Clinical and Preclinical Evidence for Adverse Neurodevelopment after Postnatal Zika Virus Infection

Although the Zika virus (ZIKV) typically causes mild or no symptoms in adults, during the 2015−2016 outbreak, ZIKV infection in pregnancy resulted in a spectrum of diseases in infants, including birth defects and neurodevelopmental disorders identified in childhood. While intense clinical and basic science research has focused on the neurodevelopmental outcomes of prenatal ZIKV infection, less is known about the consequences of infection during early life. Considering the neurotropism of ZIKV and the rapidly-developing postnatal brain, it is important to understand how infection during infancy may disrupt neurodevelopment. This paper reviews the current knowledge regarding early postnatal ZIKV infection. Emerging clinical evidence supports the hypothesis that ZIKV infection during infancy can result in negative neurologic consequences. However, clinical data regarding postnatal ZIKV infection in children are limited; as such, animal models play an important role in understanding the potential complications of ZIKV infection related to the vulnerable developing brain. Preclinical data provide insight into the potential behavioral, cognitive, and motor domains that clinical studies should examine in pediatric populations exposed to ZIKV during infancy.

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Zika viruses of both African and Asian lineages cause fetal harm in a vertical transmission model

10.1101/387118 ◽

2018 ◽

Cited By ~ 1

Author(s):

Anna S. Jaeger ◽

Reyes A. Murreita ◽

Lea R. Goren ◽

Chelsea M. Crooks ◽

Ryan V. Moriarty ◽

...

Keyword(s):

Mouse Model ◽

Vertical Transmission ◽

Birth Defects ◽

Asian American ◽

Zika Virus ◽

French Polynesia ◽

Transmission Model ◽

Foreseeable Future ◽

Zikv Infection ◽

Congenital Zika Syndrome

AbstractCongenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak 1–3. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS) 4,5. Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas 5. Here we show that African ZIKV can infect and harm fetuses and that the S139N mutation that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.

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Prevalence of individual brain and eye defects potentially related to Zika virus in pregnancy in 22 U.S. states and territories, January 2016 - June 2017

10.21203/rs.3.rs-1189990/v1 ◽

2022 ◽

Author(s):

Augustina Delaney ◽

Samantha M. Olson ◽

Nicole M. Roth ◽

Janet D. Cragan ◽

Shana Godfred-Cato ◽

...

Keyword(s):

Birth Defects ◽

Zika Virus ◽

Cortical Atrophy ◽

Zikv Infection ◽

Live Births ◽

Prevalence Estimates ◽

Surveillance Programs ◽

Prevalence Ratios ◽

Cerebral Cortical Atrophy ◽

In Pregnancy

Abstract During the Centers for Disease Control and Prevention’s Zika Virus Response, birth defects surveillance programs adapted to monitor birth defects potentially related to Zika virus (ZIKV) infection during pregnancy. Pregnancy outcomes occurring during January 2016-June 2017 in 22 U.S. states and territories were used to estimate the prevalence of those brain and eye defects potentially related to ZIKV. Jurisdictions were divided into three groups: areas with widespread ZIKV transmission, areas with limited local ZIKV transmission, and areas without local ZIKV transmission. Prevalence estimates for selected brain and eye defects and microcephaly per 10,000 live births were estimated. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for areas with widespread and limited ZIKV transmission compared to areas without local ZIKV transmission. Defects with significantly higher prevalence in areas of widespread transmission were pooled, and PRs were calculated by quarter, comparing subsequent quarters to the first quarter (January – March 2016). Nine defects had significantly higher prevalence in areas of widespread transmission. The highest PRs were seen in intracranial calcifications (PR=12.6, 95% CI [7.4, 21.3]), chorioretinal abnormalities (12.5 [7.1, 22.3]), brainstem abnormalities (9.3, [4.7, 18.4]), and cerebral/cortical atrophy (6.7, [4.2, 10.8]). The PR of the nine pooled defects was significantly higher in three quarters in areas with widespread transmission. The largest difference in prevalence was observed for defects consistently reported in infants with congenital ZIKV infection. Birth defects surveillance programs could consider monitoring a subset of birth defects potentially related to ZIKV in pregnancy.

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Trimester-specific Zika virus infection affects placental responses in women

10.1101/727081 ◽

2019 ◽

Author(s):

Fok-Moon Lum ◽

Vipin Narang ◽

Susan Hue ◽

Jie Chen ◽

Naomi McGovern ◽

...

Keyword(s):

Birth Defects ◽

Zika Virus ◽

Cellular Response ◽

Prenatal Screening ◽

Acute Infection ◽

Transcriptomic Analysis ◽

Placental Development ◽

Zikv Infection ◽

Hofbauer Cells ◽

Screening Procedures

AbstractZika virus (ZIKV) infection during pregnancy is associated with neurologic birth defects, but the effects on placental development are unclear. Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. In this study, each woman exhibited a unique immune response, but they collectively diverged from healthy controls with raised IL-1RA, IP-10, EGF and RANTES expression, and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localized to placental Hofbauer cells, the placentas showed no anatomical defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centered on differential eIF2 signaling, mitochondrial dysfunction and oxidative phosphorylation. These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.

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Risk estimates for microcephaly related to Zika virus infection - from French Polynesia to Bahia, Brazil

10.1101/051060 ◽

2016 ◽

Cited By ~ 3

Author(s):

Michael A Johansson ◽

Luis Mier-y-Teran-Romero ◽

Jennita Reefhuis ◽

Suzanne M Gilboa ◽

Susan L Hills

Keyword(s):

Virus Infection ◽

Confidence Interval ◽

Infection Rate ◽

Birth Defects ◽

Zika Virus ◽

First Trimester ◽

French Polynesia ◽

Zikv Infection ◽

Risk Estimates ◽

First Trimester Of Pregnancy

Zika virus (ZIKV) infection during pregnancy has been linked to birth defects,1 yet the magnitude of risk remains uncertain. A study of the Zika outbreak in French Polynesia estimated that the risk of microcephaly due to ZIKV infection in the first trimester of pregnancy was 0.95% (95% confidence interval: 0.34-1.91%), based on eight microcephaly cases identified retrospectively in a population of approximately 270,000 people with an estimated 66% ZIKV infection rate.2

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Host-Directed Antivirals: a Realistic Alternative to Fight Zika Virus

10.20944/preprints201807.0359.v1 ◽

2018 ◽

Author(s):

Juan-Carlos Saiz ◽

Nereida Jiménez de Oya ◽

Ana-Belén Blázquez ◽

Estela Escribano-Romero ◽

Miguel A. Martín-Acebes

Keyword(s):

Global Health ◽

Antiviral Activity ◽

Zika Virus ◽

Current Knowledge ◽

Structural Proteins ◽

Great Effort ◽

Zikv Infection ◽

Rapid Spread ◽

Viral Components ◽

Specific Antiviral Therapy

Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid spread, and an association with severe neurological and ophthalmological complications. Currently, no specific antiviral therapy against ZIKV is available, and treatments are palliative and mainly directed to symptoms relief, such as fever and rash, by administering antipyretics, anti-histamines, and fluids for dehydration. Nevertheless, lately, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from repurposing of specific compounds with known antiviral activity to the screening of libraries and of natural compounds. The identified antiviral candidates include drugs targeting viral components (structural proteins and enzymes), as well as cellular ones. Here, we present an updated review of current knowledge about anti-ZIKV strategies, focusing on host-directed antivirals as a realistic alternative to combat ZIKV infection.

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Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus

10.1101/726018 ◽

2019 ◽

Author(s):

Michelle R. Koenig ◽

Elaina Razo ◽

Ann Mitzey ◽

Christina M. Newman ◽

Dawn M. Dudley ◽

...

Keyword(s):

Birth Defects ◽

Zika Virus ◽

First Trimester ◽

Neurodevelopmental Outcomes ◽

Brain Volumes ◽

Future Studies ◽

Macaque Model ◽

Neurodevelopmental Deficits ◽

Pathway Function ◽

Quantitative Definition

AbstractCongenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

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Advances in Zika Virus–Host Cell Interaction: Current Knowledge and Future Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms20051101 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1101 ◽

Cited By ~ 14

Author(s):

Jae Lee ◽

Ok Shin

Keyword(s):

Host Cell ◽

Zika Virus ◽

Current Knowledge ◽

Cell Interaction ◽

Human Pathogens ◽

Zikv Infection ◽

In Vivo Models ◽

Host Cell Interaction

Emerging mosquito-transmitted RNA viruses, such as Zika virus (ZIKV) and Chikungunya represent human pathogens of an immense global health problem. In particular, ZIKV has emerged explosively since 2007 to cause a series of epidemics in the South Pacific and most recently in the Americas. Although typical ZIKV infections are asymptomatic, ZIKV infection during pregnancy is increasingly associated with microcephaly and other fetal developmental abnormalities. In the last few years, genomic and molecular investigations have established a remarkable progress on the pathogenic mechanisms of ZIKV infection using in vitro and in vivo models. Here, we highlight recent advances in ZIKV-host cell interaction studies, including cellular targets of ZIKV, ZIKV-mediated cell death mechanisms, host cell restriction factors that limit ZIKV replication, and immune evasion mechanisms utilized by ZIKV. Understanding of the mechanisms of ZIKV–host interaction at the cellular level will contribute crucial insights into the development of ZIKV therapeutics and vaccines.

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Insulin and the Lung: Connecting Asthma and Metabolic Syndrome

Journal of Allergy ◽

10.1155/2013/627384 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 24

Author(s):

Suchita Singh ◽

Y. S. Prakash ◽

Allan Linneberg ◽

Anurag Agrawal

Keyword(s):

Metabolic Syndrome ◽

Clinical Evidence ◽

Current Knowledge ◽

Signaling Cascades ◽

Airway Diseases ◽

Lung Structure ◽

Smooth Muscle Proliferation ◽

And Function ◽

Cellular Components ◽

Insight Into

Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin signaling provide mechanistic insight into the clinical evidence for the links between obesity, metabolic syndrome, and airway diseases, setting the stage for novel therapeutic avenues targeting these conditions.

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1873. Pregnancy and Birth Outcomes Among Colombian Women with Zika Virus Disease in 3 Surveillance Sites, Proyecto Vigilancia de Embarazadas con Zika

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.103 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S47-S47

Author(s):

Margaret (Peggy) Honein ◽

Marcela Mercado ◽

Suzanne Gilboa ◽

Diana Valencia ◽

Marcela Daza ◽

...

Keyword(s):

Pregnant Women ◽

Birth Defects ◽

Symptom Onset ◽

Zika Virus ◽

Surveillance System ◽

National Surveillance ◽

Second Trimester ◽

Zikv Infection ◽

Igm Antibodies ◽

Laboratory Evidence

Abstract Background Proyecto Vigilancia de Embarazadas con Zika (VEZ) was an intensified surveillance system built upon existing national surveillance of pregnant women with symptoms of Zika virus (ZIKV) disease and conducted in three Colombian cities with a high prevalence of Zika. This analysis of data from VEZ estimates the risk of Zika-associated birth defects among pregnant women with symptoms of ZIKV disease, and among a subset with laboratory evidence of possible ZIKV infection during pregnancy. Methods During April–November 2016, pregnant women were enrolled if they were reported to the surveillance system (Sivigila) or visited participating clinics with symptoms of ZIKV disease. Maternal and pediatric data were abstracted from prenatal care, ultrasound, and delivery records, as well as from pediatric or specialist visit records. Available maternal and infant specimens were tested for the presence of ZIKV RNA and/or anti-ZIKV immunoglobulin (IgM) antibodies. Results Of 1,223 women enrolled, 47.8% and 34.3% reported first or second trimester symptom onset, respectively. Of 381 pregnancies with maternal and/or infant specimens tested, 108 (29%) had laboratory evidence of possible ZIKV infection during pregnancy; half of these (53.3%) were positive for ZIKV RNA only, 37.4% for IgM antibodies only, and 9.3% for both. Of 1,190 of pregnancies with known outcome, 63 (5%) had Zika-associated brain or eye defects; among the subset with any laboratory evidence, 12 (11%) had Zika-associated brain or eye defects. The prevalence of Zika-associated brain or eye defects was 5.9% (35/593) and 4.5% (19/423) among pregnancies with symptom onset in the first and second trimester, respectively. Conclusion Among pregnant women with symptoms of ZIKV disease enrolled during the height of the ZIKV epidemic in Colombia, prevalence of any Zika-associated brain or eye defect was 5%, with a higher prevalence among those with laboratory evidence of possible ZIKV infection. Rapid enhancements to Colombia’s national surveillance enabled the estimation of the risk of birth defects associated with ZIKV disease in pregnancy. Disclosures All Authors: No reported Disclosures.

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Reassessment of the risk of birth defects due to Zika virus in Guadeloupe, 2016

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009048 ◽

2021 ◽

Vol 15 (3) ◽

pp. e0009048

Author(s):

Anna L. Funk ◽

Bruno Hoen ◽

Ingrid Vingdassalom ◽

Catherine Ryan ◽

Philippe Kadhel ◽

...

Keyword(s):

Pregnant Women ◽

Birth Defects ◽

Zika Virus ◽

Prospective Cohort ◽

Trial Registration ◽

Rt Pcr ◽

Zikv Infection ◽

Live Births ◽

Outbreak Period ◽

Neurological Conditions

Background In the French Territories in the Americas (FTA), the risk of birth defects possibly associated with Zika virus (ZIKV) infection was 7.0% (95%CI: 5.0 to 9.5) among foetuses/infants of 546 women with symptomatic RT-PCR confirmed ZIKV infection during pregnancy. Many of these defects were isolated measurement-based microcephaly (i.e. without any detected brain or clinical abnormalities) or mild neurological conditions. We wanted to estimate the proportion of such minor findings among live births of women who were pregnant in the same region during the outbreak period but who were not infected with ZIKV. Methods In Guadeloupe, pregnant women were recruited at the time of delivery and tested for ZIKV infection. The outcomes of live born infants of ZIKV non-infected women were compared to those of ZIKV-exposed live born infants in Guadeloupe, extracted from the FTA prospective cohort. Results Of 490 live born infants without exposure to ZIKV, 42 infants (8.6%, 95%CI: 6.2–11.4) had mild abnormalities that have been described as ‘potentially linked to ZIKV infection’; all but one of these was isolated measurement-based microcephaly. Among the 241 live born infants with ZIKV exposure, the proportion of such abnormalities, using the same definition, was similar (6.6%, 95%CI: 3.8–10.6). Conclusions Isolated anthropometric abnormalities and mild neurological conditions were as prevalent among infants with and without in-utero ZIKV exposure. If such abnormalities had not been considered as ‘potentially linked to ZIKV’ in the original prospective cohort in Guadeloupe, the overall estimate of the risk of birth defects considered due to the virus would have been significantly lower, at approximately 1.6% (95% CI: 0.4–4.1). Trial registration ClinicalTrials.gov (NCT02916732)

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