Congenital Zika Virus Syndrome Research Articles

Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection.

Fetal immune cell functions during congenital infections are poorly understood. Zika virus (ZIKV) can vertically transmit from mother to fetus, causing nervous system infection and congenital ZIKV syndrome (CZS). We identified differential functional roles for fetal monocyte/macrophage cell types and microglia in ZIKV dissemination versus clearance using mouse models. Trafficking of ZIKV-infected primitive macrophages from the yolk sac allowed initial fetal virus inoculation, while recruited monocytes promoted non-productive neuroinflammation. Conversely, brain-resident differentiated microglia were protective, limiting infection and neuronal death. Single-cell RNA sequencing identified transcriptional profiles linked to the protective versus detrimental contributions of mononuclear phagocyte subsets. In human brain organoids, microglia also promoted neuroprotective transcriptional changes and infection clearance. Thus, microglia are protective before birth, contrasting with the disease-enhancing roles of primitive macrophages and monocytes. Differential modulation of myeloid cell phenotypes by genetically divergent ZIKVs underscores the potential of immune cells to regulate diverse outcomes during fetal infections.

Prenatal Exposure to Herbicide 2,4-Dichlorophenoxyacetic Acid (2,4D) Exacerbates Zika Virus Neurotoxicity In Vitro and In Vivo.

Zika virus (ZIKV) infection during pregnancy can lead to a set of congenital malformations known as Congenital ZIKV syndrome (CZS), whose main feature is microcephaly. The geographic distribution of CZS in Brazil during the 2015-2017 outbreak was asymmetrical, with a higher prevalence in the Northeast and Central-West regions of the country, despite the ubiquitous distribution of the vector Aedes aegypti, indicating that environmental factors could influence ZIKV vertical transmission and/or severity. Here we investigate the involvement of the most used agrochemicals in Brazil with CZS. First, we exposed human neuroblastoma SK-N-AS cells to the 15 frequently used agrochemical molecules or derivative metabolites able to cross the blood-brain barrier. We found that a derived metabolite from a widely used herbicide in the Central-West region, 2,4-dichlorophenoxyacetic acid (2,4D), exacerbates ZIKV neurotoxic effects in vitro. We validate this observation by demonstrating vertical transmission leading to microcephaly in the offspring of immunocompetent C57BL/6J mice exposed to water contaminated with 0.025 mg/L of 2,4D. Newborn mice whose dams were exposed to 2,4D and infected with ZIKV presented a smaller brain area and cortical plate size compared to the control. Also, embryos from animals facing the co-insult of ZIKV and 2,4D exposition presented higher Caspase 3 positive cells in the cortex, fewer CTIP2+ neurons and proliferative cells at the ventricular zone, and a higher viral load. This phenotype is followed by placental alterations, such as vessel congestion, and apoptosis in the labyrinth and decidua. We also observed a mild spatial correlation between CZS prevalence and 2,4D use in Brazil's North and Central-West regions, with R2 = 0.4 and 0.46, respectively. Our results suggest that 2,4D exposition facilitates maternal vertical transmission of ZIKV, exacerbating CZS, possibly contributing to the high prevalence of this syndrome in Brazil's Central-West region compared to other regions.

Association between climate change and the occurrence of microcephaly due to congenital Zika virus syndrome from 2015 to 2019 in São Luís, Maranhão, Brazil.

Association between climate change and the occurrence of microcephaly due to congenital Zika virus syndrome from 2015 to 2019 in São Luís, Maranhão, Brazil.

The Relationship between HERV, Interleukin, and Transcription Factor Expression in ZIKV Infected versus Uninfected Trophoblastic Cells.

Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the placenta. This immune response counts with the participation of interleukins and transcription factors. Additionally, it has the potential involvement of human endogenous retroviruses (HERVS). Interleukins are immune response regulators that aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. HERVs are remnants of ancient viral infections that integrate into the genome and produce syncytin proteins crucial for placental development. Since ZIKV can infect trophoblast cells, we analyzed the relationship between ZIKV infection, HERV, interleukin, and transcription factor modulations in the placenta. To investigate the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asian-Brazilian) using Taqman and RT2 Profiler PCR Array assays. Our results indicate that early ZIKV infection (24-72 h) does not induce differential interleukins, transcription factors, and HERV expression. However, we show that the expression of a few of these host defense genes appears to be linked independently of ZIKV infection. Future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and transcription factors in the placenta.

Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua.

The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/- or Ifnar1+/- dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.

Infection by zika virus increase angiotensin I-converting enzyme activity in mouse brain

Congenital zika virus syndrome (CZS) has become a significant worldwide concern since the sudden rise of microcephaly related to zika virus (ZIKV) in Brazil. Primarily transmitted by Aedes mosquitoes, ZIKV shares serologic similarities with dengue virus (DENV), complicating the diagnosis and/or clinical management. The Angiotensin I-Converting Enzyme (ACE) was associated with either neuroprotective or anti-inflammatory properties in the central nervous system (CNS). The possible role(s) of ACE in these two flaviviruses infection remain largely unexplored. In this study, we evaluate ACE activity in the brain of ZIKV- or DENV-infected mice, both compared to MOCK, showing about 30 % increased ACE activity only in ZIKV-infected mice (p = 0.024), while no change was noticed in brain from DENV-infected animals (p = 0.888). In addition, the treatment with interferon beta (IFNβ), under conditions previously demonstrated to rescue the normal size of microcephalic brains determined by ZIKV infection, also restored ACE activity in ZIKV-infected animals to levels close to that of the MOCK control group. Although inflammatory responses expected for either ZIKV or DENV infections, only ZIKV was associated with microcephaly, as well as with increased ACE activity and reversion by treatment with IFNβ. Furthermore, this increase in ACE activity was observed only after intracerebroventricular (ICV) injection (F (2, 16) = 7.907, p = 0.004), but not for intraperitoneal (IP) administration of ZIKV (F (2, 26) = 1.996, p = 0.156), suggesting that the observed central ACE activity modulation may be associated with the presence of this specific flavivirus in the brain.

Association between Sleep and Language Development in Children with Congenital Zika Syndrome.

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. 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. 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. 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.

How Essential Oils Affect Children with Congenital Zika Virus Syndrome (CZVS)

Introduction: Within the field of dentistry, essential oils are well-known and extensively researched; eugenol is one of the most used, which until recently characterized the predominant smell of dental offices. Children with congenital Zika virus syndrome (CZVS) have various impairments, and in the dental area, the vast majority exhibit underdevelopment of the stomatognathic system compared to established normality standards. Many use various medications, such as anticonvulsants, muscle relaxants, sedatives, neuroleptics, among others, to control symptoms. These drug interactions can trigger involuntary muscle movements, including bruxism. There are several treatment proposals for teeth grinding and clenching, including appliance therapy, emotional therapies, medication, and also aromatherapy. Material and method: Syndromic and bruxist children were selected through validated questionnaires and clinical examination. A convenience sample of 19 syndromic children from Maceió was divided into two random groups: group 1 received a blend of essential oils, and group 2 received a control oil. They were instructed to apply it topically to the masseter, temples, and cervical area twice a day for two months. Sleep analysis was carried out through a questionnaire with 15 questions plus filling out a sleep chart for three days and collecting saliva in Salivette tubes for cortisol evaluation, with both data sets collected pre and post-use of essential oils. Discussion: Previous studies report that individuals with cognitive difficulties are more prone to bruxism due to spasticity, however, they are not definitive according to other studies. There are other factors such as stress, depression, external environmental stimuli that can influence this condition, in addition to the drug interaction they use to alleviate symptoms such as seizures, drooling, muscle spasms, muscle stiffness, insomnia. The etiology of bruxism is still considered multifactorial, requiring a multidisciplinary clinical team for more effective treatment. The use of essential oils as a stress and insomnia reliever is reported in studies with satisfactory results, being observed in this research. Result: In the finalization phase. Conclusion: Given the above, the proposal was to evaluate the efficacy of using essential oils in syndromic and bruxist children. Although we cannot confirm results yet, there are reports from mothers who evaluated the initiative positively, corroborating in some way the alleviation of symptoms and drug interactions, providing more emotional and physical comfort for those involved. However, more clinical trials are still necessary regarding the safety and efficacy aspects of essential oils.

Experience of mothers of children affected by Congenital Zika Virus Syndrome

This study aims to know the experience of mothers of children affected by Congenital Zika Virus Syndrome (CZS) in a city in northern Minas Gerais. This is a research with a qualitative approach. For the treatment of the data was performed the Content Analysis proposed by Bardin. The diagnosis of the child with CZS caused in women the loss/mourning of the idealized child and the confrontation of the reality of the real child. This new perspective demands of women, their children and their support network a new march aimed at seeking treatment and improving quality of life. The experiences reported may contribute to the qualification of health services that deal directly with children with CZS, as it can be an important tool for guiding and evaluating the management and implementation of health care aimed at the healthy development of these children and promoting the quality of life of their entire family.

Construction of exosome-loaded LL-37 and its protection against zika virus infection

Zika virus (ZIKV) is an enveloped, single-stranded and positive-stranded RNA virus of the genus Flavivirus in the family Flaviviridae. ZIKV can cross the placental barrier and infect the fetus, causing microcephaly, congenital ZIKV syndrome, and even fetal death. ZIKV infection can also lead to testicular damage and male sterility. But no effective drugs and vaccines are available up to now. Previous studies have shown that the cathelicidin antimicrobial peptide LL-37 can protect against ZIKV infection. However, LL-37 is a secreted peptide, which can be easily degraded in vivo. We herein constructed exosome-loaded LL-37 (named LL-37-TM-exo and TM-LL-37-exo) using the transmembrane protein TM to load LL-37 onto the membrane of exosome. We found that exosome-loaded LL-37 could significantly inhibit ZIKV infection in vitro and in vivo, and LL-37-TM-exo had stronger antiviral activity than that of TM-LL-37-exo, which could significantly reduce ZIKV-induced testicular injury and sperm injury, and had broad-spectrum antiviral effect. Compared to free LL-37, exosome-loaded LL-37 showed a better serum stability, higher efficiency to cross the placental barrier, and stronger antiviral activity. The mechanism of exosome-loaded LL-37 against ZIKV infection was consistent with that of free LL-37, which could directly inactivate viral particles, reduce the susceptibility of host cells, and act on viral replication stage. Our study provides a novel strategy for the development of LL-37 against viral infection.

Terapia com cães para crianças com síndrome do zika: percepção de mães e profissionais

ABSTRACT Objective: To assess the perceptions of mothers and health professionals about the dog-assisted therapy for children with congenital Zika Virus syndrome. Method: Qualitative, descriptive-exploratory research, with six mothers of children with congenital Zika Virus syndrome and six health professionals. Data were obtained at a Brazilian Specialized rehabilitation center in Paraíba, through semi-structured interviews, between February and October 2019. The empirical material was subjected to Inductive Thematic Analysis and interpreted using the Bronfenbrenner’s Bioecological Theory. Results: Dog-Assisted Therapy allowed the enhancement of skills that were previously not performed by children, such as: spontaneous hand opening, head control, improved social interaction, reduction of seizure episodes and disruption of spasticity patterns. Final considerations: Dog-Assisted Therapy was perceived as qualified, humanized and satisfactory support for the evolution of the neuropsychomotor development of children with congenital Zika Virus syndrome.

Síndrome congênita do Zika vírus: o papel da atenção primária e da rede de saúde

Abstract The article aims to understand the care network and the challenges that children with congenital Zika virus syndrome (CZS) and their caregivers face to ensure comprehensive care. This is a qualitative study, part of research carried out at the Hospital das Clínicas of the Federal University of Pernambuco, which followed 151 children suspected of having CZS. Two focus groups were carried out, one with health workers and the other with caregivers. Children with CZS travel long distances, attending various network services. Difficulty in conducting and recognizing the role of the PHC reference team was observed, resulting in fractional care, with obstacles to communication between services and lack of attention to caregivers. A fragile network was perceived, with fragmented meetings and a reduced look. It is fundamental that the efforts prioritize the strengthening of the bond between the nodes of the care and support network. The essential and derivative attributes of PHC are crucial for the network of services and the provision of care for children with CZS and their families.

Caracterização do desenvolvimento infantil e linguístico de crianças acometidas da Síndrome Congênita do Zika Vírus comparadas com crianças de desenvolvimento típico

ABSTRACT Purpose: to describe the development, focusing on language, of children affected by congenital Zika syndrome and compare it with that of typically developing children. Methods: a quantitative, observational, cross-sectional, case-control study. Data from the group of children with congenital Zika virus syndrome (case) were matched for sex and age with data from the group of typically developing children without comorbidities (control). The research included 20 parents/guardians of the children in the case group and 20 parents/guardians of the children in the control group, using interview as an adapted instrument. The data underwent descriptive and inferential statistical analysis, through association tests and comparison of means, with the significance level set at 5%. Results: there was a statistical difference in motor, auditory, and language development between the groups, according to the parents' perception. Conclusion: Based on the caregivers’ reports, most of the case group communicated non-verbally through babbling, shouting, and eye contact, whereas the minority communicated through dialogue, understood simple orders, and performed imitative behaviors, symbolic play, and shared attention. On the other hand, the control group communicated through complex sentences constructed into narratives.

The implementation of intersectoral actions to assist children with congenital Zika virus syndrome in the state of Rio de Janeiro

Resumo Este trabalho analisa as ações e parcerias estabelecidas entre os integrantes das Secretarias Estaduais de Saúde e da Assistência Social do Rio de Janeiro e outras organizações da área da saúde e assistência para atender à emergência sanitária desencadeada pela síndrome congênita do vírus Zika entre os anos de 2015 e 2018. O contexto caracterizava-se por acentuada crise econômica, erosão da capacidade de governança das autoridades políticas no estado, e reduzido conhecimento técnico-científico sobre a epidemia. Além de análise de documentos relativos ao tema, foram feitas 17 entrevistas com gestores e profissionais das duas secretarias. Roteiros semiestruturados focalizaram ações intersetoriais e processos de cooperação e coordenação inter e intraorganizacional. A grade analítica contemplou aspectos dos papéis interpessoais, informacionais e de tomada de decisão dos gestores e técnicos. Os resultados mostram que, apesar da crise política e econômica, os atores das secretarias conseguiram criar um fluxo de atenção aos pacientes. Observou-se que mecanismos informais de cooperação e coordenação foram fundamentais para a criação de estratégias intersetoriais de longo prazo.

Associations of mothers and family members affected by congenital Zika virus syndrome: profile and main related discussions

Resumo No Brasil, o impacto de emergências sanitárias consecutivas nos últimos cinco anos, como a epidemia de zika (2015) e a pandemia de Covid-19 (2020), atingiu de forma aguda as famílias de crianças com síndrome congênita do zika (SCZ). Este artigo explora processos epidêmicos que replicam as intersecções de deficiência, cuidado, gênero, classe e raça, e propõe a construção de um perfil das associações civis de mães e familiares de crianças com SCZ, bem como suas mobilizações, sobretudo da União Mães de Anjos (UMA). A partir da literatura sobre o tema, realização de entrevistas e oficinas com as mães de crianças com SCZ ligadas às associações em diferentes partes do Brasil, observou-se que as epidemias produzem impactos desiguais em relação a idade, raça, classe, gênero, localidade e deficiência. Embora os impactos das emergências de saúde possam ser contínuos para as pessoas que vivem na intersecção de múltiplas opressões, destacamos a resistência na forma de capacidade organizacional para navegar no acesso a direitos e reconfigurar dinâmicas de poder.

Congenital Zika virus syndrome: the role of primary health care and healthcare network

Resumo O artigo objetiva compreender a rede de atenção e os desafios que as crianças com síndrome congênita do Zika vírus (SCZ) e seus cuidadores enfrentam para garantir o cuidado integral. Trata-se de estudo qualitativo, parte de pesquisa desenvolvida no Hospital das Clínicas da Universidade Federal de Pernambuco, que acompanhou 151 crianças com suspeita para SCZ. Foram realizados dois grupos focais, um com trabalhadores de saúde e outro com cuidadores. As crianças com SCZ percorrem longas distâncias, frequentando diversos serviços da rede. Observou-se a dificuldade de condução e de reconhecimento do papel de equipe de referência da APS, resultando em um cuidado fracionado, com obstáculos à comunicação entre serviços e ausência de atenção às cuidadoras. Percebeu-se uma rede fragilizada, com encontros fragmentados e olhar reduzido. É fundamental que os esforços priorizem o fortalecimento do vínculo entre os nós da rede de atenção e apoio. Os atributos essenciais e derivados da APS são determinantes para a rede de serviços e a oferta de cuidados às crianças com a SCZ e seus familiares.

A implementação de ações intersetoriais na assistência a crianças com síndrome congênita do vírus Zika no estado do Rio de Janeiro

Abstract This paper focuses on the actions and partnerships established between members of the State Secretariats of Health and Social Assistance in Rio de Janeiro and other organizations in the health and assistance areas to respond to the health emergency triggered by the congenital Zika virus syndrome between 2015 and 2018. Some characteristics of the context were: a severe economic crisis, the erosion of the governance capacities of the state political authorities as well and scarce technical-scientific knowledge about the epidemic. The study was grounded on an analysis of documents related to the topic, 17 semi-structured interviews with managers and professionals from the two secretariats. Interview scripts focused on intersectoral actions and processes of cooperation and coordination within and between organizations. The analytical grid included aspects of the interpersonal, informational, and decision-making roles of managers and technicians. The results show that, despite the political and economic crisis, the Secretariat actors managed to create a flow of care for patients. Informal cooperation and coordination mechanisms were crucial for the creation of long-term intersectoral strategies.

Characterization of linguistic development of children affected by congenital Zika virus syndrome as compared to typically developing peers

RESUMO Objetivo: descrever o desenvolvimento infantil, com enfoque na linguagem, de crianças acometidas da síndrome congênita do Zika e compará-lo com o de crianças com desenvolvimento típico. Métodos: trata-se de um estudo observacional, transversal, do tipo caso-controle, e de natureza quantitativa. Os dados do grupo de crianças com Síndrome Congênita do Zika vírus (caso) foram pareados por sexo e idade com os dados do grupo de crianças sem comorbidades e desenvolvimento típico (controle). Participaram da pesquisa, 20 responsáveis pelas crianças do grupo caso e 20 pelas crianças do grupo controle e o instrumento utilizado foi uma entrevista adaptada. Os dados foram examinados por meio de uma análise estatística descritiva e inferencial por meio de testes de associação e de comparação de médias, com nível de significância de 5%. Resultados: foi observada diferença estatística entre os grupos estudados, referente ao desenvolvimento infantil, no âmbito motor, auditivo e de linguagem, com base na percepção dos pais. Conclusão: diante das informações dos cuidadores, a comunicação da maioria do grupo caso ocorre de forma não verbal por meio de gorjeios, gritos e contato visual; e a minoria comunica-se por diálogo, compreende ordens simples, realiza condutas imitativas, brincar simbólico e tem atenção compartilhada. Diferentemente, o grupo controle comunica-se por meio de frases complexas presentes em narrativas.

Respostas do sistema de saúde brasileiro à emergência do Zika vírus: as distintas estratégias adotadas pelos estados do Ceará e do Rio de Janeiro

Abstract The article analyzes the cases of health system reprogramming in response to the Zika emergency in the states of Ceará (CE) and Rio de Janeiro (RJ), from 2015 to 2017. The research was anchored in the historical and institutionalist approach and the literature on regionalization and health care networks. It involved analyzing government documents and conducting interviews with key actors mobilized in the states’ response to the epidemic. For each state, the following aspects were primarily explored: context, political-financial situation and health agenda at the time of the epidemic; and the design and implementation of responses (meanings, actors, resources, strategies and repercussions). The reprogramming of the health system in the states of CE and RJ presented different conditions and different meanings of actions, strategies, mobilized actors and developments, with a focus on care initiatives for children with Congenital Zika Virus Syndrome (SCZV). The importance of the regionalized and coordinated network was highlighted, with deconcentration of the offer of specialized services and early stimulation procedures; the coordinating and investing role of the state government; the qualification initiatives of health professionals; of the performance of research institutions in the service, production of knowledge and in the dialogue with affected families.

Fim de emergências de saúde inacabadas e as redes de cuidados com a síndrome congênita do Zika vírus

Abstract Understanding health problems as always unfinished, this article examines consequences of the declaration of the end of a health emergency on the practice of different and interconnected care networks. As part of the “Action Ethnography on Care…” research project, this is a qualitative case study of three documents produced after the announcement of the end of the Congenital Zika Virus Syndrome epidemic. It shows the contexts of narrative production involving researchers, managers/ public service workers, mothers and families of the ill, and mothers’ associations and their different perspectives about what care is. Analyses of a presentation for researchers and of a working paper for the Applied Economics Research Institute (IPEA) question the technical narrative celebrating the end of the emergency based on knowledge and health service without taking into account the relational, affective and political care (of mothers, families and associations), leaving the latter invisible. It describes the process of elaboration of a motion by the Zika Pandemic Forum, listing and systematizing action proposals produced in an explicit dialogue among participants in different care networks to approach unfinished post-emergency questions. It suggests that similar practices of dialogue between networks can promote greater inclusion and sensitivity to care that contribute to reducing suffering and defending the rights of people who continue to live daily with a syndrome or disease whose consequences persist.