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BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Viral outbreaks can cause widespread disruption, creating the need for diagnostic tools that provide high performance and sample versatility at the point of use with moderate complexity. Current gold standards such as PCR and rapid antigen tests fall short in one or more of these aspects. Here, we report a label-free and amplification-free nanopore sensor platform that overcomes these challenges via direct detection and quantification of viral RNA in clinical samples from a variety of biological fluids. The assay uses an optofluidic chip that combines optical waveguides with a fluidic channel and integrates a solid-state nanopore for sensing of individual biomolecules upon translocation through the pore. High specificity and low limit of detection are ensured by capturing RNA targets on microbeads and collecting them by optical trapping at the nanopore location where targets are released and rapidly detected. We use this device for longitudinal studies of the viral load progression for Zika and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections in marmoset and baboon animal models, respectively. The up to million-fold trapping-based target concentration enhancement enables amplification-free RNA quantification across the clinically relevant concentration range down to the assay limit of RT-qPCR as well as cases in which PCR failed. The assay operates across all relevant biofluids, including semen, urine, and whole blood for Zika and nasopharyngeal and throat swab, rectal swab, and bronchoalveolar lavage for SARS-CoV-2. The versatility, performance, simplicity, and potential for full microfluidic integration of the amplification-free nanopore assay points toward a unique approach to molecular diagnostics for nucleic acids, proteins, and other targets.

BACKGROUND: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. METHODS: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. FINDINGS: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378-521), affecting 3·40 billion (3·20-3·62) individuals (43·1%, 40·5-45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7-26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6-38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5-32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7-2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimers disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. INTERPRETATION: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. FUNDING: Bill & Melinda Gates Foundation.

Pathogen lineage nomenclature systems are a key component of effective communication and collaboration for researchers and public health workers. Since February 2021, the Pango dynamic lineage nomenclature for SARS-CoV-2 has been sustained by crowdsourced lineage proposals as new isolates were sequenced. This approach is vulnerable to time-critical delays as well as regional and personal bias. Here we developed a simple heuristic approach for dividing phylogenetic trees into lineages, including the prioritization of key mutations or genes. Our implementation is efficient on extremely large phylogenetic trees consisting of millions of sequences and produces similar results to existing manually curated lineage designations when applied to SARS-CoV-2 and other viruses including chikungunya virus, Venezuelan equine encephalitis virus complex and Zika virus. This method offers a simple, automated and consistent approach to pathogen nomenclature that can assist researchers in developing and maintaining phylogeny-based classifications in the face of ever-increasing genomic datasets.

The distribution and intensity of viral diseases transmitted by Aedes aegypti mosquitoes, including dengue, have rapidly increased over the last century. Here, we study dengue virus (DENV) transmission across the ecologically and demographically distinct regions or Ecuador. We analyzed province-level age-stratified dengue incidence data from 2000-2019 using catalytic models to estimate the force of infection of DENV over eight decades. We found that provinces established endemic DENV transmission at different time periods. Coastal provinces with the largest and most connected cities had the earliest and highest increase in DENV transmission, starting around 1980 and continuing to the present. In contrast, remote and rural areas with reduced access, like the northern coast and the Amazon regions, experienced a rise in DENV transmission and endemicity only in the last 10 to 20 years. The newly introduced chikungunya and Zika viruses have age-specific distributions of hospital-seeking cases consistent with recent emergence across all provinces. To evaluate factors associated with geographic differences in DENV transmission potential, we modeled DENV vector risk using 11,693 Aedes aegypti presence points to the resolution of 1 hectare. In total, 56% of the population of Ecuador, including in provinces identified as having increasing DENV transmission in our models, live in areas with high risk of Aedes aegypti, with population size, trash collection, elevation, and access to water as important determinants. Our investigation serves as a case study of the changes driving the expansion of DENV and other arboviruses globally and suggest that control efforts should be expanded to semi-urban and rural areas and to historically isolated regions to counteract increasing dengue outbreaks.

Mosquito-borne illnesses represent a significant global health peril, resulting in approximately one million fatalities annually. West Nile, dengue, Zika, and malaria are continuously expanding their global reach, driven by factors that escalate mosquito populations and pathogen transmission. Innovative control measures are imperative to combat these catastrophic ailments. Conventional approaches, such as eliminating breeding sites and using insecticides, have been helpful, but they face challenges such as insecticide resistance and environmental harm. Given the mounting severity of mosquito-borne diseases, there is promise in exploring innovative approaches using synthetic biology to bolster mosquitoes' resistance to pathogens, or even eliminate the mosquito vectors, as a means of control. This review outlines current strategies, future goals, and the importance of gene editing for global health defenses against mosquito-borne diseases.

Difference-in-differences is undoubtedly one of the most widely used methods for evaluating the causal effect of an intervention in observational (i.e., nonrandomized) settings. The approach is typically used when pre- and postexposure outcome measurements are available, and one can reasonably assume that the association of the unobserved confounder with the outcome has the same absolute magnitude in the two exposure arms and is constant over time; a so-called parallel trends assumption. The parallel trends assumption may not be credible in many practical settings, for example, if the outcome is binary, a count, or polytomous, as well as when an uncontrolled confounder exhibits nonadditive effects on the distribution of the outcome, even if such effects are constant over time. We introduce an alternative approach that replaces the parallel trends assumption with an odds ratio equi-confounding assumption under which an association between treatment and the potential outcome under no treatment is identified with a well-specified generalized linear model relating the pre-exposure outcome and the exposure. Because the proposed method identifies any causal effect that is conceivably identified in the absence of confounding bias, including nonlinear effects such as quantile treatment effects, the approach is aptly called universal difference-in-differences. We describe and illustrate both fully parametric and more robust semiparametric universal difference-in-differences estimators in a real-world application concerning the causal effects of a Zika virus outbreak on birth rate in Brazil. A supplementary digital video is available at: http://links.lww.com/EDE/C90.

Each year, hundreds of millions of people are infected with arboviruses such as dengue, yellow fever, chikungunya, and Zika, which are all primarily spread by the notorious mosquito Aedes aegypti. Traditional control measures have proven insufficient, necessitating innovations. In response, here we generate a next-generation CRISPR-based precision-guided sterile insect technique (pgSIT) for Ae. aegypti that disrupts genes essential for sex determination and fertility, producing predominantly sterile males that can be deployed at any life stage. Using mathematical models and empirical testing, we demonstrate that released pgSIT males can effectively compete with, suppress, and eliminate caged mosquito populations. This versatile species-specific platform has the potential for field deployment to effectively control wild populations of disease vectors.

Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein degradation of human STAT2 (hSTAT2). However, how flavivirus NS5s have evolved for species-specific IFN-suppression remains unclear. Here we report structure-function characterization of the DENV serotype 2 (DENV2) NS5-hSTAT2 complex. The MTase and RdRP domains of DENV2 NS5 form an extended conformation to interact with the coiled-coil and N-terminal domains of hSTAT2, thereby promoting hSTAT2 degradation in cells. Disruption of the extended conformation of DENV2/ZIKV NS5, but not the alternative compact state, impaired their hSTAT2 binding. Our comparative structural analysis of flavivirus NS5s further reveals a conserved protein-interaction platform with subtle amino-acid variations likely underpinning diverse IFN-suppression mechanisms. Together, this study uncovers a conformational selection mechanism underlying species-specific hSTAT2 inhibition by flavivirus NS5.

The Zika virus (ZIKV) epidemic in Latin America (2015–2016) has primarily been studied in urban centers, with less understanding of its impact on smaller rural communities. To address this gap, we analyzed ZIKV seroepidemiology in 6 rural Ecuadorian communities (2018–2019) with varying access to a commercial hub. Seroprevalence ranged from 19% to 54%, measured by nonstructural protein 1 blockade of binding enzyme-linked immunosorbent assay. We observed a decline in ZIKV seroprevalence between 2018 and 2019 that was greater among younger populations, suggesting that the attack rates in the 2015–2016 epidemic were significantly higher than our 2018 observations. These data indicate that the 2015–2016 epidemic included significant transmission in rural and more remote settings. Our observations of high seroprevalence in our area of study highlights the importance of surveillance and research in rural areas lacking robust health systems to manage future Zika outbreaks and vaccine initiatives. [ABSTRACT FROM AUTHOR]

The zinc finger antiviral protein 1 (ZAP) has broad antiviral activity. ZAP is an interferon (IFN)-stimulated gene, which itself may enhance type I IFN antiviral response. In a previous study, Zika virus was identified as ZAP-resistant and not sensitive to ZAP antiviral activity. Here, we found that ZAP was associated with the inhibition of Zika virus in Vero cells, in the absence of a robust type I IFN system because Vero cells are deficient for IFN-alpha and -beta. Also, quantitative RNA-seq data indicated that endogenous ZAP is associated with altered global gene expression both in the steady state and during Zika virus infection. Further studies are warranted to elucidate this IFN-alpha and -beta independent anti-Zika virus activity and involvement of ZAP. [ABSTRACT FROM AUTHOR]

During the recent yellow fever (YF) epidemics in Brazil, human cases were attributed to spillover infections via sylvatic mosquito transmission. Despite YF virus (YFV) transmission in major urban centers with insufficient vaccination coverage and abundant populations of the domestic vector, Aedes aegypti, there was no evidence of human-amplified transmission. Furthermore, the historic absence of YF in Asia, despite abundant Ae. aegypti and an immunologically naive human population, is unexplained. We tested the hypothesis that pre-existing, heterologous flavivirus immunity, specifically from dengue (DENV) and Zika (ZIKV) viruses, limits YFV viremia and transmission by Ae. aegypti. We infected cynomolgus macaques with DENV or ZIKV, then challenged them 6–9 months later with YFV. We then measured viremia and disease and allowed Ae. aegypti mosquitoes to feed during peak macaque viremia. Although prior heterologous immunity had variable effects on disease, DENV and ZIKV immunity consistently suppressed YFV viremia. Despite no statistical difference due to a small sample size, the suppression in viremia led to a significant reduction in Ae. aegypti infection and a lack of transmission potential. These results support the hypothesis that, in DENV- and ZIKV-endemic regions such as South America and Asia, human flavivirus immunity suppresses YFV human amplification potential, reducing the risk of urban outbreaks. Epidemiology of yellow fever suggests that other flaviviruses may provide some level of cross-protection. Here the authors show in a non-human primate model that pre-existing dengue-2 or Zika virus immunity results in lower yellow fever viremia compared to naïve animals, limiting the transmission potential by Aedes aegypti mosquitoes. [ABSTRACT FROM AUTHOR]

ABSTRACT Arthropod‐borne flaviviruses (ABFs), transmitted by mosquitoes or ticks, are increasing due to climate change and globalization. This scoping review examines the epidemiology, clinical characteristics, diagnostics, treatment, and outcomes of ABF infection in solid organ transplant recipients (SOTRs). A database search up to January 25, 2024, focused on ABFs such as West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), Powassan virus (POWV), yellow fever virus (YFV), and Zika virus (ZIKV), limited to SOTRs.We identified 173 WNV cases from 84 studies, with 28 donor‐derived infections (DDIs). Common clinical features included fever (78.5%), altered mental status (65.1%), and weakness or paralysis (45.6%). Treatment involved reducing immunosuppression (IS) in 93 cases, with intravenous immunoglobulin (IVIG), interferon alfa‐2b, and ribavirin used in 75 cases. Seven cases involved graft loss or rejection post‐infection. WNV infection had a 23.7% mortality rate, with severe neurological complications in 43.9%For DENV infection, 386 cases from 47 studies were identified, including 14 DDI cases. Symptoms included fever (85%), myalgias (56.4%), and headache or retro‐orbital pain (34.6%). Severe dengue occurred in 50 cases (13.0%). IVIG was administered in six cases. Reduction in IS was reported in 116 patients. DENV mortality rate was 4.9%.Additionally, 26 cases of less common ABFs such as JEV, POWV, YFV, and ZIKV were described.In summary, ABF infections among SOTRs are associated with higher morbidity and mortality compared to the general population, emphasizing the need for improved preventive strategies, timely diagnosis, and optimized management protocols. [ABSTRACT FROM AUTHOR]

Objective: To assess fetal and neonatal eyes abnormalities and their progression during the last ZIKV outbreak and summarize learned lessons. Methods: A systematic review and meta-analysis was conducted by a team of obstetricians and ophthalmologists. Results: Studies reporting ocular abnormalities during the prenatal (n = 5) and postnatal (n = 24) periods were included in the analysis. In the prenatal period, the most common ocular findings were intraocular calcification cases (4/6, 66.6%) and microphthalmia (3/6, 50%). Postnatal ocular abnormalities of congenital ZIKV infection were described after birth in 479 cases. Among them microphthalmia was reported in 13 cases (13/479, 2.7%). Posterior segment (retina and optic nerve) was the most affected structure, consisting of pigmentary changes (229/479, 47.8%), macular chorioretinal atrophy (216/479, 45%), optic nerve atrophy (181/479, 37.8%), increased cup-to-disk ratio (190/479, 39.6.%), optic nerve hypoplasia (93/479,19.4%), vascular changes (26/479, 5.4%), and retinal coloboma (20/479, 4.1%). The anterior segment was involved in 4.6% (22/479) of cases, including cataract (9/479, 1.8%), lens subluxation (1/479, 0.2%), iris coloboma (5/479, 1%), and congenital glaucoma (7/479, 1.4%). These ocular anomalies were isolated in one case (1/479, 0.2%) and multiple anomalies were found in the other cases. Long-term visual disorders have been described, with no possible improvement and even a worsening of some of the ocular anomalies previously observed. No reactivation of ocular lesions was observed. Conclusion: This review highlights the severe ocular abnormalities associated with congenital ZIKV infections. The importance of multidisciplinary communication between the obstetrician, the maternal-fetal medicine specialist, and the ophthalmologist is emphasized. Protocol registration: This systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration440 188. [ABSTRACT FROM AUTHOR]

The Zika virus (ZIKV) is classified within the Flavivirus genus of the Flaviviridae family and is categorized as an arbovirus. The virus was initially identified in a rhesus monkey in Uganda in 1947 and later in a human in Nigeria in 1952. Since 2007, the prevalence of the virus has been on the rise, culminating in a major outbreak in the United States (US) in 2015. During this outbreak, the adult population was severely impacted, experiencing a range of symptoms, including organ failure, microcephaly, fetal death, and Guillain-Barré syndrome (GBS). Additionally, skin rash, limb swelling, fever, headache, and heightened sensitivity are found in most adults with Zika syndrome. Although the virus can be transmitted through blood, vertical transmission from mother to child, and sexual contact, the primary way of transmission of the virus is through the Aedes mosquito. Cells such as neurons, macrophages, peripheral dendritic cells, and placental cells are among the target cells that the virus can infect. The TAM AXL receptor plays a crucial role in infection. After the virus enters the body through the bloodstream, it spreads in the body with a latent period of 3 to 12 days. Currently, there is no specific treatment or publicly available vaccine for the ZIKV. Limited laboratory testing has been conducted, and existing drugs originally designed for other pathogens have been repurposed for treatment. Given the Aedes mosquito's role as a vector and the wide geographical impact of the virus, this study aims to comprehensively investigate Zika's pathogenesis and clinical symptoms based on existing knowledge and research. By doing so, we seek to enhance our understanding of the virus and inform future prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Arboviruses, transmitted by medical arthropods, pose a serious health threat worldwide. During viral infection, Post Translational Modifications (PTMs) are present on both host and viral proteins, regulating multiple processes of the viral lifecycle. In this study, a mammalian E3 ubiquitin ligase WWP2 (WW domain containing E3 ubiquitin ligase 2) is identified, which interacts with the NS1 protein of Zika virus (ZIKV) and mediates K63 and K48 ubiquitination of Lys 265 and Lys 284, respectively. WWP2‐mediated NS1 ubiquitination leads to NS1 degradation via the ubiquitin‐proteasome pathway, thereby inhibiting ZIKV infection in mammalian hosts. Simultaneously, it is found Su(dx), a protein highly homologous to host WWP2 in mosquitoes, is capable of ubiquitinating NS1 in mosquito cells. Unexpectedly, ubiquitination of NS1 in mosquitoes does not lead to NS1 degradation; instead, it promotes viral infection in mosquitoes. Correspondingly, the NS1 K265R mutant virus is less infectious to mosquitoes than the wild‐type (WT) virus. The above results suggest that the ubiquitination of the NS1 protein confers different adaptations of ZIKV to hosts and vectors, and more importantly, this explains why NS1 K265‐type strains have become predominantly endemic in nature. This study highlights the potential application in antiviral drug and vaccine development by targeting viral proteins' PTMs. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) and dengue virus (DENV) are closely related flaviviruses co-circulating in the same endemic areas. Infection can raise cross-reactive antibodies that can be either protective or increase risk of severe disease, depending on the infection sequence, DENV serotype and elapsed time between infection. On the contrast, T cell-mediated immunity against DENV and ZIKV is considered protective. Therefore, we have developed a T cell vaccine enriched in immunodominant T cell epitopes derived from ZIKV and evaluated its immunogenicity and efficacy against ZIKV and DENV infection. Mice were vaccinated using DNA vaccine platform using the tetrafunctional amphiphilic block copolymer 704. We show that vaccination of 2 different HLA class I transgenic mice with the ZIKV non-structural (NS) poly-epitope elicits T cell response against numerous ZIKV epitopes. Moreover, vaccination induces a significant protection against ZIKV infection, in the absence of neutralizing or enhancing antibodies against ZIKV. However, vaccination does not induce a significant protection against DENV2. In contrast, immunization with a DENV1-NS poly-epitope induces a significant protection against both DENV1 and DENV2, in the absence of humoral immunity. Taken together, we have shown that T-cell based vaccination could protect against multiple flavivirus infections and could overcome the complexity of antibody-mediated enhancement. Author summary: Dengue virus (DENV) and Zika virus (ZIKV) are two closely related flaviviruses transmitted by Aedes species mosquito. In endemic regions with high circulation of ZIKV and multiple DENV serotypes, and the presence of cross-reactive or sub-neutralizing antibodies that could enhance dengue disease severity, alternative approaches to antibody-induced vaccination must be considered. This work describes a novel strategy for the development of a T-cell based vaccine composed of immunodominant T cell epitopes from ZIKV. This vaccine induces a significant protection against ZIKV infection in mice expressing different HLA class I molecules, in the absence of neutralizing antibodies. Likewise, DNA vaccination with mosaic sequence enriched in DENV T cell epitopes with identical sequences between DENV1 and DENV2 induces a significant protection against these 2 DENV serotypes, without inducing neutralizing antibodies. This study paves the way for T-cell based vaccines that could overcome the risk for antibody-mediated enhancement and protect against multiple flavivirus infections. [ABSTRACT FROM AUTHOR]

Flaviviruses represent a significant global health threat and relatively few licensed vaccines exist to protect against them. Insect-specific flaviviruses (ISFVs) are incapable of replication in humans and have emerged as a novel and promising tool for flavivirus vaccine development. ISFV-based flavivirus vaccines have shown exceptional safety, immunogenicity, and efficacy, however, a detailed assessment of the correlates of protection and immune responses induced by these vaccines are still needed for vaccine optimization. Here, we explore the mechanisms of protective immunity induced by a previously created pre-clinical Zika virus (ZIKV) vaccine candidate, called Aripo/Zika (ARPV/ZIKV). In brief, immunocompromised IFN-αβR-/- mice passively immunized with ARPV/ZIKV immune sera experienced protection after lethal ZIKV challenge, although this protection was incomplete. ARPV/ZIKV-vaccinated IFN-αβR-/- mice depleted of CD4+ or CD8+ T-cells at the time of ZIKV challenge showed no morbidity or mortality. However, the adoptive transfer of ARPV/ZIKV-primed T-cells into recipient IFN-αβR-/- mice resulted in a two-day median increase in survival time compared to controls. Altogether, these results suggest that ARPV/ZIKV-induced protection is primarily mediated by neutralizing antibodies at the time of challenge and that T-cells may play a comparatively minor but cumulative role in the protection observed. Lastly, ARPV/ZIKV-vaccinated Tcra KO mice, which are deficient in T-cell responses, experienced significant mortality post-challenge. These results suggest that ARPV/ZIKV-induced cell-mediated responses are critical for development of protective immune responses at vaccination. Despite the strong focus on neutralizing antibody responses to novel flavivirus vaccine candidates, these results suggest that cell-mediated responses induced by ISFV-based vaccines remain important to overall protective responses. Author summary: Conventional vaccine development platforms may involve trade-offs between vaccine safety and immunogenicity, but insect-specific viruses have recently emerged as a promising platform to overcome this challenge. We previously developed a preclinical Zika virus (ZIKV) vaccine candidate named Aripo/Zika virus (ARPV/ZIKV) based on a novel ISFV called Aripo virus (ARPV). Our previous studies demonstrated the high degree of safety as well as the single dose efficacy of ARPV/ZIKV. Here, we begin to elucidate the mechanisms of protection for this vaccine candidate. We demonstrate the dominant role of neutralizing antibodies in providing protection post-challenge, but also the importance of ARPV/ZIKV-induced T-cell responses in the priming phase of immunity. Overall, even high efficacy ISFV-based vaccine candidates such as ARPV/ZIKV may benefit from adjuvants or optimization strategies to increase protective T-cell responses. However, ARPV/ZIKV remains a promising ZIKV vaccine candidate, and contributes to the rapidly growing body of work that supports the potential of ISFVs as a new tool for protecting the health of the millions of people currently at risk of infection. [ABSTRACT FROM AUTHOR]

Background: Yellow fever virus (YFV) and dengue virus (DENV) are among the major re-emerging arboviruses that pose a significant threat to public health. Their associated burden and prevalence can be substantially underestimated due to insufficient surveillance and inadequate diagnosis. This study aimed to determine evidence of dengue, yellow and related flaviviruses circulation among the rural human populations residing in Nguruman (Kajiado County) and Kerio Valley (Baringo County), two dryland ecosystems in the Kenyan Rift Valley. Methods: Serum samples obtained from febrile patients between 5 and 85 years through a hospital-based cross-sectional survey from July 2020 – May 2023, were screened for neutralizing antibodies to YFV, DENV-2 and related flaviviruses, West Nile virus (WNV) and Zika virus (ZIKV) via Plaque reduction neutralization test (PRNT). The study sites and important demographic characteristics were obtained using a structural questionnaire and the data analyzed and seroprevalence compared. A multinomial logistic regression model was done to predict risk for each of the most prevalent viruses with covariates; age, gender, and occupation. Results: Overall, 54.5% (50.1–59.0% 95% confidence interval (CI) of the samples tested positive for at least one of the four Flaviviruses. The percentage was significantly higher in Kerio Valley (64.34%, 184/286) than in Nguruman (40.2%, 78/194) (P<0.0001). YFV had the highest prevalence, followed by WNV (16.25%), ZIKV (5.2%), and DENV-2 (1%). Kerio Valley had a significantly higher YFV seroprevalence (51%) than Nguruman (6%) (P<0.0001), while DENV-2 was observed only in Nguruman with a low seropositivity of 2%. In contrast to Nguruman, where seropositivity rates were higher in males at 47.47% (P=0.049), in Kerio Valley, females showed considerably higher viral seropositivity at 60.82% than males (P<0001). Conclusion: The study suggests that there is significant circulation of Flaviviruses in both regions, posing a public health risk, that could potentially contribute to clinical disease. However, seropositivity rates vary for each specific site. Furthermore, there could be a risk of YFV, WNV, and ZIKV transmission in both sites with DENV transmission specifically noted in Nguruman. The study findings inform direct cost-effective actions (such as YF vaccines) and precise surveillance data of vector populations for improved disease risk prediction. [ABSTRACT FROM AUTHOR]

Background: Zika virus (ZIKV) is an emerging public health threat, rendering development of a safe and effective vaccine against the virus a high priority to face this unmet medical need. Our vaccine candidate has been developed on the same platform used for the licensed vaccine IXIARO®, a vaccine against Japanese Encephalitis virus, another closely related member of the Flaviviridae family.Methods: Between February 24, 2018 and November 16, 2018, we conducted a randomized, observer-blinded, placebo controlled, single center phase 1 study to assess the safety and immunogenicity of an adjuvanted, inactivated, purified whole-virus Zika vaccine candidate in the U.S. A total of 67 healthy flavivirus-naïve adults aged 18 to 49 years were randomly assigned to one of five study arms to receive two immunizations of either high dose or low dose (6 antigen units or 3 antigen units) with both dose levels applied in two different immunization regimens or placebo as control.Results: Our vaccine candidate showed an excellent safety profile independent of dose and vaccination regimen with predominantly mild adverse events. No serious adverse event has been reported. The ZIKV vaccine induced neutralizing antibodies in all tested doses and regimens with seroconversion rates up to 85.7% (high dose), which remained up to 40% (high dose) at 6 months follow-up. Of note, the rapid regimen triggered a substantial immune response within days.Conclusions: The rapid development and production of a ZIKV vaccine candidate building on a commercial Vero-cell manufacturing platform resulted in a safe and immunogenic vaccine suitable for further clinical development. To optimize antibody persistence, higher doses and a booster administration might be considered. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects of a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated, and the s pecific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using CRISPR-Cas9 system to delete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. We also determined that ATF3 enhances the expression of antiviral genes such as STAT1 and other components in the innate immunity pathway to induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between the integrated stress response and innate immune response pathways and highlights an important role for ATF3 in establishing an antiviral effect during ZIKV infection. [ABSTRACT FROM AUTHOR]

Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small membrane (M) protein plays well-defined roles during viral egress and remains within virion membranes following release and maturation. However, it is unclear whether M plays a functional role in this setting. Here, we show that M forms oligomeric membrane-permeabilising channels in vitro, with increased activity at acidic pH and sensitivity to the prototypic channel- blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements of two trans-membrane domain protomers were shown to comprise more stable assemblages than other oligomers using molecular dynamics simulations. Models contained a predicted lumenal rimantadine-binding site, as well as a second druggable target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to either one site or the other. Hits displayed superior potency in vitro and in cell culture compared with rimantadine, with efficacy demonstrably linked to virion-resident channels. Finally, rimantadine effectively blocked ZIKV viraemia in preclinical models, supporting that M constitutes a physiologically relevant target. This could be explored by repurposing rimantadine, or development of new M-targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Congenital Zika Syndrome (CZS) comprises congenital anomalies that occur in individuals, embryos or fetuses exposed to Zika virus infection during pregnancy and can result in systemic manifestations as well as alterations in the oral cavity of these children. The aim of this study was to conduct a systematic literature review of the most frequent oral and craniofacial manifestations in children aged 0 to 6 years with CZS compared to neurotypical children without CZS. In this review, a search was conducted in the PubMed, Medline, Embase, Web of Science databases and grey literature, as well as a manual search of the reference lists of the included articles, without restriction on year or language. Inclusion criteria were studies reporting oral alterations in children up to six years old or newborns with CZS, with or without a control group. Methodological quality of the studies was assessed by the Mixed Methods Appraisal Tool (MMAT). Twenty-seven articles were retrieved, 19 quantitative non-randomized and 09 quantitative descriptive studies. Three studies presented a high risk of bias. The main reported manifestations were delayed eruption (51,8%), dental enamel defects (25,9%), deep palate (29,6%), number alterations (14,8%), bruxism (29,6%), and malocclusion (25,9%). Short conclusion: CZS can lead to several manifestations of dental interest and may interfere with the individual's oral health. The pediatric dentistry thus requiring the dentist to be attentive to these changes to offer the best and comprehensive treatment to this patient. [ABSTRACT FROM AUTHOR]

Recently, lipid nanoparticles (LNPs)‐based mRNA delivery has been approved by the FDA for SARS‐CoV‐2 vaccines. However, there are still considerable points for improvement in LNPs. Especially, local administration of LNPs‐formulated mRNA can cause off‐target translation of mRNA in distal organs which can induce unintended adverse effects. With the hypothesis that large and rigid nanoparticles can be applied to enhance retention of nanoparticles at the injection site, a polyethyleneimine (PEI)‐coated porous silica nanoparticles (PPSNs)‐based mRNA delivery platform is designed. PPSNs not only facilitate localized translation of mRNA at the site of injection but also prolonged protein expression. It is further demonstrated that the development of a highly efficacious Zika virus (ZIKV) vaccine using mRNA encoding full‐length ZIKV pre‐membrane (prM) and envelope (E) protein delivered by PPSNs. The ZIKV prME mRNA‐loaded PPSNs vaccine elicits robust immune responses, including high levels of neutralizing antibodies and ZIKV E‐specific T cell responses in C57BL/6 mice. Moreover, a single injection of prME‐PPSNs vaccine provided complete protection against the ZIKV challenge in mice. [ABSTRACT FROM AUTHOR]

Aedes mosquito-borne viruses (ABVs) place a substantial strain on public health resources in the Americas. Vector control of Aedes mosquitoes is an important public health strategy to decrease or prevent spread of ABVs. The ongoing Targeted Indoor Residual Spraying (TIRS) trial is an NIH-sponsored clinical trial to study the efficacy of a novel, proactive vector control technique to prevent dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) infections in the endemic city of Merida, Yucatan, Mexico. The primary outcome of the trial is laboratory-confirmed ABV infections in neighborhood clusters. Despite the difficulties caused by the COVID-19 pandemic, by early 2021 the TIRS trial completed enrollment of 4,792 children aged 2–15 years in 50 neighborhood clusters which were allocated to control or intervention arms via a covariate-constrained randomization algorithm. Here, we describe the makeup and ABV seroprevalence of participants and mosquito population characteristics in both arms before TIRS administration. Baseline surveys showed similar distribution of age, sex, and socio-economic factors between the arms. Serum samples from 1,399 children were tested by commercially available ELISAs for presence of anti-ABV antibodies. We found that 45.1% of children were seropositive for one or more flaviviruses and 24.0% were seropositive for CHIKV. Of the flavivirus-positive participants, most were positive for ZIKV-neutralizing antibodies by focus reduction neutralization testing which indicated a higher proportion of participants with previous ZIKV than DENV infections within the cohort. Both study arms had statistically similar seroprevalence for all viruses tested, similar socio-demographic compositions, similar levels of Ae. aegypti infestation, and similar observed mosquito susceptibility to insecticides. These findings describe a population with a high rate of previous exposure to ZIKV and lower titers of neutralizing antibodies against DENV serotypes, suggesting susceptibility to future outbreaks of flaviviruses is possible, but proactive vector control may mitigate these risks. [ABSTRACT FROM AUTHOR]

The main vectors of Zika virus (ZIKV) and dengue virus (DENV) are Aedes aegypti and Ae. albopictus, with Ae. aegypti being more competent. However, the underlying mechanisms remain unclear. Here, we find Ae. albopictus shows comparable vector competence to ZIKV/DENV with Ae. aegypti by blood-feeding after antibiotic treatment or intrathoracic injection. This suggests that midgut microbiota can influence vector competence. Enterobacter hormaechei_B17 (Eh_B17) is isolated from field-collected Ae. albopictus and conferred resistance to ZIKV/DENV infection in Ae. aegypti after gut-transplantation. Sphingosine, a metabolite secreted by Eh_B17, effectively suppresses ZIKV infection in both Ae. aegypti and cell cultures by blocking viral entry during the fusion step, with an IC50 of approximately 10 μM. A field survey reveals that Eh_B17 preferentially colonizes Ae. albopictus compared to Ae. aegypti. And field Ae. albopictus positive for Eh_B17 are more resistant to ZIKV infection. These findings underscore the potential of gut symbiotic bacteria, such as Eh_B17, to modulate the arbovirus vector competence of Aedes mosquitoes. As a natural antiviral agent, Eh_B17 holds promise as a potential candidate for blocking ZIKV/DENV transmission. Here the authors show that arbovirus vector competence of Aedes mosquitoes is modulated by the midgut microbiota and identify the metabolite sphingosine from the gut symbiotic bacterium Enterobacter hormaechei_B17 (Eh_B17) as a factor mediating resistance to ZIKV and DENV infection. [ABSTRACT FROM AUTHOR]

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$$ {c}&#x0005E;{\ast }>0 $$ such that the model has a traveling wave solution with speed c>c∗$$ c>{c}&#x0005E;{\ast } $$, and there is no traveling wave solution with speed less than c∗$$ {c}&#x0005E;{\ast } $$. 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]

The Zika virus (ZIKV) is a global health threat due to its rapid spread and severe health implications, including congenital abnormalities and neurological complications. Differentiating ZIKV from other arboviruses such as dengue virus (DENV) is crucial for effective diagnosis and treatment. This study presents the development of a biosensor for detecting the ZIKV non‐structural protein 1 (NS1) using gold nanoparticles (AuNPs) functionalized with monoclonal antibodies employing dynamic light scattering (DLS). The biosensor named ZINS1‐mAb‐AuNP exhibited specific binding to the ZIKV NS1 protein, demonstrating high colloidal stability indicated by a hydrodynamic diameter (DH) of 140 nm, detectable via DLS. In the absence of the protein, the high ionic strength medium caused particle aggregation. This detection method showed good sensitivity and specificity, with a limit of detection (LOD) of 0.96 μg mL−1, and avoided cross‐reactivity with DENV2 NS1 and SARS‐CoV‐2 spike proteins. The ZINS1‐mAb‐AuNP biosensor represents a promising tool for the early and accurate detection of ZIKV, facilitating diagnostic and treatment capabilities for arboviral infections. [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]

This review examines the potential applications of peptides in biotechnology, medicine, and pharmacy, while highlighting the important antibacterial and antiviral properties of peptides. Peptides and chemical peptide synthesis have become a field of study that is gaining great momentum today. Some of the main reasons for this are high specificity, biodegradability and versatility of peptides. Peptides also have some specific properties that make them attractive for pharmaceutical development. As a case study, it can be used to create peptides that can be used to replace or fix damaged proteins in the body by mimicking the action of naturally occurring proteins. Delivering drugs or other therapeutic agents to specific cells or tissues is another method that can help increase the effectiveness of treatment and reduce unwanted effects. Various types of antimicrobial peptides (AMPs), such as defensins and cathelicidins, and their anti‐infective properties are also discussed. Finally, peptides (melittin, lactoferricin, etc.) can be used to trigger an immune response against certain infections, such as COVID‐19 and Zika virus, by acting as vaccines. In our study, a comprehensive review was made on antiviral and AMPs, and especially peptides containing arginine and lysine were mentioned. The properties of these peptides, examples of these peptides and their developments in the pharmaceutical field are emphasized. [ABSTRACT FROM AUTHOR]

To identify the 5' untranslated region of Zika virus (ZIKV 5'UTR) RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site (IRES) located in ZIKV 5'UTR and virus production. Interacting proteins in U251 cells were captured using tRSA-tagged ZIKV 5'UTR RNA and tRSA-ZIKV 5'UTR RNA-binding proteins were visualized by SDS-PAGE silver staining. Subsequently, liquid chromatographytandem mass spectrometry (LC-MS/MS), bioinformatics analysis, and Western blot were used to identify the candidate proteins binding to ZIKV 5'UTR. Dicistronic expression assay and plaque forming assay were performed to analyze the effect of the binding protein on ZIKV IRES activity and ZIKV production, respecitvely. tRSA RNA pull-down assay, LC-MS/MS, and Western blot analysis showed that polypyrimidine tract-binding protein (PTB) bound to the ZIKV 5'UTR. Furthermore, dual luciferase reporter assay revealed that overexpression of PTB significantly enhanced the IRES activity of ZIKV (t = 10.220, P < 0.001), while PTB knockdown had the opposite effect (t = 4.897, P < 0.01). Additionally, virus plaque forming assay demonstrated that up-regulation of PTB expression significantly enhanced viral titer (t = 6.400, P < 0.01), whereas reducing PTB expression level weakened virus infectivity (t = 5.055, P < 0.01). PTB positively interacts with the ZIKV 5'UTR and enhances IRES activity and virus production. [ABSTRACT FROM AUTHOR]

Background and Objectives: 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. Materials and Methods: 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. Results: 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. Conclusion: 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]

The Zika virus has been shown to infect glioblastoma stem cells via the membrane receptor α v β 5 , which is activated by the stem-specific transcription factor SOX2. Since the expression level of SOX2 is an important predictive marker for successful virotherapy, it is important to understand the fundamental mechanisms of the role of SOX2 in the dynamics of cancer stem cells and Zika viruses. In this paper, we develop a mathematical ODE model to investigate the effects of SOX2 expression levels on Zika virotherapy against glioblastoma stem cells. Our study aimed to identify the conditions under which SOX2 expression level, viral infection, and replication can reduce or eradicate the glioblastoma stem cells. Analytic work on the existence and stability conditions of equilibrium points with respect to the basic reproduction number are provided. Numerical results were in good agreement with analytic solutions. Our results show that critical threshold levels of both SOX2 and viral replication, which change the stability of equilibrium points through population dynamics such as transcritical and Hopf bifurcations, were observed. These critical thresholds provide the optimal conditions for SOX2 expression levels and viral bursting sizes to enhance therapeutic efficacy of Zika virotherapy against glioblastoma stem cells. This study provides critical insights into optimizing Zika virus-based treatment for glioblastoma by highlighting the essential role of SOX2 in viral infection and replication. [ABSTRACT FROM AUTHOR]

Congenital Zika syndrome (CZS) has been identified a constellation of congenital anomalies caused by Zika Virus (ZKV) infection during pregnancy. The infection with ZKV could lead to microcephaly of the fetus due to a severe decrease in brain volume and reduced brain growth. The preliminary screening of CZS is based on measuring head circumference; the diagnosis is made if this measurement is below two standard deviations below the mean. The analyses of the 3D head features of infected infants are limited. This study analyzed 3D head images of 35 ZKV-positive cases with an average age of 16.8 ± 2 months and 35 controls with an average age of 14.4 ± 5 months. This study focused on identifying potential diagnostic characteristics of CZS. The 3D head images were captured using a 3D imaging system. The averaged images of the two groups were aligned to illustrate the size and shape differences. There were significant differences in centroid size, head circumference (HC), head height (HH), and chin height (CH) between the two groups. We also identified significant differences in the indices of chin height/total facial height (CH/TFH) and head height/head circumference ratio (HH/HC) between the CZS and control cases. An HH/HC of 0.49 showed a sensitivity of 0.86 and a specificity of 0.74 in diagnosing CZS, which is more sensitive than the routinely used HC measurement. The index of HH/HC has potential to be used as the gold standard for the early screening for the detection of CZS cases. [ABSTRACT FROM AUTHOR]

The establishment of effective antiviral responses within host cells is intricately related to their metabolic status, shedding light on immunometabolism. In this study, we investigated the hypothesis that cellular reliance on glutamine metabolism contributes to the development of a potent antiviral response. We evaluated the antiviral response in the presence or absence of L-glutamine in the culture medium, revealing a bivalent response hinging on cellular metabolism. While certain interferon-stimulated genes (ISGs) exhibited higher expression in an oxidative phosphorylation (OXPHOS)-dependent manner, others were surprisingly upregulated in a glycolytic-dependent manner. This metabolic dichotomy was influenced in part by variations in interferon-β (IFN-β) expression. We initially demonstrated that the presence of L-glutamine induced an enhancement of OXPHOS in A549 cells. Furthermore, in cells either stimulated by poly:IC or infected with dengue virus and Zika virus, a marked increase in ISGs expression was observed in a dose-dependent manner with L-glutamine supplementation. Interestingly, our findings unveiled a metabolic dependency in the expression of specific ISGs. In particular, genes such as ISG54, ISG12 and ISG15 exhibited heightened expression in cells cultured with L-glutamine, corresponding to higher OXPHOS rates and IFN-β signaling. Conversely, the expression of viperin and 2′-5′-oligoadenylate synthetase 1 was inversely related to L-glutamine concentration, suggesting a glycolysis-dependent regulation, confirmed by inhibition experiments. This study highlights the intricate interplay between cellular metabolism, especially glutaminergic and glycolytic, and the establishment of the canonical antiviral response characterized by the expression of antiviral effectors, potentially paving the way for novel strategies to modulate antiviral responses through metabolic interventions. [ABSTRACT FROM AUTHOR]

High-throughput experiments often produce ranked gene outputs, with forward genetic screening being a notable example. While there are various tools for analyzing individual datasets, those that perform comparative and meta-analytical examination of such ranked gene lists remain scarce. Here, we introduce Gene Rank Meta Analyzer (GeneRaMeN), an R Shiny tool utilizing rank statistics to facilitate the identification of consensus, unique, and correlated genes across multiple hit lists. We focused on two key topics to showcase GeneRaMeN: virus host factors and cancer dependencies. Using GeneRaMeN 'Rank Aggregation', we integrated 24 published and new flavivirus genetic screening datasets, including dengue, Japanese encephalitis, and Zika viruses. This meta-analysis yielded a consensus list of flavivirus host factors, elucidating the significant influence of cell line selection on screening outcomes. Similar analysis on 13 SARS-CoV-2 CRISPR screening datasets highlighted the pivotal role of meta-analysis in revealing redundant biological pathways exploited by the virus to enter human cells. Such redundancy was further underscored using GeneRaMeN's 'Rank Correlation', where a strong negative correlation was observed for host factors implicated in one entry pathway versus the alternate route. Utilizing GeneRaMeN's 'Rank Uniqueness', we analyzed human coronaviruses 229E, OC43, and SARS-CoV-2 datasets, identifying host factors uniquely associated with a defined subset of the screening datasets. Similar analyses were performed on over 1000 Cancer Dependency Map (DepMap) datasets spanning 19 human cancer types to reveal unique cancer vulnerabilities for each organ/tissue. GeneRaMeN, an efficient tool to integrate and maximize the usability of genetic screening datasets, is freely accessible via https://ysolab.shinyapps.io/GeneRaMeN. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), transmitted by Aedes mosquitoes, has been a global health concern since 2007. It primarily causes fetal microcephaly and neuronal defects through maternal transmission and induces neurological complications in adults. Recent studies report elevated proinflammatory cytokines and persistent neurological alterations post recovery, but the in vivo mechanisms remain unclear. In our study, viral RNA loads in the brains of mice infected with ZIKV peaked at 7 days post infection and returned to baseline by day 21, indicating recovery. RNA sequencing of the cerebral cortex at 7 and 21 days revealed upregulated genes related to neuroinflammation and microglial activation. Histological analyses indicated neuronal cell death and altered neurite morphology owing to severe neuroinflammation. Additionally, sustained microglial activation was associated with increased phospho-Tau levels, constituting a marker of neurodegeneration. These findings highlight how persistent microglial activation leads to neuronal dysfunction post ZIKV recovery, providing insights into the molecular pathogenesis of ZIKV-induced brain abnormalities. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV; family, Flaviviridae), which causes congenital Zika syndrome, Guillain-Barré Syndrome, and other severe diseases, is transmitted mainly by mosquitoes; however, the virus can be transmitted through other routes. Among the three structural and seven nonstructural proteins, the surface envelope (E) protein of ZIKV plays a critical role in viral entry and pathogenesis, making it a key target for the development of effective entry inhibitors. This review article describes the life cycle, genome, and encoded proteins of ZIKV, illustrates the structure and function of the ZIKV E protein, summarizes E protein-targeting entry inhibitors (with a focus on those based on natural products and small molecules), and highlights challenges that may potentially hinder the development of effective inhibitors of ZIKV infection. Overall, the article will provide useful guidance for further development of safe and potent ZIKV entry inhibitors targeting the viral E protein. [ABSTRACT FROM AUTHOR]

Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, with a focus on NS2B-NS3 inhibition. We systematically examined clinical trials, preclinical efficacy studies, and modes of action for various viral replication inhibitors, emphasizing allosteric and orthosteric drugs inhibiting NS2B-NS3 protease with in vivo efficacy and in vitro-tested competitive NS2B-NS3 inhibitors with cellular efficacy. Our findings revealed that several compounds with in vivo preclinical efficacy failed to show clinical antiviral efficacy. NS3-NS4B inhibitors, such as JNJ-64281802 and EYU688, show promise, recently entering clinical trials, underscoring the importance of developing novel viral replication inhibitors targeting viral machinery. To date, the only NS2B-NS3 inhibitor that has undergone clinical trials is doxycycline, however, its mechanism of action and clinical efficacy as viral growth inhibitor require additional investigation. SYC-1307, an allosteric inhibitor, exhibits high in vivo efficacy, while temoporfin and methylene blue represent promising orthosteric non-competitive inhibitors. Compound 71, a competitive NS2B-NS3 inhibitor, emerges as a leading preclinical candidate due to its high cellular antiviral efficacy, minimal cytotoxicity, and favorable in vitro pharmacokinetic parameters. Challenges remain in developing competitive NS2B-NS3 inhibitors, including appropriate biochemical inhibition assays as well as the selectivity and conformational flexibility of the protease, complicating effective antiviral treatment design. [ABSTRACT FROM AUTHOR]

Recent advancements in the large-scale cultivation of Tetraselmis sp. in Korea have enabled year-round production of this marine microalgae. This study explores the potential industrial applications of Tetraselmis sp. biomass by investigating the antiviral properties of its extracts and primary components. The antiviral effects of Tetraselmis sp. extracts were evaluated in Zika virus (ZIKV)-infected cells. Following extensive isolation and purification, the main compounds were characterized using liquid chromatography–mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) analyses. Their antiviral activities were confirmed using in vitro and in silico tests. Tetraselmis sp. extracts reduced infectious viral particles and non-structural protein 1 messenger RNA levels in ZIKV-infected cells without inducing cytotoxicity. Additionally, they modulated the interferon-mediated immune system responses. Tetraselmis sp. extracts are composed of four main chlorophylls: chlorophyll a, chlorin e6-131-152-dimethyl-173-phytyl ester, hydroxychlorophyll a, and hydroxypheophytin a. Among them, chlorophyll a, chlorin e6-131-152-dimethyl-173-phytyl ester, and hydroxypheophytin showed the antiviral activities in ZIKV-infected cells and molecular docking simulations predicted interactions between these chlorophylls and ZIKV. Our findings suggest that Tetraselmis sp. chlorophyll extracts exert antiviral effects against ZIKV and could serve as potential therapeutic candidates against ZIKV infection. [ABSTRACT FROM AUTHOR]

Declared as a Public Health Emergency in 2016 by the World Health Organization (WHO), the Zika virus (ZIKV) continues to cause outbreaks that are linked to increased neurological complications. Transmitted mainly by Aedes mosquitoes, the virus is spread mostly amongst several tropical regions with the potential of territorial expansion due to environmental and ecological changes. The ZIKV envelope protein's domain III, crucial for vaccine development due to its role in receptor binding and neutralizing antibody targeting, was integrated into sterically optimized AP205 VLPs to create an EDIII-based VLP vaccine. To increase the potential size of domains that can be accommodated by AP205, two AP205 monomers were fused into a dimer, resulting in 90 rather than 180 N-/C- termini amenable for fusion. EDIII displayed on AP205 VLPs has several immunological advantages, like a repetitive surface, a size of 20–200 nm (another PASP), and packaged bacterial RNA as adjuvants (a natural toll-like receptor 7/8 ligand). In this study, we evaluated a novel vaccine candidate for safety and immunogenicity in mice, demonstrating its ability to induce high-affinity, ZIKV-neutralizing antibodies without significant disease-enhancing properties. Due to the close genetical and structural characteristics, the same mosquito vectors, and the same ecological niche of the dengue virus and Zika virus, a vaccine covering all four Dengue viruses (DENV) serotypes as well as ZIKV would be of significant interest. We co-formulated the ZIKV vaccine with recently developed DENV vaccines based on the same AP205 VLP platform and tested the vaccine mix in a murine model. This combinatory vaccine effectively induced a strong humoral immune response and neutralized all five targeted viruses after two doses, with no significant antibody-dependent enhancement (ADE) observed. Overall, these findings highlight the potential of the AP205 VLP-based combinatory vaccine as a promising approach for providing broad protection against DENV and ZIKV infections. Further investigations and preclinical studies are required to advance this vaccine candidate toward potential use in human populations. [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]

Temperature is a determining factor for the viral cycle. In this study, we investigate the effect of different temperatures on the cycles of two important arboviruses—Zika (ZIKV) and Chikungunya (CHIKV)—in Vero (mammalian) and C6/36 (mosquito) cells. We compare genome quantification to infectivity at 28 °C and 37 °C in both cell types. Virus–cell interaction was also examined by transmission electron microscopy, allowing the observation of phenomena such as virus-surfing and giant forms for CHIKV, as well as the the scarcity of ZIKV in C6/36 cells compared to its cycle in mammalian cells. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), a mosquito-borne flavivirus, is a significant global health concern due to its association with neurodevelopmental disorders such as congenital Zika syndrome (CZS). This study aimed to compare the replication kinetics, viral persistence, cytopathogenic effects, and immune gene expression in human microglia cells (CHME-3) infected with an Asian lineage ZIKV (PRVABC59, referred to as ZIKV-PRV) and an African lineage ZIKV (IBH30656, referred to as ZIKV-IBH). We found that ZIKV-PRV replicated more efficiently and persisted longer while inducing lower levels of cell death and inflammatory gene activation compared with ZIKV-IBH. These findings suggest that the enhanced replication and persistence of ZIKV-PRV, along with its ability to evade innate immune responses, may underlie its increased neuropathogenic potential, especially in the context of CZS. In contrast, ZIKV-IBH, with its stronger immune gene activation and higher cytopathogenicity, may lead to more acute infections with faster viral clearance, thereby reducing the likelihood of chronic central nervous system (CNS) infection. This study provides crucial insights into the molecular and cellular mechanisms driving the differential pathogenicity of ZIKV lineages and highlights the need for further research to pinpoint the viral factors responsible for these distinct clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and Objectives: The steady spread of dengue virus (DENV) poses a profound public health threat worldwide. Reverse transcription real-time polymerase chain reaction (RT2-PCR) has been increasingly recognized as a reference method for the diagnosis of acute dengue infection. The goal of this study was to assess the diagnostic accuracy of five different RT2-PCR kits for the detection of DENV in a historically processed set of sera samples. Materials and Methods: In this retrospective study, 25 sera samples from routinely processed unique adult patients with a known DENV status (previously tested in both molecular and serological assays) were tested in parallel using four conventional (RealStar Dengue PCR Kit 3.0, Clonit'ngo Zika, Dengue & Chikungunya, BioPerfectus Zika Virus/Dengue Virus/Chikungunya Virus Real Time PCR Kit and Novaplex Tropical fever virus) and one sample-to-result (STANDARD M10 Arbovirus Panel) RT2-PCR assays. Additionally, an end-point dilution analysis was conducted in quintuplicate on six serial dilutions of an RNA preparation obtained from a culture-grown DENV serotype 1 strain for a total of 150 tests. Results: The overall accuracy of the evaluated tests ranged from 84% to 100%. In particular, the sensitivity of three conventional RT2-PCR assays (RealStar, Clonit'ngo and Novaplex) was 100% (95% CI: 79.6–100%), while it was lower (73.3%; 95% CI: 48.1–89.1%) for the BioPerfectus kit. The sample-to-result STANDARD M10 panel performed comparatively well, showing a sensitivity of 92.9% (95% CI: 68.5–98.7%). No false positive results were registered in any assay. The end-point dilution analysis suggested that the RealStar kit had the lowest limit of detection. Conclusions: Available RT2-PCR kits for the detection of DENV are highly specific and generally sensitive and, therefore, their implementation in diagnostic pathways is advisable. [ABSTRACT FROM AUTHOR]

Abstract The zinc finger antiviral protein 1 (ZAP) has broad antiviral activity. ZAP is an interferon (IFN)-stimulated gene, which itself may enhance type I IFN antiviral response. In a previous study, Zika virus was identified as ZAP-resistant and not sensitive to ZAP antiviral activity. Here, we found that ZAP was associated with the inhibition of Zika virus in Vero cells, in the absence of a robust type I IFN system because Vero cells are deficient for IFN-alpha and -beta. Also, quantitative RNA-seq data indicated that endogenous ZAP is associated with altered global gene expression both in the steady state and during Zika virus infection. Further studies are warranted to elucidate this IFN-alpha and -beta independent anti-Zika virus activity and involvement of ZAP.

Abstract Background Congenital Zika Syndrome (CZS) comprises congenital anomalies that occur in individuals, embryos or fetuses exposed to Zika virus infection during pregnancy and can result in systemic manifestations as well as alterations in the oral cavity of these children. The aim of this study was to conduct a systematic literature review of the most frequent oral and craniofacial manifestations in children aged 0 to 6 years with CZS compared to neurotypical children without CZS. Main body of the abstract In this review, a search was conducted in the PubMed, Medline, Embase, Web of Science databases and grey literature, as well as a manual search of the reference lists of the included articles, without restriction on year or language. Inclusion criteria were studies reporting oral alterations in children up to six years old or newborns with CZS, with or without a control group. Methodological quality of the studies was assessed by the Mixed Methods Appraisal Tool (MMAT). Twenty-seven articles were retrieved, 19 quantitative non-randomized and 09 quantitative descriptive studies. Three studies presented a high risk of bias. The main reported manifestations were delayed eruption (51,8%), dental enamel defects (25,9%), deep palate (29,6%), number alterations (14,8%), bruxism (29,6%), and malocclusion (25,9%). Short conclusion CZS can lead to several manifestations of dental interest and may interfere with the individual's oral health. The pediatric dentistry thus requiring the dentist to be attentive to these changes to offer the best and comprehensive treatment to this patient.