RESUMEN

The Zika virus (ZIKV) epidemic declared in Brazil between 2015 and 2016 was associated with an increased prevalence of severe congenital malformations, including microcephaly. The distribution of microcephaly cases was not uniform across the country, with a disproportionately higher incidence in the Northeast region (NE). Our previous work demonstrated that saxitoxin (STX), a toxin present in the drinking water reservoirs of the NE, exacerbated the damaging effects of ZIKV on the developing brain. We hypothesized that the impact of STX might vary among different neural cell types. While ZIKV infection caused severe damages on astrocytes and neural stem cells (NSCs), the addition of STX did not exacerbate these effects. We observed that neurons subjected to STX exposure were more prone to apoptosis and displayed higher ZIKV infection rate. These findings suggest that STX exacerbates the harmful effects of ZIKV on neurons, thereby providing a plausible explanation for the heightened severity of ZIKV-induced congenital malformations observed in Brazil's NE. This study highlights the importance of understanding the interactive effects of environmental toxins and infectious pathogens on neural development, with potential implications for public health policies.

Asunto(s)

Astrocitos , Células-Madre Neurales , Neuronas , Saxitoxina , Infección por el Virus Zika , Virus Zika , Células-Madre Neurales/virología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Humanos , Virus Zika/fisiología , Astrocitos/virología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Neuronas/virología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Infección por el Virus Zika/virología , Infección por el Virus Zika/patología , Saxitoxina/toxicidad , Apoptosis/efectos de los fármacos , Microcefalia/virología , Muerte Celular/efectos de los fármacos , Brasil , Células Cultivadas

RESUMEN

AIM: Congenital Zika Virus Syndrome (CZS) presents notable hurdles to neurodevelopment, with language development emerging as a crucial aspect. This study investigates sleep patterns and language skills in children with CZS, aiming to explore the potential synchronization of sleep development with their neurodevelopment. METHOD: We studied cross-sectionally 135 children with CZS aged 0 to 48 months, investigating sleep using the BISQ Questionnaire. Language development was assessed using the Early Language Milestone Scale, while motor development and cognitive and social ability were assessed using the Bayley Scales of Infant and Young Child Development 3rd edition. We also studied longitudinally a cohort of 16 children (initially aged 0 to 12 months) whom we followed for four years, assessing at one-year intervals. RESULTS: Sleep disturbances and language deficits were highly frequent in this population. In the 0-12 months group, a late bedtime and frequent nighttime awakenings were associated with poorer auditory expressive skills. At 13-24 months, nighttime awakenings were associated with poorer auditory expressive skills, while among 25-36-month-olds decreased auditory receptive skills were associated with longer sleep onset latency and reduced nighttime sleep duration. CONCLUSION: The brain alterations caused by Zika virus infection affect both sleep disturbances and delays in language development. It is possible that sleep disturbance may be a mediating factor in the pathway between CZS and delayed language development, as the three analyzed language skills showed a correlation with sleep parameters.

Asunto(s)

Desarrollo del Lenguaje , Sueño , Infección por el Virus Zika , Humanos , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/fisiopatología , Infección por el Virus Zika/virología , Infección por el Virus Zika/congénito , Lactante , Femenino , Masculino , Preescolar , Sueño/fisiología , Recién Nacido , Estudios Transversales , Trastornos del Sueño-Vigilia/fisiopatología , Trastornos del Sueño-Vigilia/virología , Virus Zika/fisiología , Estudios Longitudinales , Encuestas y Cuestionarios , Trastornos del Desarrollo del Lenguaje/fisiopatología , Trastornos del Desarrollo del Lenguaje/virología

RESUMEN

Monocytes are the primary targets of Zika virus (ZIKV) and are associated with ZIKV pathogenesis. Currently, there is no effective treatment for ZIKV infection. It is known that 1,25-dihydroxy vitamin D3 (VitD3) has strong antiviral activity in dengue virus-infected macrophages, but it is unknown whether VitD3 inhibits ZIKV infection in monocytes. We investigated the relationship between ZIKV infection and the expression of genes of the VitD3 pathway, as well as the inflammatory response of infected monocytes in vitro. ZIKV replication was evaluated using a plaque assay, and VitD3 pathway gene expression was analyzed by RT-qPCR. Pro-inflammatory cytokines/chemokines were quantified using ELISA. We found that VitD3 did not suppress ZIKV replication. The results showed a significant decrease in the expression of vitamin D3 receptor (VDR), cytochrome P450 family 24 subfamily A member 1 (CYP24A1), and cathelicidin antimicrobial peptide (CAMP) genes upon ZIKV infection. Treatment with VitD3 was unable to down-modulate production of pro-inflammatory cytokines, except TNF-α, and chemokines. This suggests that ZIKV infection inhibits the expression of VitD3 pathway genes, thereby preventing VitD3-dependent inhibition of viral replication and the inflammatory response. This is the first study to examine the effects of VitD3 in the context of ZIKV infection, and it has important implications for the role of VitD3 in the control of viral replication and inflammatory responses during monocyte infection.

Asunto(s)

Catelicidinas , Monocitos , Replicación Viral , Vitamina D3 24-Hidroxilasa , Infección por el Virus Zika , Virus Zika , Humanos , Péptidos Catiónicos Antimicrobianos/metabolismo , Péptidos Catiónicos Antimicrobianos/farmacología , Citocinas/metabolismo , Citocinas/genética , Monocitos/virología , Monocitos/metabolismo , Monocitos/inmunología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Replicación Viral/efectos de los fármacos , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismo , Virus Zika/fisiología , Infección por el Virus Zika/virología , Infección por el Virus Zika/metabolismo

RESUMEN

Zika (ZIKV) and chikungunya (CHIKV) are arboviruses that cause infections in humans and can cause clinical complications, representing a worldwide public health problem. Aedes aegypti is the primary vector of these pathogens and Culex quinquefasciatus may be a potential ZIKV vector. This study aimed to evaluate fecundity, fertility, survival, longevity, and blood feeding activity in Ae. aegypti after exposure to ZIKV and CHIKV and, in Cx. quinquefasciatus exposed to ZIKV. Three colonies were evaluated: AeCamp (Ae. aegypti-field), RecL (Ae. aegypti-laboratory) and CqSLab (Cx. quinquefasciatus-laboratory). Seven to 10 days-old females from these colonies were exposed to artificial blood feeding with CHIKV or ZIKV. CHIKV caused reduction in fecundity and fertility in AeCamp and reduction in survival and fertility in RecL. ZIKV impacted survival in RecL, fertility in AeCamp and, fecundity and fertility in CqSLab. Both viruses had no effect on blood feeding activity. These results show that CHIKV produces a higher biological cost in Ae. aegypti, compared to ZIKV, and ZIKV differently alters the biological performance in colonies of Ae. aegypti and Cx. quinquefasciatus. These results provide a better understanding over the processes of virus-vector interaction and can shed light on the complexity of arbovirus transmission.

Asunto(s)

Aedes , Virus Chikungunya , Culex , Fertilidad , Mosquitos Vectores , Infección por el Virus Zika , Virus Zika , Animales , Aedes/virología , Aedes/fisiología , Virus Chikungunya/fisiología , Virus Chikungunya/patogenicidad , Virus Zika/fisiología , Virus Zika/patogenicidad , Culex/virología , Culex/fisiología , Mosquitos Vectores/virología , Mosquitos Vectores/fisiología , Femenino , Infección por el Virus Zika/transmisión , Infección por el Virus Zika/virología , Fiebre Chikungunya/transmisión , Fiebre Chikungunya/virología , Conducta Alimentaria/fisiología , Humanos , Longevidad

RESUMEN

Gliomas account for approximately 75-80% of all malignant primary tumors in the central nervous system (CNS), with glioblastoma multiforme (GBM) considered the deadliest. Despite aggressive treatment involving a combination of chemotherapy, radiotherapy, and surgical intervention, patients with GBM have limited survival rates of 2 to 5 years, accompanied by a significant decline in their quality of life. In recent years, novel management strategies have emerged, such as immunotherapy, which includes the development of vaccines or T cells with chimeric antigen receptors, and oncolytic virotherapy (OVT), wherein wild type (WT) or genetically modified viruses are utilized to selectively lyse tumor cells. In vitro and in vivo studies have shown that the Zika virus (ZIKV) can infect glioma cells and induce a robust oncolytic activity. Consequently, interest in exploring this virus as a potential oncolytic virus (OV) for high-grade gliomas has surged. Given that ZIKV actively circulates in Colombia, evaluating its neurotropic and oncolytic capabilities holds considerable national and international importance, as it may emerge as an alternative for treating highly complex gliomas. Therefore, this literature review outlines the generalities of GBM, the factors determining ZIKV's specific tropism for nervous tissue, and its oncolytic capacity. Additionally, we briefly present the progress in preclinical studies supporting the use of ZIKV as an OVT for gliomas.

Asunto(s)

Neoplasias Encefálicas , Glioma , Viroterapia Oncolítica , Virus Oncolíticos , Virus Zika , Animales , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/virología , Glioblastoma/terapia , Glioblastoma/virología , Glioma/terapia , Glioma/virología , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Virus Oncolíticos/fisiología , Virus Zika/fisiología , Infección por el Virus Zika/virología

RESUMEN

Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.

Asunto(s)

Astrocitos , Trastorno del Espectro Autista , Enfermedades Neuroinflamatorias , Sinapsis , Infección por el Virus Zika , Virus Zika , Infección por el Virus Zika/patología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/virología , Infección por el Virus Zika/complicaciones , Trastorno del Espectro Autista/virología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/patología , Humanos , Animales , Ratones , Virus Zika/fisiología , Femenino , Niño , Sinapsis/metabolismo , Sinapsis/patología , Enfermedades Neuroinflamatorias/virología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/etiología , Astrocitos/virología , Astrocitos/metabolismo , Astrocitos/patología , Masculino , Interleucina-6/metabolismo , Interleucina-6/genética , Embarazo , Factores de Riesgo , Células Madre Pluripotentes Inducidas/virología , Células Madre Pluripotentes Inducidas/metabolismo , Brasil/epidemiología , Modelos Animales de Enfermedad , Neurogénesis

RESUMEN

The congenital Zika syndrome (CZS) has been characterized as a set of several brain changes, such as reduced brain volume and subcortical calcifications, in addition to cognitive deficits. Microcephaly is one of the possible complications found in newborns exposed to Zika virus (ZIKV) during pregnancy, although it is an impacting clinical sign. This study aimed to investigate the consequences of a model of congenital ZIKV infection by evaluating the histopathology, blood-brain barrier, and neuroinflammation in pup rats 24 h after birth, and neurodevelopment of the offspring. Pregnant rats were inoculated subcutaneously with ZIKV-BR at the dose 1 × 107 plaque-forming unit (PFU mL-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). A set of pups, 24 h after birth, was euthanized. The brain was collected and later evaluated for the histopathology of brain structures through histological analysis. Additionally, analyses of the blood-brain barrier were conducted using western blotting, and neuroinflammation was assessed using ELISA. Another set of animals was evaluated on postnatal days 3, 6, 9, and 12 for neurodevelopment by observing the developmental milestones. Our results revealed hippocampal atrophy in ZIKV animals, in addition to changes in the blood-brain barrier structure and pro-inflammatory cytokines expression increase. Regarding neurodevelopment, a delay in important reflexes during the neonatal period in ZIKV animals was observed. These findings advance the understanding of the pathophysiology of CZS and contribute to enhancing the rat model of CZS.

Asunto(s)

Microcefalia , Complicaciones Infecciosas del Embarazo , Infección por el Virus Zika , Virus Zika , Embarazo , Humanos , Femenino , Ratas , Animales , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/diagnóstico , Virus Zika/fisiología , Complicaciones Infecciosas del Embarazo/patología , Barrera Hematoencefálica/patología , Enfermedades Neuroinflamatorias , Microcefalia/etiología , Microcefalia/patología , Atrofia/patología , Hipocampo/patología

RESUMEN

Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence in various cell types in the brain and for their suggested involvement in neurodevelopment and neurodegenerative diseases. Only recently have the roles of LD in neuroinfections begun to be explored. Recent findings reveal that lipid remodelling and increased LD biogenesis play important roles for Zika virus (ZIKV) replication and pathogenesis in neural cells. Moreover, blocking LD formation by targeting DGAT-1 in vivo inhibited virus replication and inflammation in the brain. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development. Here, we review the progress in understanding LD functions in the central nervous system in the context of the host response to Zika infection.

Asunto(s)

Infecciones del Sistema Nervioso Central , Gotas Lipídicas , Infección por el Virus Zika , Virus Zika , Humanos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/fisiología , Gotas Lipídicas/virología , Lípidos/fisiología , Replicación Viral/fisiología , Virus Zika/fisiología , Infección por el Virus Zika/fisiopatología , Infección por el Virus Zika/virología , Infecciones del Sistema Nervioso Central/fisiopatología , Infecciones del Sistema Nervioso Central/virología

RESUMEN

A detailed understanding of how host fitness changes in response to variations in microbe density (an ecological measure of disease tolerance) is an important aim of infection biology. Here, we applied dose-response curves to study Aedes aegypti survival upon exposure to different microbes. We challenged female mosquitoes with Listeria monocytogenes, a model bacterial pathogen, Dengue 4 virus and Zika virus, two medically relevant arboviruses, to understand the distribution of mosquito survival following microbe exposure. By correlating microbe loads and host health, we found that a blood meal promotes disease tolerance in our systemic bacterial infection model and that mosquitoes orally infected with bacteria had an enhanced defensive capacity than insects infected through injection. We also showed that Aedes aegypti displays a higher survival profile following arbovirus infection when compared to bacterial infections. Here, we applied a framework for investigating microbe-induced mosquito mortality and details how the lifespan of Aedes aegypti varies with different inoculum sizes of bacteria and arboviruses.

Asunto(s)

Aedes , Infecciones por Arbovirus , Arbovirus , Virus del Dengue , Infección por el Virus Zika , Virus Zika , Femenino , Animales , Virus del Dengue/fisiología , Mosquitos Vectores/microbiología , Virus Zika/fisiología , Bacterias

RESUMEN

IMPORTANCE: One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5'-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.

Asunto(s)

Virus del Dengue , Estrés Fisiológico , Replicación Viral , Virus Zika , eIF-2 Quinasa , Animales , Humanos , Células A549 , Chlorocebus aethiops , Dengue/inmunología , Dengue/virología , Virus del Dengue/fisiología , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Eliminación de Gen , Biosíntesis de Proteínas/genética , Biosíntesis de Proteínas/inmunología , Estrés Fisiológico/genética , Estrés Fisiológico/inmunología , Células Vero , Replicación Viral/genética , Replicación Viral/inmunología , Virus Zika/fisiología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/virología , ARN Bicatenario/metabolismo

RESUMEN

INTRODUCTION: Zika virus (ZIKV) is a human teratogen that causes congenital Zika syndrome (CZS). AXL, TLR3, and STAT2 are proteins involved in the ZIKV's entry into cells (AXL) and host's immune response (TLR3 and STAT2). In this study, we evaluated the role of genetic polymorphisms in these three genes as risk factors to CZS, and highlighted which proteins that interact with them could be important for ZIKV infection and teratogenesis. MATERIALS AND METHODS: We evaluate eighty-eight children exposed to ZIKV during the pregnancy, 40 with CZS and 48 without congenital anomalies. The evaluated polymorphisms in AXL (rs1051008), TLR3 (rs3775291), and STAT2 (rs2066811) were genotyped using TaqMan® Genotyping Assays. A protein-protein interaction network was created in STRING database and analyzed in Cytoscape software. RESULTS: We did not find any statistical significant association among the polymorphisms and the occurrence of CZS. Through the analyses of the network composed by AXL, TLR3, STAT2 and their interactions targets, we found that EGFR and SRC could be important proteins for the ZIKV infection and its teratogenesis. CONCLUSION: In summary, our results demonstrated that the evaluated polymorphisms do not seem to represent risk factors for CZS; however, EGFR and SRC appear to be important proteins that should be investigated in future studies.

Asunto(s)

Teratogénesis , Infección por el Virus Zika , Virus Zika , Embarazo , Niño , Femenino , Humanos , Infección por el Virus Zika/genética , Virus Zika/fisiología , Tirosina Quinasa del Receptor Axl , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Proto-Oncogénicas/genética , Mapas de Interacción de Proteínas/genética , Receptores ErbB/metabolismo , Factor de Transcripción STAT2/genética , Factor de Transcripción STAT2/metabolismo

RESUMEN

In recent years, the Zika Virus (ZIKV) has caused pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZS). Although all strains associated with worldwide outbreaks derive from the Asian lineage, the reasons for their enhanced spread and severity are not fully understood. In this study, we conducted a comparative analysis of miRNAs (miRNA-155/146a/124) and their cellular targets (SOCS1/3, SHP1, TRAF6, IRAK1), as well as pro- and anti-inflammatory and anti-viral cytokines (IL-6, TNF-α, IFN-γ, IL-10, and IFN-ß) and peroxisome proliferator-activated receptor γ (PPAR-γ) expression in BV2 microglia cells infected with ZIKV strains derived from African and Asian lineages (ZIKVMR766 and ZIKVPE243). BV2 cells were susceptible to both ZIKV strains, and showed discrete levels of viral replication, with delayed release of viral particles without inducing significant cytopathogenic effects. However, the ZIKVMR766 strain showed higher infectivity and replicative capacity, inducing a higher expression of microglial activation markers than the ZIKVPE243 strain. Moreover, infection with the ZIKVMR766 strain promoted both a higher inflammatory response and a lower expression of anti-viral factors compared to the ZIKVPE243 strain. Remarkably, the ZIKKPE243 strain induced significantly higher levels of the anti-inflammatory nuclear receptor-PPAR-γ. These findings improve our understanding of ZIKV-mediated modulation of inflammatory and anti-viral innate immune responses and open a new avenue to explore underlining mechanisms involved in the pathogenesis of ZIKV-associated diseases.

Asunto(s)

MicroARNs , Infección por el Virus Zika , Virus Zika , Humanos , Virus Zika/fisiología , Microglía/metabolismo , Receptores Activados del Proliferador del Peroxisoma , Replicación Viral/fisiología , Antivirales

RESUMEN

Aedes aegypti are vector insects of arboviruses such as dengue, Zika, and chikungunya. All available vector control methods have limited efficacy, highlighting the urgent need to find alternative ones. Evidence shows that arachnids like ticks are sources of biologically active compounds. Moreover, chemical modulation of the locomotor and immune systems of vector insects can be used to control arbovirus transmission. The present study evaluated the effectiveness of crude saliva of female Amblyomma cajennense sensu stricto (s.s.) ticks in reducing locomotor activity and inducing an immune response in Ae. aegypti females. Additionally, the study evaluated the protein constitution of tick saliva. For this purpose, the crude saliva obtained from several semi-engorged A. cajennense females was used. A volume of 0.2 nL of crude tick saliva was administered to mosquitoes by direct intrathoracic microinjection. The effect of the tick's saliva on the locomotor activity of the mosquito was observed using Flybox, a video-automated monitoring system, and the hemolymph hemocyte levels were quantified by reading slides under a light microscope. The protein concentration of the crude tick saliva was 1.27 µg/µL, and its electrophoretic profile indicates the presence of proteins with a molecular weight ranging between ∼17 and 95 kDa. Microplusins, ixodegrins, cystatin, actins, beta-actin, calponin, albumin, alpha-globulins, and hemoglobin were the main proteins identified by proteomics in the saliva of A. cajennense. The microinjected saliva had low toxicity for Ae. aegypti females and significantly reduced their locomotor activity, especially in the transition between the light and dark phases. The crude tick saliva did not change the period and rhythmicity of the circadian cycle. The tick saliva significantly increased the number of hemocytes two days after injection and reduced it after five days. These results suggest that further evaluation of the biological properties of tick saliva proteins against Ae. aegypti would be of interest.

Asunto(s)

Aedes , Ixodidae , Infección por el Virus Zika , Virus Zika , Animales , Femenino , Saliva , Amblyomma , Hemocitos , Mosquitos Vectores , Locomoción , Virus Zika/fisiología

RESUMEN

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with several neurodevelopmental outcomes after in utero infection. Here, we studied a congenital ZIKV infection model with immunocompetent Wistar rats, able to predict disabilities and that could pave the way for proposing new effective therapies. We identified neurodevelopmental milestones disabilities in congenital ZIKV animals. Also, on 22nd postnatal day (PND), blood-brain barrier (BBB) proteins disturbances were detected in the hippocampus with immunocontent reduction of ß_Catenin, Occludin and Conexin-43. Besides, oxidative stress imbalance on hippocampus and cortex were identified, without neuronal reduction in these structures. In conclusion, even without pups' microcephaly-like phenotype, congenital ZIKV infection resulted in neurobehavioral dysfunction associated with BBB and oxidative stress disturbances in young rats. Therefore, our findings highlighted the multiple impact of the congenital ZIKV infection on the neurodevelopment, which reinforces the continuity of studies to understand the spectrum of this impairment and to provide support to future treatment development for patients affected by congenital ZIKV.

Asunto(s)

Enfermedades Transmisibles , Complicaciones Infecciosas del Embarazo , Infección por el Virus Zika , Virus Zika , Humanos , Embarazo , Femenino , Ratas , Animales , Virus Zika/fisiología , Barrera Hematoencefálica , Ratas Wistar

RESUMEN

Zika virus (ZIKV) is a strongly neurotropic flavivirus whose infection has been associated with microcephaly in neonates. However, clinical and experimental evidence indicate that ZIKV also affects the adult nervous system. In this regard, in vitro and in vivo studies have shown the ability of ZIKV to infect glial cells. In the central nervous system (CNS), glial cells are represented by astrocytes, microglia, and oligodendrocytes. In contrast, the peripheral nervous system (PNS) constitutes a highly heterogeneous group of cells (Schwann cells, satellite glial cells, and enteric glial cells) spread through the body. These cells are critical in both physiological and pathological conditions; as such, ZIKV-induced glial dysfunctions can be associated with the development and progression of neurological complications, including those related to the adult and aging brain. This review will address the effects of ZIKV infection on CNS and PNS glial cells, focusing on cellular and molecular mechanisms, including changes in the inflammatory response, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate homeostasis, neural metabolism, and neuron-glia communication. Of note, preventive and therapeutic strategies that focus on glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration and its consequences.

Asunto(s)

Infección por el Virus Zika , Virus Zika , Humanos , Virus Zika/fisiología , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/tratamiento farmacológico , Infección por el Virus Zika/patología , Neuroglía/metabolismo , Sistema Nervioso Central/metabolismo , Encéfalo/metabolismo

RESUMEN

Zika virus (ZIKV) is an arbovirus that was responsible for multiple outbreaks from 2007 to 2015. It has been linked to cases of microcephaly in Brazil in 2015, among other neurological disorders. Differences among strains might be the reason for different clinical outcomes of infection. To evaluate this hypothesis, we performed a comparative proteomic analysis of Vero cells infected with the African strain MR766 (ZIKVAFR) and the Brazilian strain 17 SM (ZIKVBR). A total of 550 proteins were identified as differentially expressed in ZIKVAFR- or ZIKVBR-infected cells compared to the control. The main findings included upregulation of immune system pathways (neutrophil degranulation and adaptive/innate immune system) and potential activation of immune-system-related pathways by ZIKVAFR (mTOR, JAK-STAT, NF-κB, and others) compared with the ZIKVBR/control. In addition, phagocytosis by macrophages and engulfment of leukocytes were activated in ZIKVAFR infection. An in vivo analysis using an immunocompetent C57BL/6N mouse model identified interstitial pneumonia with neutrophil infiltration in the lungs only in mice infected with ZIKVBR at 48 hours postinfection, with a significant amount of virus detected. Likewise, only animals infected with ZIKVBR had viral material in the cytoplasm of lung macrophages. These results suggest that activation of the immune system by ZIKVAFR infection may lead to faster viral clearance by immune cells.

Asunto(s)

Evasión Inmune , Infección por el Virus Zika , Virus Zika , Animales , Ratones , Brasil , Chlorocebus aethiops , Ratones Endogámicos C57BL , Proteómica , Células Vero , Virus Zika/fisiología , Infección por el Virus Zika/inmunología

RESUMEN

Zika virus (ZIKV) is an arbovirus that belongs to the Flaviviridae family and inflammatory responses play a critical role in ZIKV pathogenesis. As a first-line defense, monocytes are key components of innate immunity and host response to viruses. Monocytes are considered the earliest blood cell type to be infected by ZIKV and have been shown to be associated with ZIKV pathogenesis. The first ZIKV epidemic was reported in Africa and Asia although, it is less well known whether African- and Asian- lineages of ZIKV have different impacts on host immune response. We studied the pro-inflammatory and antiviral response of ZIKV-infected monocytes using publicly available RNA-seq analysis (GSE103114). We compared the transcriptomic profiles of human monocytes infected with ZIKV Puerto Rico strain (PRVABC59), American-Asian lineage, and ZIKV Nigeria strain (IBH30656), African lineage. We validated RNA-seq results by ELISA or RT-qPCR, in human monocytes infected with a clinical isolate of ZIKV from Colombia (American-Asian lineage), or with ZIKV from Dakar (African lineage). The transcriptomic analysis showed that ZIKV Puerto Rico strain promotes a higher pro-inflammatory response through TLR2 signaling and NF-kB activation and induces a strong IL27-dependent antiviral activity than ZIKV Nigeria strain. Furthermore, human monocytes are more susceptible to infection with ZIKV from Colombia than ZIKV from Dakar. Likewise, Colombian ZIKV isolate activated IL27 signaling and induced a robust antiviral response in an IFN-independent manner. Moreover, we show that treatment of monocytes with IL27 results in decreased release of ZIKV particles in a dose-dependent manner with an EC50 =2.870 ng/mL for ZIKV from Colombia and EC50 =10.23 ng/mL to ZIKV from Dakar. These findings highlight the differential inflammatory response and antiviral activity of monocytes infected with different lineages of ZIKV and may help better management of ZIKV-infected patients.

Asunto(s)

Interleucina-27 , Infección por el Virus Zika , Virus Zika , Humanos , Virus Zika/fisiología , Monocitos , Antivirales , Senegal , Replicación Viral

RESUMEN

Zika virus (ZIKV) is a teratogen that causes congenital anomalies, being linked to microcephaly in children exposed during pregnancy. Animal studies have been conducted to investigate the molecular mechanisms related to ZIKV teratogenesis. Although animal models can mimic the effects of ZIKV in human embryo development, few in vivo studies have addressed molecular changes following ZIKV infection in embryos. Moreover, few literature reviews have been conducted with these studies. The aim of this systematic review is to evaluate the molecular mechanisms of ZIKV teratogenesis determined from studies in animal models. PubMed/MEDLINE, EMBASE, Web of Science, and Scopus as well as grey literature were searched for studies that evaluated molecular alterations related to ZIKV teratogenesis which occurred during embryonic development. Nine studies were included: six with mice, one with mice and guinea pigs, one with pigs and one with chickens. In general, studies presented an unclear or high risk of bias for methodological criteria. Most of studies reported embryos exposed to ZIKV presenting microcephaly, reduced cortex thickness, and growth restriction. Different techniques were used to evaluated molecular changes in the animals following ZIKV infection: RNA sequencing, RT-qPCR, and in situ hybridization. It was found that common pathways are changed in most studies, being pathways related to immune response upregulated and those involved to neurodevelopment downregulated.

Asunto(s)

Microcefalia , Malformaciones del Sistema Nervioso , Teratogénesis , Infección por el Virus Zika , Virus Zika , Embarazo , Humanos , Niño , Femenino , Animales , Ratones , Cobayas , Virus Zika/fisiología , Infección por el Virus Zika/complicaciones , Pollos , Modelos Animales

RESUMEN

Zika virus (ZIKV) is a single-strand RNA mosquito-borne flavivirus with significant public health impact. ZIKV infection induces double-strand DNA breaks (DSBs) in human neural progenitor cells that may contribute to severe neuronal manifestations in newborns. The DNA-PK complex plays a critical role in repairing DSBs and in the innate immune response to infection. It is unknown, however, whether DNA-PK regulates ZIKV infection. Here we investigated the role of DNA-PKcs, the catalytic subunit of DNA-PK, during ZIKV infection. We demonstrate that DNA-PKcs restricts the spread of ZIKV infection in human epithelial cells. Increased ZIKV replication and spread in DNA-PKcs deficient cells is related to a notable decrease in transcription of type I and III interferons as well as IFIT1, IFIT2, and IL6. This was shown to be independent of IRF1, IRF3, or p65, canonical transcription factors necessary for activation of both type I and III interferon promoters. The mechanism of DNA-PKcs to restrict ZIKV infection is independent of DSB. Thus, these data suggest a non-canonical role for DNA-PK during Zika virus infection, acting downstream of IFNs transcription factors for an efficient antiviral immune response.

Asunto(s)

Infección por el Virus Zika , Virus Zika , Recién Nacido , Animales , Humanos , Virus Zika/fisiología , Replicación Viral , Interferones/farmacología , Antivirales/uso terapéutico , ADN

RESUMEN

Dengue fever, chikungunya, and zika are highly prevalent arboviruses transmitted by hematophagous arthropods, with a widely neglected impact in developing countries. These diseases cause acute illness in diverse populations, as well as potential cardiovascular complications. A systematic review was carried out to investigate the burden of cardiac involvement related to these arboviruses. Multiple databases were searched for articles that investigated the association of cardiovascular diseases with arboviruses, published up to March 2022. Relevant articles were selected and rated by two independent reviewers. Proportion meta-analysis was applied to assess the frequency-weighted mean of the cardiovascular findings. A total of 42 articles were selected (n = 76,678 individuals), with 17 manuscripts on dengue and 6 manuscripts on chikungunya undergoing meta-analysis. The global pooled incidence of cardiac events in dengue fever using a meta-analysis was 27.21% (95% CI 20.21-34.83; I2 = 94%). The higher incidence of dengue-related myocarditis was found in the population younger than 20 years old (33.85%; 95% CI 0.00-89.20; I2 = 99%). Considering the studies on chikungunya (n = 372), the global pooled incidence of cardiac involvement using a meta-analysis was 32.81% (95% CI 09.58-61.49, I2 = 96%). Two Zika studies were included that examined cases of infection by vertical transmission in Brazil, finding everything from structural changes to changes in heart rate variability that increase the risk of sudden death. In conclusion, cardiac involvement in arboviruses is not uncommon, especially in dengue fever.

Asunto(s)

Arbovirus , Fiebre Chikungunya , Dengue , Cardiopatías , Infección por el Virus Zika , Adulto , Fiebre Chikungunya/complicaciones , Fiebre Chikungunya/epidemiología , Virus Chikungunya/fisiología , Cardiopatías/complicaciones , Humanos , Adulto Joven , Virus Zika/fisiología