited replication of all arboviruses, while 2′C-methyl-cytidine reduced only USUV and ZIKV titers. Collectively, USUV can infect human brain tissue, showing similarities in tropism and neurovirulence as WNV and ZIKV. These data suggest that a blockade to infection of the human brain may not be the explanation for the low clinical incidence of USUV-associated neurological disease. However, USUV replicated more slowly and to lower titers than WNV, which could help to explain the reduced severity of neurological disease resulting from USUV infection.

Abstract The microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection. Elizabethkingia anophelis, originally isolated from the midgut of Anopheles gambiae possess a broad-spectrum antiviral phenotype, yet a gap in knowledge regarding the mechanistic basis of its interaction with viruses exists. The current study aims to identify pathways and genetic factors linked to E. anophelis antiviral activity. The understanding of E. anophelis antiviral mechanism could lead to novel transmission barrier tools to prevent arboviral outbreaks. We utilized a non-targeted multi-omics approach, analyzing extracellular lipids, proteins, metabolites of culture supernatants coinfected with ZIKV and E. anophelis. We observed a significant decrease in arginine and phenylalanine levels, metabolites that are essential for viral replication and progression of viral infection. This study provides insights into the molecular basis of E. anophelis antiviral phenotype. The findings lay a foundation for in-depth mechanistic studies.