Congenital Zika Virus Infection Research Articles

The Interplay Between Spasticity and Clinical Variables in Children with Congenital Zika Virus Infection (P1-15.003)

The Interplay Between Spasticity and Clinical Variables in Children with Congenital Zika Virus Infection (P1-15.003)

Congenital Zika virus infection impacts on male mouse offspring's reproductive biology.

Congenital ZIKV infection promotes alarming effects on male offspring's reproductive biology. This study showed the presence of the ZIKV antigen in the testis parenchyma, decreased testosterone levels, and sperm abnormalities in male offspring born to infected mothers. Infection with ZIKV during pregnancy is associated with fetal developmental problems. Although neurological issues are being explored more in experimental studies, limited research has focused on the reproductive health consequences for offspring born to infected mothers. In this context, this study aimed to assess the impact of ZIKV infection during pregnancy on the testes and sperm of adult male offspring. Female mice were intraperitoneally inoculated with a Brazil strain of ZIKV during the 5.5th day of embryonic gestation. The offspring were evaluated 12 weeks after birth to analyze cellular and molecular changes in the testes and sperm. A novel approach combining variable-angle spectroscopic ellipsometry and machine learning modeling was also introduced for sperm sample analysis. The study revealed the presence of ZIKV protein in the testis parenchyma of adult male offspring born to infected mothers. It was shown that the testes exhibited altered steroidogenesis and inflammatory mediators, in addition to significant issues with spermiogenesis that resulted in sperm with DNA fragmentation, head defects, and protamination failure. Additionally, sperm dielectric properties and artificial intelligence showed potential for rapid identification and classification of sperm samples from infected mice. These findings provide crucial insights into the reproductive risks for men born from ZIKV-infected pregnant women.

Population-based surveillance for birth defects potentially related to Zika virus infection including 3-year mortality and developmental outcomes, and Early Intervention Program service use-New York City, 2016 birth cohort.

In response to the 2015-2017 Zika virus outbreak, New York City (NYC) identified and monitored infants with birth defects potentially related to congenital Zika virus. Administrative data matches were used to describe the birth characteristics of children born in 2016 meeting screening criteria for birth defects potentially related to congenital Zika virus infection relative to other NYC births and to monitor mortality and Early Intervention Program use through age 2. Among 120,367 children born in NYC in 2016, 463 met screening criteria and 155 met the Centers for Disease Control and Prevention's case definition for birth defects potentially related to congenital Zika virus infection (1.3 per 1000; 95% confidence interval [CI], 1.1-1.5). Post-neonatal deaths occurred among 7.7% of cases (12) and 5.2% of non-cases (8). Odds of referral to the Early intervention Program among children who met screening criteria were lower among children of mothers who were married (OR, 0.60; 95% CI, 0.37-0.97) and among children not classified as cases whose mothers were born in Latin America and the Caribbean (OR, 0.59; 95% CI, 0.37-1.09). Prevalence of birth defects potentially related to congenital Zika virus infection was similar to that seen in other jurisdictions without local transmission. Birth defects attributable to congenital Zika virus infection may also have been present among screened children who did not meet the case definition.

Neuroinflammation, blood-brain barrier dysfunction, hippocampal atrophy and delayed neurodevelopment: Contributions for a rat model of congenital Zika syndrome

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.

Avaliação do processo maturacional auditivo em crianças portadoras da síndrome da infecção congênita pelo Zika vírus

ABSTRACT Purpose: to analyze the absolute latencies of waves I. III and V and the interpeak intervals I-III. III-V and I-V of the ABR recorded from different age groups of children with congenital zika virus infection and their peers without risk indicators for hearing impairment. Methods: 84 newborns and infants (N=51 study group and N=33 control group) divided into groups with different post-conceptual ages. with the results of their hearing exams analyzed by age group and compared with their peers without other risk indicators for hearing impairment. The assessment of the auditory pathway was conducted through tympanometry. otoacoustic emissions and auditory brain stem responses. Results: only the latency of wave I and the interpeak III-V showed no significant difference between the study and control groups. The absolute latency and interpeak values found in the study group were significantly lower than those found in the control group. Conclusion: the maturation of the brain stem in children with ZIKV infection occurred within normal limits. with no retrocochlear disorders until the age of 5 years.

Perinatal characteristics and longer-term outcomes in Brazilian children with confirmed or suspected congenital Zika infection: ZIKAction Paediatric Registry.

Despite growing scientific knowledge of Zika virus (ZIKV) infection, questions remain regarding ZIKV infection in pregnancy and congenital ZIKV syndrome (CZS). The ZIKAction Paediatric Registry is an international registry of children with documented ZIKV exposure in utero and/or with confirmed or suspected CZS. Its aim is to characterize these children (i.e., clinical, radiological, neurodevelopmental features) and describe outcomes, longer-term sequelae and management through retrospective case note review. This analysis described the maternal and perinatal characteristics of children in the Registry's Bahia arm, assessed their neuroimaging, ophthalmic, hearing and electroencephalography abnormalities by microcephaly classification and reported on hospitalisations. Children born in 2015-2018 and enrolled 2020-2021 in three public health facilities in Salvador were included. Of 129 (57% female) children, 15 (11·6%) had laboratory-confirmed congenital ZIKV infection and 114 (88·4%) suspected CZS. At delivery, 15 (11·6%) were normocephalic, 30 (23·3%) moderately microcephalic, and 84 (65·1%) severely microcephalic. Median birth head circumference z-score was -3·51 [IQR, -4·69,-2·73]. During follow-up, all children had abnormal neuroimaging, 80·3% (94/117) abnormal electroencephalogram, 62·2% (77/120) ophthalmic abnormalities, and 27·4% (34/124) hearing impairment. Microcephaly classification was significantly associated with gestational age, and ophthalmological and electroencephalography abnormalities. Of 125 children with hospitalisation data, 52 (41·6%) had been hospitalised by most recent follow-up, at median age of 15·8 [4·0, 34·4] months; infections were the leading cause. Congenital ZIKV infection is an emerging disease with a varied and incompletely understood spectrum. Continued long-term follow-up is essential to understand longer-term prognosis and to inform future health and educational needs.

Changes in ADAR RNA editing patterns in CMV and ZIKV congenital infections

BackgroundRNA editing is a process that increases transcriptome diversity, often through Adenosine Deaminases Acting on RNA (ADARs) that catalyze the deamination of adenosine to inosine. ADAR editing plays an important role in regulating brain function and immune activation, and is dynamically regulated during brain development. Additionally, the ADAR1 p150 isoform is induced by interferons in viral infection and plays a role in antiviral immune response. However, the question of how virus-induced ADAR expression affects host transcriptome editing remains largely unanswered. This question is particularly relevant in the context of congenital infections, given the dynamic regulation of ADAR editing during brain development, the importance of this editing for brain function, and subsequent neurological symptoms of such infections, including microcephaly, sensory issues, and other neurodevelopmental abnormalities. Here, we begin to address this question, examining ADAR expression in publicly available datasets of congenital infections of human cytomegalovirus (HCMV) microarray expression data, as well as mouse cytomegalovirus (MCMV) and mouse/ human induced pluripotent neuroprogenitor stem cell (hiNPC) Zika virus (ZIKV) RNA-seq data.ResultsWe found that in all three datasets, ADAR1 was overexpressed in infected samples compared to uninfected samples. In the RNA-seq datasets, editing rates were also analyzed. In all mouse infections cases, the number of editing sites was significantly increased in infected samples, albeit this was not the case for hiNPC ZIKV samples. Mouse ZIKV samples showed altered editing of well-established protein-recoding sites such as Gria3, Grik5, and Nova1, as well as editing sites that may impact miRNA binding.ConclusionsOur findings provide evidence for changes in ADAR expression and subsequent dysregulation of ADAR editing of host transcriptomes in congenital infections. These changes in editing patterns of key neural genes have potential significance in the development of neurological symptoms, thus contributing to neurodevelopmental abnormalities. Further experiments should be performed to explore the full range of editing changes that occur in different congenital infections, and to confirm the specific functional consequences of these editing changes.

Zika virus infection leads to hormone deficiencies of the hypothalamic-pituitary-gonadal axis and diminished fertility in mice.

Zika virus (ZIKV) infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in children without microcephaly. However, the consequences of congenital ZIKV infection on fertility in these children remain unclear. Here, using an immunocompetent mouse model, we reveal that congenital ZIKV infection can cause hormonal disorders of the hypothalamic-pituitary-gonadal axis, leading to reduced fertility and decreased sexual preference. Our study has for the first time linked the hypothalamus to the reproductive system and social behaviors after ZIKV infection. Although the extent to which these observations in mice translate to humans remains unclear, these findings did suggest that the reproductive health and hormone levels of ZIKV-exposed children should receive more attention to improve their living quality.

A Birth Cohort Follow-Up Study on Congenital Zika Virus Infection in Vietnam.

We assessed the development, sensory status, and brain structure of children with congenital Zika virus (ZIKV) infection (CZI) at two years and preschool age. CZI was defined as either ZIKV RNA detection or positive ZIKV IgM and neutralization test in the cord or neonatal blood. Twelve children with CZI born in 2017-2018 in Vietnam, including one with Down syndrome, were assessed at 23-25.5 months of age, using Ages and Stages Questionnaire (ASQ-3), ASQ:Social-Emotional (ASQ:SE-2), Modified Checklist for Autism in Toddlers, automated auditory brainstem response (AABR), and Spot Vision Screener (SVS). They underwent brain CT and MRI. They had detailed ophthalmological examinations, ASQ-3, and ASQ:SE-2 at 51-62 months of age. None had birthweight or head circumference z-score < -3 except for the one with Down syndrome. All tests passed AABR (n = 10). No ophthalmological problems were detected by SVS (n = 10) and detailed examinations (n = 6), except for a girl's astigmatism. Communication and problem-solving domains in a boy at 24 months, gross-motor area in a boy, and gross-motor and fine-motor areas in another boy at 59-61 months were in the referral zone. Brain CT (n = 8) and MRI (n = 6) revealed no abnormalities in the cerebrum, cerebellum, or brainstem other than cerebellar hypoplasia with Down syndrome. The CZI children were almost age-appropriately developed with no brain or eye abnormalities. Careful and longer follow-up is necessary for children with CZI.

Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly

Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.

Infection of the maternal-fetal interface and vertical transmission following low-dose inoculation of pregnant rhesus macaques (Macaca mulatta) with an African-lineage Zika virus.

Congenital Zika virus (ZIKV) infection can result in birth defects, including malformations in the fetal brain and visual system. There are two distinct genetic lineages of ZIKV: African and Asian. Asian-lineage ZIKVs have been associated with adverse pregnancy outcomes in humans; however, recent evidence from experimental models suggests that African-lineage viruses can also be vertically transmitted and cause fetal harm. To evaluate the pathway of vertical transmission of African-lineage ZIKV, we inoculated nine pregnant rhesus macaques (Macaca mulatta) subcutaneously with 44 plaque-forming units of a ZIKV strain from Senegal, (ZIKV-DAK). Dams were inoculated either at gestational day 30 or 45. Following maternal inoculation, pregnancies were surgically terminated seven or 14 days later and fetal and maternal-fetal interface tissues were collected and evaluated. Infection in the dams was evaluated via plasma viremia and neutralizing antibody titers pre- and post- ZIKV inoculation. All dams became productively infected and developed strong neutralizing antibody responses. ZIKV RNA was detected in maternal-fetal interface tissues (placenta, decidua, and fetal membranes) by RT-qPCR and in situ hybridization. In situ hybridization detected ZIKV predominantly in the decidua and revealed that the fetal membranes may play a role in ZIKV vertical transmission. Infectious ZIKV was detected in the amniotic fluid of three pregnancies and one fetus had ZIKV RNA detected in multiple tissues. No significant pathology was observed in any fetus; and ZIKV did not have a substantial effect on the placenta. This study demonstrates that a very low dose of African-lineage ZIKV can be vertically transmitted to the macaque fetus during pregnancy. The low inoculating dose used in this study suggests a low minimal infectious dose for rhesus macaques. Vertical transmission with a low dose in macaques further supports the high epidemic potential of African ZIKV strains.

Zika Virus affects neurobehavioral development, and causes oxidative stress associated to blood–brain barrier disruption in a rat model of congenital infection

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 β_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.

Zika Virus from the Perspective of Observational Studies: a Review.

Since 1952 when Zika Virus (ZIKV): a Flavivirus, was first discovered in humans, it has not received enough scientific research compared to some of the other members of the family Flaviviridae; like Dengue Virus (DENV). However, this has not stopped the virus from infecting the human population globally. In particular, the global spread of ZIKV has led to a surge in observational studies. Regarding recently published ZIKV-related literature, we are not aware of any reviews strictly focusing on ZIKV from the perspective of observational studies. Therefore, we reviewed recently published observational studies exploring the global spread of ZIKV and its association with Congenital ZIKV Infection (CZI) and clinical manifestations in adults. Online databases including google scholar, PubMed and Elsevier were used for retrieving relevant studies. ZIKV cases have been reported in different parts of the world, with certain regions reporting more cases than the rest, like Brazil. ZIKV causes a wide spectrum of diseases and disorders including microcephaly, developmental disorders, and Guillain-Barre syndrome to name a few. Furthermore, CZI in neonates mainly manifests into neurological disorders and diseases, whereas ZIKV in adults' targets various organs. ZIKV poses a serious threat to human population and observational studies provide a different perspective on the damaging capabilities of ZIKV in real-life settings. Moreover, there are gaps in the literature regarding ZIKV-related-complications that future experimental studies need to address. These complications include in-utero transmission, Guillain-Barre syndrome, cross-reactivity, sexual transmission, along with its persistence in the male reproductive tract.

Evaluation of the immunogenicity and efficacy of an rVSV vaccine against Zika virus infection in macaca nemestrina.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes an acute febrile illness. ZIKV can be transmitted between sexual partners and from mother to fetus. Infection is strongly associated with neurologic complications in adults, including Guillain-Barré syndrome and myelitis, and congenital ZIKV infection can result in fetal injury and congenital Zika syndrome (CZS). Development of an effective vaccine is imperative to protect against ZIKV vertical transmission and CZS. Recombinant Vesicular Stomatitis virus (rVSV) is a highly effective and safe vector for the delivery of foreign immunogens for vaccine purposes. Here, we evaluate an rVSV vaccine expressing the full length pre-membrane (prM) and ZIKV envelope (E) proteins (VSV-ZprME), shown to be immunogenic in murine models of ZIKV infection, for its capacity to induce immune responses in nonhuman primates. Moreover, we assess the efficacy of the rVSVΔM-ZprME vaccine in the protection of pigtail macaques against ZIKV infection. Administration of the rVSVΔM-ZprME vaccine was safe, but it did not induce robust anti-ZIKV T-cell responses, IgM or IgG antibodies, or neutralizing antibodies in most animals. Post ZIKV challenge, animals that received the rVSVΔM control vaccine lacking ZIKV antigen had higher levels of plasma viremia compared to animals that received the rVSVΔM-ZprME vaccine. Anti-ZIKV neutralizing Ab titers were detected in a single animal that received the rVSVΔM-ZprME vaccine that was associated with reduced plasma viremia. The overall suboptimal ZIKV-specific cellular and humoral responses post-immunization indicates the rVSVΔM-ZprME vaccine did not elicit an immune response in this pilot study. However, recall antibody response to the rVSVΔM-ZprME vaccine indicates it may be immunogenic and further developments to the vaccine construct could enhance its potential as a vaccine candidate in a nonhuman primate pre-clinical model.

Identification of desoxyrhapontigenin as a novel antiviral agent against congenital Zika virus infection

Zika virus (ZIKV) infection arises as a global health threat owing to its association with Guillain-Barre syndrome and microcephaly in adults and fetuses since the most recent epidemics. Although extraordinary efforts have been underway globally to identify safe and effective treatments for ZIKV, therapeutic progressions seem to remain stagnant, especially for treating congenital ZIKV infection. Bio-compounds from medicinal plants evolutionarily optimized as drug-like molecules offer eligible sources of pharmaceuticals and lead drugs to fight against viral infections. Here, we identified desoxyrhapontigenin (DES), a naturally occurring bioactive product, as the strongest inhibitory compound against ZIKV infection among six conventional polyphenols in vitro. We also leveraged the trophoblast cell line, human trophoblast stem cells, and complex placental organoid models to provide solid evidence to support the anti-ZIKV bioactivity of DES. Notably, DES treatment effectively reduced the ZIKV burden in serum and target tissues, and correspondingly improved ZIKV-induced pathologic changes including weight loss, tissue inflammation, cell apoptosis, and adverse pregnancy outcomes, while it did not lead to obvious toxicity in both adult and pregnant mice. Furthermore, mechanistic studies revealed that DES could suppress ZIKV entry via dual mechanisms of direct targeting ZIKV E proteins and downregulating putative ZIKV receptors. These findings elucidate a previously unappreciated protective role of desoxyrhapontigenin against ZIKV infection both in vitro and in vivo, which shed light on the development of a novel and potent treatment for congenital ZIKV infection.

Microcephaly in South Brazil: Are cases of Congenital Zika Syndrome increasing in recent years?

Northeast Brazil was the first region to detect a significant increase in babies born with microcephaly associated with prenatal zika virus infection in 2015. Rio Grande do Sul (RS) state was less impacted due to the temperate climate preventing the spread of the vector. This study investigated the prevalence and etiology of congenital microcephaly in RS in two different periods. This cross-sectional descriptive study included all live births with congenital microcephaly in RS from 2015 to 2022. Cases were divided into two groups: P1 "outbreak" (2015-16); and P2 "endemic" (2017-22). There were 58 cases of microcephaly (3.8/10,000) in P1 and 148 (1.97/10,000) in P2. Congenital Zika Virus infection was the etiology in 5.2% (n=3) in P1 and 6.7% (n=10) in P2. In conclusion, although the ZIKV outbreak in Brazil has receded, RS remains an area of concern, with a possible slight increase of live births with microcephaly secondary to ZIKV prenatal infection relative to the number of cases due to congenital infections. The broader distribution of the vector Aedes aegypti with warmer temperatures in our state might be linked to the increase in recent years. This study can be an alert to other regions of temperate or subtropical climates.

Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: An individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts Consortium.

Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%.

Differential Susceptibility of Fetal Retinal Pigment Epithelial Cells, hiPSC- Retinal Stem Cells, and Retinal Organoids to Zika Virus Infection.

Zika virus (ZIKV) causes microcephaly and congenital eye disease. The cellular and molecular basis of congenital ZIKV infection are not well understood. Here, we utilized a biologically relevant cell-based system of human fetal retinal pigment epithelial cells (FRPEs), hiPSC-derived retinal stem cells (iRSCs), and retinal organoids to investigate ZIKV-mediated ocular cell injury processes. Our data show that FRPEs were highly susceptible to ZIKV infection exhibiting increased apoptosis, whereas iRSCs showed reduced susceptibility. Detailed transcriptomics and proteomics analyses of infected FRPEs were performed. Nucleoside analogue drug treatment inhibited ZIKV replication. Retinal organoids were susceptible to ZIKV infection. The Asian genotype ZIKV exhibited higher infectivity, induced profound inflammatory response, and dysregulated transcription factors involved in retinal organoid differentiation. Collectively, our study shows that ZIKV affects ocular cells at different developmental stages resulting in cellular injury and death, further providing molecular insight into the pathogenesis of congenital eye disease.

Acquired Hip Dysplasia in Children with Congenital Zika Virus Infection in the First Four Years of Life.

Acquired hip dysplasia has been described in children with cerebral palsy (CP); periodic surveillance is recommended in this population to prevent hip displacement and dislocation. Children with congenital zika syndrome (CZS) may present a spectrum of neurological impairments with changes in tonus, posture, and movement similar to children with CP. However, the relationship between CZS and hip dysplasia has not been characterized. In this prospective cohort study, we aimed to describe the occurrence of hip dysplasia in patients with CZS. Sixty-four children with CZS from 6 to 48 months of age were included and followed at a tertiary referral center in Rio de Janeiro, Brazil, with periodic radiologic and clinical hip assessments. Twenty-six (41%) patients were diagnosed with hip dysplasia during follow-up; mean age at diagnosis was 23 months. According to the Gross Motor Function Classification System (GMFCS), 58 (91%) patients had severe impairment (GMFCS IV and V) at the first evaluation. All patients with progression to hip dysplasia had microcephaly and were classified as GMFCS IV or V. Pain and functional limitation were reported by 22 (84%) caregivers of children with hip dysplasia. All patients were referred to specialized orthopedic care; eight (31%) underwent surgical treatment during follow-up. Our findings highlight the importance of implementing a hip surveillance program and improving access to orthopedic treatment for children with CZS in order to decrease the chances of dysplasia-related complications and improve quality of life.

A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specificIgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.