Search Results (169)

The human placenta plays a critical role as an immune and mechanical barrier. Notwithstanding, viral pathogens can still cross this barrier. Previously, differential gene expression has been described for protein-coding genes in human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts (TBs) from dizygotic twins discordant for congenital Zika syndrome (CZS), in which only one of the twin subjects presented the microcephaly phenotype. However, the involvement of long non-coding RNAs (lncRNAs) in TB development and in the TB response to ZIKV infection remained unexplored. To address this gap, we constructed a trophoblast-specific, lncRNA-enriched transcriptome resource and used it to define co-expression networks linking lncRNAs to trophoblast differentiation and to the antiviral response to ZIKV infection. Here, public RNA-Seq data from hiPSCs and hiPSC-derived TBs from dizygotic twins discordant for CZS were re-mapped to the human reference genome (GRCh38) using an ad hoc compiled hiPSC-TB-specific transcriptome enriched for lncRNAs, followed by differential expression analysis, co-expression network analysis and gene ontology (GO) enrichment. Expression validation by RT-qPCR of a set of novel and known lncRNAs associated with trophoblast differentiation and ZIKV infection was obtained. When comparing hiPSCs and TBs, 218 known and 26 novel lncRNAs were differentially expressed (DE) (FDR < 0.001). Correlated modules were enriched with GO terms related to “epithelial cell differentiation” and “tissue morphogenesis”. Upon comparing TBs derived from the dizygotic twins, before and after ZIKV infection, 96 known and 6 novel lncRNAs were DE (FDR < 0.05). Correlated modules were enriched with interferon-related GO terms, including “regulation of defense response to virus” and “response to interferon”. ZIKV-infected TBs from microcephaly-affected twins showed a 2.5-fold lower number of DE protein-coding genes and a 2-fold lower number of DE lncRNAs, compared with ZIKV-infected TBs from non-affected twins. These results indicate lncRNAs associated with TB development and response to ZIKV infection, highlighting candidates to be prioritized in future functional studies, such as CARINH, PSMB8-AS1, HCP5, BISPR and imprinted H19 and MEG3 lncRNAs. Full article

Zika virus (ZIKV) infection during pregnancy is a critical driver of Congenital Zika Syndrome (CZS), yet the mechanisms of pathogenesis at the placental barrier remain incompletely understood. This article is a translational, observational, and experimental study combining clinical placental analyses, placental explants cultures and in vivo murine model to investigate the mechanisms involved in ZIKV infection. We evaluate the histopathological analyses to verify presence of inflammation in ZIKV-infected human placentas from newborns with CZS and without CZS (N-CZS), identifying more intense Hofbauer cell hyperplasia, villitis and decidual inflammation in CZS group. Moreover, placental immunohistochemistry analyses identified decreased TLR4 expression in the villi and reduced TNF and IL-10 levels across placental layers of CZS group. Next, we investigated the effects of inflammation on viral replication and explored whether the flavonoid Naringenin (NGN) could modulate this inflammation. Using a placental villous explant model, we verified that inflammation induced by LPS exacerbates viral replication and pathological markers. Notably, treatment with the NGN rescued the inflammatory and virological outcomes. These findings were further validated in a murine model of congenital infection, where NGN administration alleviated microcephaly-related structural alterations in ZIKV-exposed neonates. Our results indicate that placental inflammation is a key provocateur of ZIKV replication and subsequent fetal brain malformation. Furthermore, we identify NGN as a promising bifunctional antiviral and anti-inflammatory candidate for mitigating the developmental impacts of ZIKV infection. Full article

Zika virus (ZIKV) infection is associated with severe neurodevelopmental disorders. However, the molecular mechanisms involved in the imbalance of excitatory and inhibitory neurotransmitter systems remain poorly understood. In this study, we evaluated the expression of components of the GABA–glutamate system in neonatal BALB/c mice inoculated with ZIKV at 10 days post-infection (dpi). Analysis of GABA-A and NMDA receptors revealed widespread downregulation of GABA-A and NMDA receptor subunits in the cerebral cortex and cerebellum, except for the alpha-5 and epsilon GABA-A subunits, which were upregulated in the cerebellum. Infected mice also showed increased GABA immunoreactivity and glutamate loss. The enzymes involved in neurotransmitter synthesis or transport confirmed these findings when assessed by qRT-PCR or Western blot, revealing increased expression of GAD-65/67, accompanied by a loss of glutamate dehydrogenase (GLUD) in the cerebral cortex and cerebellum, along with decreased expression of the glutamate transporter (VGLUT) in the cerebral cortex. These findings suggest that GABA synthesis increases during ZIKV infection, creating a neurochemical environment that favors viral replication and contributes to the migration and synaptic defects observed in congenital Zika syndrome. Full article

A decade has elapsed since the first recognized cluster of congenital anomalies associated with Zika virus (ZIKV) was reported in Brazil in 2015, culminating in the formal delineation of Congenital Zika Syndrome (CZS) as a specific pattern of birth defects. This narrative review examines the ten-year trajectory of CZS as a tropical infectious disease, from its initial emergence and public health emergency declaration by the World Health Organization (WHO) in February 2016, through evolving epidemiological, clinical, and scientific understanding. CZS is characterized by a spectrum of severe neurological manifestations—including microcephaly, subcortical calcifications, malformations of cortical development, ventriculomegaly, and corpus callosum abnormalities—alongside ophthalmic, auditory, and musculoskeletal complications. Transmitted primarily by Aedes aegypti mosquitoes in tropical and subtropical regions, ZIKV disproportionately affects low- and middle-income countries in Latin America, Africa, and Southeast Asia, underscoring its nature as a quintessential tropical disease linked to poverty, inadequate vector control, and health inequity. Over ten years, substantial advances have been made in understanding ZIKV pathogenesis, neurodevelopmental outcomes, diagnostic criteria, and multidisciplinary clinical management of affected children. In the therapeutic and preventive domain, over 45 vaccine candidates have been identified, with 16 reaching Phase 1 or 2 clinical trials by late 2025, though no licensed vaccine or specific antiviral therapy yet exists. This review contextualizes CZS within the broader framework of neglected tropical diseases, evaluates its global and family-level burden, and critically appraises progress and remaining gaps in clinical care, vaccination, and vector control over the past ten years. Full article

Background: Zika virus (ZIKV) is a mosquito-borne flavivirus associated with severe neurological disease, including congenital Zika syndrome (CZS) following utero infection and Guillain–Barré syndrome in adults. The 2015–2016 epidemic in the Americas highlighted the profound maternal and neonatal consequences of ZIKV infection. Although reported transmission has declined, ongoing circulation of competent vectors and population susceptibility sustain a substantial risk of future outbreaks, underscoring the need for effective vaccines. Methods: We developed a recombinant Modified Vaccinia Ankara (MVA)-based vaccine candidate expressing the ZIKV pre-membrane (prM) and envelope (E) proteins and evaluated its immunogenicity and protective efficacy in interferon receptor-deficient AG129 mice. Results: Vaccination induced strong humoral and cellular immune responses and conferred significant protection against viral replication in key target organs, including the brain and testes, following ZIKV challenge. Conclusions: These preclinical findings support further development of this MVA-based ZIKV vaccine as a promising strategy to prevent ZIKV infection and its associated neurological complications. Full article

Background/Objectives: The Zika virus (ZIKV) represents an ongoing threat to public health due to its neurological and congenital complications. Even after 10 years since the first major outbreak, correlated with an increase in congenital ZIKV syndrome, there is still no vaccine or treatment for this infection. Among the various existing platforms, DNA vaccines combined with the use of immunoinformatics tools allow for the efficient selection of immunogenic epitopes and immunostimulatory molecules with greater flexibility, in addition to being simple to manufacture and having a higher cost–benefit ratio in production. Methods: In this work, we conducted an integrated approach, combining in silico analyses and in vivo experimental validations, for the development of multi-epitope DNA vaccines against ZIKV. The computational analyses confirmed structural stability, adequate solubility, absence of toxicity, and immune induction potential for constructs based on epitopes from the Envelope (E) and NS1 proteins. Therefore, we evaluated DNA constructs containing the ENV + NS1 epitopes, both with and without fusion to the ssPGIP signal peptide, in BALB/c mice. Results: Both vaccines increased the population of CD4⁺ and CD8⁺ T lymphocytes, in addition to the production of IgG antibodies associated with the Th1 profile. The fusion with ssPGIP broadened the response, stimulating the release of Th1, Th2, and Th17 cytokines, as well as enhancing antibody formation. In contrast, its absence was associated with a slight increase in CD4⁺ and CD8⁺ T cells, accompanied by restricted cytokine production. Conclusions: These results indicate that epitope-targeted techniques offer a viable and safe method for inducing robust immune responses, demonstrating that combining immunoinformatics methods with early preclinical testing is an effective strategy for ZIKV vaccine development. Furthermore, although the present study focused on initial immunogenic characterization, future studies involving viral challenge in a suitable animal model will be essential to conclusively determine the protective efficacy of these vaccine candidates. Full article

Zika virus (ZIKV) was first identified in Africa in the mid-20th century and circulated for decades with limited and often unnoticed human cases. This situation changed with the emergence of the Asian lineage, responsible for large outbreaks in the Pacific and the Americas and for severe complications such as Guillain–Barré syndrome and Congenital Zika Syndrome (CZS). In contrast, the African lineage, although frequently more efficient in replication, cytopathogenicity, and mosquito transmission in experimental systems, has not been linked to comparable epidemics or congenital disease clusters. This review summarizes current knowledge on the differences between African and Asian lineages at the molecular, cellular, and epidemiological levels. It highlights how genetic variation interacts with host immunity, ecological factors, and human activity to shape epidemic potential. Understanding these interactions is essential for anticipating future outbreaks and for improving strategies to mitigate the impact of emerging arboviruses. Full article

Children with Congenital Zika Virus Syndrome (CZVS) experience severe neurological and nutritional impairments. Although immediate clinical consequences are well-documented, long-term anthropometric and nutritional outcomes remain poorly understood. This study assessed longitudinal anthropometric and nutritional outcomes in children affected by CZVS. A cohort of 38 children aged ≥ 5 years diagnosed with CZVS was followed at a reference center in Northeast Brazil. Anthropometric measures (weight, height, BMI, head circumference) were collected using standardized methods, including digital scales and anthropometric tape measures. Growth was analyzed using WHO Anthro and WHO Anthro Plus software (version 3.2.2). Dietary intake was evaluated through two 24 h recalls and analyzed with NutWIN 2.5 software. Nutritional status was classified using WHO growth standards, and associations between dietary intake and BMI were statistically examined. Children showed significant linear growth improvement (p = 0.007) without corresponding weight gain, leading to worsening BMI classifications (p = 0.017). Dietary evaluations revealed limited dietary diversity, frequent intake of ultra-processed foods, inadequate fruit consumption, and widespread insufficiencies in caloric and micronutrient intake (zinc, calcium, iron, vitamin D). Low carbohydrate intake was significantly associated with inadequate BMI (p = 0.030). Multidisciplinary nutritional interventions addressing medical, dietary, educational, and socioeconomic factors are essential for improving health outcomes in children with CZVS. Full article

Zika virus (ZIKV) remains a pressing global health concern due to its association with congenital Zika syndrome and the current lack of approved antiviral therapies. In this study, we evaluated the antiviral activity of three novel thiazolidinedione derivatives, GQ-402, GQ-396, and ZKC-10, against ZIKV in vitro and investigated their potential molecular targets through in silico analysis. GQ-402 exhibited the highest antiviral potency, with an IC₅₀ of 15.7 µM, while ZKC-10 achieved the most substantial reduction in viral RNA levels, as determined by RT-qPCR. Molecular docking studies identified GQ-396 as the top-ranked inhibitor of the NS2B-NS3 protease and NS5 RNA-dependent RNA polymerase, suggesting distinct mechanisms of action among the compounds. These findings highlight the therapeutic potential of thiazolidinedione derivatives and underscore the need for further investigation to develop effective treatments for ZIKV infection. Full article

Background/Objectives: Congenital microcephaly is a clinical manifestation with a heterogeneous etiology, and its epidemiological surveillance relies on the systematic identification of cases and investigation of their underlying causes to inform preventive strategies and improve prognostic assessments. In Latin America, despite the existence of congenital anomaly reporting programs since 1967, the surveillance of microcephaly only gained substantial attention following the Zika virus (ZIKV) epidemic in 2015. Since then, efforts have predominantly concentrated on cases of infectious origin, often at the expense of recognizing endogenous etiologies, particularly those of genetic nature. This review aims to examine the role of genetic alterations in microcephaly pathogenesis and evaluates the limitations of current surveillance systems. Methods: A literature review centered on syndromic and non-syndromic genetic etiologies, alongside an analysis of Latin American surveillance frameworks (ECLAMC, RyVEMCE, ICBDSR, ReLAMC) was performed. Results: The findings reveal improved case detection and increased reported prevalence; however, the proportion of genetically attributed cases has remained stable. No systematic studies were found identifying the most common genetic causes; instead, genetic investigations were limited to isolated cases with a family history. Conclusions: While epidemiological surveillance systems in Latin America have advanced in the reporting of congenital microcephaly cases, substantial gaps remain in case ascertainment and etiological investigation, particularly concerning genetic contributions Full article

Zika virus (ZIKV) infection during pregnancy can cause a broad range of neurological birth defects, collectively named Congenital Zika Syndrome (CZS). We have previously shown that infection with the Puerto Rican isolate PRVABC59 (ZIKV-PR) results in abnormal oxygen transport in the placenta due to villous damage and uterine vasculitis in a nonhuman primate model. To investigate whether this type of damage occurs with endemically circulating strains in Thailand, we investigated a CZS case isolate, MU1-2017 (ZIKV-TH), in pregnant rhesus macaques. Pregnant animals (n = 3 per group) were infected subcutaneously with either ZIKV-PR or ZIKV-TH at ~50 days gestation (GD) and monitored for 40 days post-infection (GD90). Similar courses of viremia and immune activation were observed for both viruses when compared to uninfected controls. In addition, both viruses induced changes to the placental architecture, including spiral artery remodeling and the development of infarctions. Similar levels of viral RNA were detected at necropsy in maternal and fetal tissues. Overall, our results show that the ZIKV-TH strain MU1-2017 behaves similarly to the ZIKV-PR strain, and, importantly, provide evidence of in-utero infection with an additional contemporary strain of ZIKV. Full article

The Zika virus (ZIKV) gained prominence as a significant global pathogen after the 2015–2016 outbreaks associated it with an increase in neurological complications in adults and congenital malformations. Different mechanisms have been proposed by which ZIKV may cross the blood–brain barrier and reach the central nervous system to cause neuroinflammation. Although ZIKV infection triggers a robust immune response, the virus has developed different strategies to escape it. Furthermore, although the virus is present in areas with cocirculation of other pathogenic agents, few studies have evaluated the cross-immune reactions and coinfection of ZIKV. Coinfections of ZIKV with other viruses, parasites, and bacteria are described. Such interactions can worsen infections and alter the immune response, imposing new therapeutic challenges and highlighting the need for more studies in the field. In this review, we discuss various aspects of ZIKV biology, focusing on the impacts of coinfections. Full article

Background: The Zika virus (ZIKV) is an arbovirus linked to “Congenital Zika Syndrome” and a range of neurodevelopmental disorders (NDDs), with microcephaly as the most severe manifestation. Milder NDDs, such as autism spectrum disorders and delays in neuropsychomotor and language development, often go unnoticed in neonates, resulting in long-term social and academic difficulties. Murine models of ZIKV infection can be used to mimic part of the spectrum of motor and cognitive deficits observed in humans. These can be evaluated through behavioral tests, enabling comparison with gene expression profiles and aiding in the characterization of ZIKV-induced NDDs. Objectives: This study aimed to identify genes associated with behavioral changes following a subtle ZIKV infection in juvenile BALB/c mice. Methods: Neonatal mice were subcutaneously inoculated with ZIKV (MH544701.2) on postnatal day 1 (DPN) at a dose of 6.8 × 10³ PFU. Viral presence in the cerebellum and cortex was quantified at 10- and 30-days post-infection (DPI) using RT-qPCR. Neurobehavioral deficits were assessed at 30 DPI through T-maze, rotarod, and open field tests. Next-Generation Sequencing (NGS) was performed to identify differentially expressed genes (DEGs), which were analyzed through Gene Ontology (GO) and KEGG enrichment. Gene interaction networks were then constructed to explore gene interactions in the most enriched biological categories. Results: A ZIKV infection model was successfully established, enabling brain infection while allowing survival beyond 30 DPI. The infection induced mild cognitive behavioral changes, though motor and motivational functions remained unaffected. These cognitive changes were linked to the functional repression of synaptic vesicles and alterations in neuronal structure, suggesting potential disruptions in neuronal plasticity. Conclusions: Moderate ZIKV infection with circulating strains from the 2016 epidemic may cause dysregulation of genes related to immune response, alterations in cytoskeletal organization, and modifications in cellular transport mediated by vesicles. Despite viral control, neurocognitive effects persisted, including memory deficits and anxiety-like behaviors, highlighting the long-term neurological consequences of ZIKV infection in models that show no apparent malformations. Full article

Oropouche fever is caused by the Oropouche virus (OROV; Bunyaviridae, Orthobunyavirus), one of the most frequent arboviruses that infect humans in the Brazilian Amazon. This year, an OROV outbreak was identified in Brazil, and its vertical transmission was reported, which was associated with fetal death and microcephaly. We describe the clinical manifestations identified in three cases of congenital OROV infection with confirmed serology (OROV-IgM) in the mother-newborn binomial. One of the newborns died, and post-mortem molecular analysis using real-time RT-qPCR identified the OROV genome in several tissues. All three newborns were born in the Amazon region in Brazil, and the mothers reported fever, rash, headache, myalgia, and/or retro-orbital pain during pregnancy. The newborns presented with severe microcephaly secondary to brain damage and arthrogryposis, suggestive of an embryo/fetal disruptive process at birth. Brain and spinal images identified overlapping sutures, cerebral atrophy, brain cysts, thinning of the spinal cord, corpus callosum, and posterior fossa abnormalities. Fundoscopic findings included macular chorioretinal scars, focal pigment mottling, and vascular attenuation. The clinical presentation of vertical OROV infection resembled congenital Zika syndrome to some extent but presents some distinctive features on brain imaging and in several aspects of its neurological presentation. A recognizable syndrome with severe brain damage, neurological alterations, arthrogryposis, and fundoscopic abnormalities can be associated with in utero OROV infection. Full article