Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know

2016 ◽  
Vol 141 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Maria Gabriela Alvarado ◽  
David A. Schwartz
Keyword(s):  
Brain Damage ◽  
Zika Virus ◽  
Experimental Studies ◽  
Fetal Brain ◽  
Zikv Infection ◽  
Host Genetics ◽  
Fetal Infection ◽  
Congenital Zika Syndrome ◽  
Experimental Laboratory ◽  
Congenital Microcephaly

Context.—The global epidemic of Zika virus (ZIKV) infection has emerged as an important public health problem affecting pregnant women and their infants. Objectives.—To review the causal association between ZIKV infection during pregnancy and intrauterine fetal infection, microcephaly, brain damage, congenital malformation syndrome, and experimental laboratory models of fetal infection. Many questions remain regarding the risk factors, pathophysiology, epidemiology, and timing of maternal-fetal transmission and disease. These include mechanisms of fetal brain damage and microcephaly; the role of covariables, such as viral burden, duration of viremia, and host genetics, on vertical transmission; and the clinical and pathologic spectrum of congenital Zika syndrome. Additional questions include defining the potential long-term physical and neurobehavioral outcomes for infected infants, whether maternal or fetal host genetics influence the clinical outcome, and whether ZIKV infection can cause maternal morbidity. Finally, are experimental laboratory and animal models of ZIKV infection helpful in addressing maternal-fetal viral transmission and the development of congenital microcephaly? This communication provides current information and attempts to address some of these important questions. Data Sources.—Comprehensive review of published scientific literature. Conclusions.—Recent advances in epidemiology, clinical medicine, pathology, and experimental studies have provided a great amount of new information regarding vertical ZIKV transmission and the mechanisms of congenital microcephaly, brain damage, and congenital Zika syndrome in a relatively short time. However, much work still needs to be performed to more completely understand the maternal and fetal aspects of this new and emerging viral disease.

scholarly journals DNA vaccination before conception protects Zika virus–exposed pregnant macaques against prolonged viremia and improves fetal outcomes

2019 ◽  
Vol 11 (523) ◽  
pp. eaay2736 ◽  
Author(s):  
Koen K. A. Van Rompay ◽  
Rebekah I. Keesler ◽  
Amir Ardeshir ◽  
Jennifer Watanabe ◽  
Jodie Usachenko ◽  
...  
Keyword(s):  
Zika Virus ◽  
Fetal Loss ◽  
Fetal Brain ◽  
Neutralizing Antibody ◽  
Fetal Outcomes ◽  
Zikv Infection ◽  
Macaque Model ◽  
Fetal Infection ◽  
Congenital Zika Syndrome ◽  
Antibody Titers

Zika virus (ZIKV) infection of pregnant women is associated with congenital Zika syndrome (CZS) and no vaccine is available, although several are being tested in clinical trials. We tested the efficacy of ZIKV DNA vaccine VRC5283 in a rhesus macaque model of congenital ZIKV infection. Most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. In the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed if the virus is endemic. To more accurately mimic how this vaccine would be used, we immunized macaques before conception and then exposed them repeatedly to ZIKV during early and mid-gestation. In comparison to unimmunized animals, vaccinated animals had a significant reduction in peak magnitude and duration of maternal viremia, early fetal loss, fetal infection, and placental and fetal brain pathology. Vaccine-induced neutralizing antibody titers on the day of first ZIKV exposure were negatively associated with the magnitude of maternal viremia, and the absence of prolonged viremia was associated with better fetal outcomes. These data support further clinical development of ZIKV vaccine strategies to protect against negative fetal outcomes.

scholarly journals Clinical Outcomes of a Zika Virus Mother–Child Pair Cohort in Spain

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 352 ◽  
Author(s):  
Antoni Soriano-Arandes ◽  
Marie Antoinette Frick ◽  
Milagros García López-Hortelano ◽  
Elena Sulleiro ◽  
Carlota Rodó ◽  
...  
Keyword(s):  
Zika Virus ◽  
Adverse Outcomes ◽  
Zikv Infection ◽  
Child Pair ◽  
Referral Hospitals ◽  
Congenital Zika Syndrome ◽  
Endemic Areas ◽  
Neurodevelopmental Abnormalities ◽  
Congenital Microcephaly

Background: Zika virus (ZIKV) infection has been associated with congenital microcephaly and other neurodevelopmental abnormalities. There is little published research on the effect of maternal ZIKV infection in a non-endemic European region. We aimed to describe the outcomes of pregnant travelers diagnosed as ZIKV-infected in Spain, and their exposed children. Methods: This prospective observational cohort study of nine referral hospitals enrolled pregnant women (PW) who travelled to endemic areas during their pregnancy or the two previous months, or those whose sexual partners visited endemic areas in the previous 6 months. Infants of ZIKV-infected mothers were followed for about two years. Results: ZIKV infection was diagnosed in 163 PW; 112 (70%) were asymptomatic and 24 (14.7%) were confirmed cases. Among 143 infants, 14 (9.8%) had adverse outcomes during follow-up; three had a congenital Zika syndrome (CZS), and 11 other potential Zika-related outcomes. The overall incidence of CZS was 2.1% (95%CI: 0.4–6.0%), but among infants born to ZIKV-confirmed mothers, this increased to 15.8% (95%CI: 3.4–39.6%). Conclusions: A nearly 10% overall risk of neurologic and hearing adverse outcomes was found in ZIKV-exposed children born to a ZIKV-infected traveler PW. Longer-term follow-up of these children is needed to assess whether there are any later-onset manifestations.

scholarly journals Multimerization of Zika Virus-NS5 causes a ciliopathy and forces premature neurogenesis

2019 ◽  
Author(s):  
Murielle Saade ◽  
Diego S Ferrero ◽  
José Blanco-Ameijeiras ◽  
Elena Gonzalez-Gobartt ◽  
Victor M Ruiz-Arroyo ◽  
...  
Keyword(s):  
Zika Virus ◽  
Primary Cilia ◽  
Neural Progenitor Cells ◽  
Fetal Brain ◽  
Ependymal Cells ◽  
Host Proteins ◽  
Cellular Events ◽  
Neural Tissues ◽  
Congenital Zika Syndrome ◽  
Congenital Microcephaly

AbstractZika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear. Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also exhibit a severe ciliopathy. While the enzymatic activity of ZikV-NS5 appears to be dispensable, the Y25, K28 and K29 residues in the protein, that are involved in NS5-oligomerization, are essential for the localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation to develop therapies that target ZikV-NS5-multimerization, preventing the developmental malformations associated with congenital Zika syndrome

scholarly journals Is Zika Virus an Emerging TORCH Agent? An Invited Commentary

2017 ◽  
Vol 8 ◽  
pp. 1178122X1770899 ◽  
Author(s):  
Mohammad Zare Mehrjardi
Keyword(s):  
Public Health ◽  
Zika Virus ◽  
Imaging Modality ◽  
Fold Increase ◽  
Northeastern Brazil ◽  
Caribbean Region ◽  
Fetal Ultrasound ◽  
Zikv Infection ◽  
Congenital Zika Syndrome ◽  
Congenital Microcephaly

Zika virus (ZIKV) is a mosquito-borne arbovirus from the family Flaviviridae, which had caused some epidemics since its discovery in 1947 without any significant impacts on public health. In 2015, however, a 20-fold increase in congenital microcephaly cases in northeastern Brazil was attributed to prenatally acquired ZIKV infection. Traditionally, TORCH agents have 4 common characteristics including causing a mild illness in infected mother, vertical transmission to fetus, developing several anomalies in the affected fetus, and in some instances, maternal therapy may not ameliorate fetal prognosis. Prenatal ZIKV infection has shown the aforementioned characteristics during the recent epidemics in South America and the Caribbean region; therefore, it should be considered as an emerging TORCH agent that may seriously threaten public health. Fetal ultrasound can be used as a safe, inexpensive, and easy-to-access imaging modality for detecting suspicious cases of congenital Zika syndrome in utero and suggesting confirmatory diagnostic examinations to these patients.

scholarly journals Differential Type 1 IFN Gene Expression in CD14+ Placenta Cells Elicited by Zika Virus Infection During Pregnancy

2021 ◽  
Vol 1 ◽  
Author(s):  
Nicole N. Haese ◽  
Hannah Smith ◽  
Kosiso Onwuzu ◽  
Craig N. Kreklywich ◽  
Jessica L. Smith ◽  
...  
Keyword(s):  
Zika Virus ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Fetal Brain ◽  
Bioinformatic Analysis ◽  
Interferon Response ◽  
Zikv Infection ◽  
Expression Of Genes ◽  
Congenital Zika Syndrome

Zika virus (ZIKV) is an arthropod-borne Flavivirus that can also be transmitted vertically from infected mother to fetus. Infection of the fetus during pregnancy can lead to congenital malformations and severely impact fetal brain development causing a myriad of diseases now labeled Congenital Zika Syndrome (CZS). The mechanisms by which ZIKV crosses the placenta into the fetal circulation and the extent of ZIKV-induced changes remain unclear. We have previously shown that ZIKV infection of pregnant rhesus macaques results in abnormal oxygen transport across the placenta which may promote uterine vasculitis and placental villous damage. Changes in immune cell frequencies and activation status were also detected, as were distinct changes in the proportions of CD14+ cell subsets with an altered ratio of classical to non-classical CD14+ monocyte cells in both the maternal decidua and placental villous from ZIKV-infected animals compare to uninfected controls. In the current study, we performed single cell RNA sequencing on CD14+ cells isolated from the decidua of animals that were ZIKV infected at 31, 51, or 115 days of gestation (where term is ~168 days) compared to pregnant, time-matched uninfected controls. Bioinformatic analysis identified unique transcriptional phenotypes between CD14+ cells of infected and uninfected animals suggesting a distinct and sustained difference in transcriptomes between infected and uninfected CD14+ cells derived from the decidua. The timing of ZIKV infection had no effect on the CD14+ cell transcriptional profiles. Interestingly, ZIKV infection caused changes in expression of genes in pathways related to cellular stress and metabolism as well as immune response activation. Type 1 interferon response genes (ISGs) were among those that were differentially expressed following infection and these included members of the ISG12 family, IFI27 and IFI6. These ISGs have been recently described as effectors of the IFN response to flaviviruses. Supplementing our animal findings, in CD14+ cells isolated from human placenta, ZIKV infection similarly induced the expression of IFI27 and IFI6. Overall, our results showed that ZIKV infection during pregnancy induces the stable expression of antiviral genes within CD14+ cells of the placenta, which may provide an immune shield to protect the placenta from further infection and damage.

scholarly journals Risk of Zika microcephaly correlates with features of maternal antibodies

2019 ◽  
Vol 216 (10) ◽  
pp. 2302-2315 ◽  
Author(s):  
Davide F. Robbiani ◽  
Priscilla C. Olsen ◽  
Federico Costa ◽  
Qiao Wang ◽  
Thiago Y. Oliveira ◽  
...  
Keyword(s):  
Risk Factors ◽  
Antibody Response ◽  
Brain Damage ◽  
Zika Virus ◽  
Congenital Abnormalities ◽  
Serum Antibody ◽  
Fetal Brain ◽  
Maternal Antibodies ◽  
Zikv Infection ◽  
Increased Risk

Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015–2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.

scholarly journals Zika virus infection at mid-gestation results in fetal cerebral cortical injury and fetal death in the olive baboon

2018 ◽  
Author(s):  
Sunam Gurung ◽  
Nicole Reuter ◽  
Alisha Preno ◽  
Jamie Dubaut ◽  
Hugh Nadeau ◽  
...  
Keyword(s):  
Virus Infection ◽  
Zika Virus ◽  
Fetal Death ◽  
Fetal Brain ◽  
Zikv Infection ◽  
Vertical Transfer ◽  
Zika Virus Infection ◽  
Congenital Zika Syndrome ◽  
Human Primate ◽  
In Pregnancy

ABSTRACTZika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to a Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and macaques. While microcephaly has been achieved in mice via direct injection of ZIKV into the fetal brain or via interference with interferon signaling, in macaques the primary fetal CZS outcome are ocular defects. In the present study we develope the olive baboon (Papio anubis), as a model for the vertical transfer of ZIKV during pregnancy. We infected four mid-gestation, timed-pregnant baboons with the French Polynesian ZIKV isolate (104ffu) and examined the acute phase of vertical transfer by stopping the study of one dam at 7 days post infection (dpi), two at 14 dpi and one at 21 dpi. All dams exhibited mild to moderate rash and conjunctivitis; three of four dams exhibited viremia at 7 dpi. Of the three dams studied to 14 to 21 days, only one still exhibited viremia on day 14. Vertical transfer of ZIKV to the fetus was found in two pregnancies; in one, vertical transfer was associated with fetal death at ∼14 dpi. In the other, vertical transfer was observed at 21 dpi. Both fetuses had ZIKV RNA in the fetal cerebral cortex as well as other tissues. The 21 dpi fetal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, loss and or damage of immature oligodendrocytes and a loss in neuroprogenitor cells (NPCs). In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL-6 expression. The dams studied to 14 dpi (n=2) and 21 dpi (n=1) exhibited a anti-ZIKV IgM response and IgG response (21 dpi) that included transfer of the IgG to the fetal compartment (cord blood). The severity of systemic inflammatory response (cytokines and chemokines) reflected the vertical transfer of ZIKV in the two pregnancies. As such, these events likely represent the early mechanisms that lead to microcephaly and/or other CNS pathologies in a primate infected with ZIKV and are the first to be described in a non-human primate during the acute phase of ZIKV infection with a contemporaneous ZIKV strain. The baboon thus represents a major NHP for advancing as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs such as macaques.AUTHOR SUMMARYZika virus is endemic in the Americas, primarily spread through mosquitos and sexual contact. Zika virus infection during pregnancy in women is associated with a variety of fetal pathologies now referred to as Congenital Zika Syndrome (CZS), with the most severe pathology being fetal microcephaly. Developing model organisms that faithfully recreate Zika infection in humans is critical for future development of treatments and preventions. In our present study, we infected Olive baboons at mid-gestation with Zika virus and studied the acute period of viremia and transfer of Zika virus to the fetus during the first three weeks after infection to better understand the timing and mechanisms leading to CZS. We observed Zika virus transfer to fetuses resulting in fetal death in one pregnancy and in a second pregnancy, significant damage to the frontal cortex of the fetal brain consistent with development of microcephaly, closely resembling infection in pregnant women. Our baboon model differs from macaque non-human primate models where the primary fetal outcome during pregnancy following infection with contemporary strains of Zika virus is ocular pathology. Thus, the baboon provides a promising new non-human primate model to further compare and contrast the consequences of Zika virus infection in pregnancy to humans and macaques to better understand the disease.

scholarly journals Association between Genetic Variants in NOS2 and TNF Genes with Congenital Zika Syndrome and Severe Microcephaly

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 325
Author(s):  
Julia A. Gomes ◽  
Eduarda Sgarioni ◽  
Juliano A. Boquett ◽  
Ana Cláudia P. Terças-Trettel ◽  
Juliana H. da Silva ◽  
...  
Keyword(s):  
Risk Factors ◽  
Zika Virus ◽  
Genetic Variants ◽  
Educational Level ◽  
Congenital Anomalies ◽  
Family Income ◽  
First Trimester ◽  
In Utero ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in VEGFA, PTGS2, NOS3, TNF, and NOS2 genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (p < 0.001) and had mothers with lower educational level (p < 0.001) and family income (p < 0.001). We found higher risk of CZS due the allele rs2297518[A] of NOS2 (OR = 2.28, CI 95% 1.17–4.50, p = 0.015). T allele and TT/CT genotypes of the TNF rs1799724 and haplotypes associated with higher expression of TNF were more prevalent in children with CZS and severe microcephaly (p = 0.029, p = 0.041 and p = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in NOS2 and TNF genes affect the risk of CZS and severe microcephaly.

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

2018 ◽  
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.

scholarly journals Zika Virus Pathogenesis: From Early Case Reports to Epidemics

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 886 ◽  
Author(s):  
Ryan D. Pardy ◽  
Martin J. Richer
Keyword(s):  
Risk Factors ◽  
Zika Virus ◽  
Case Reports ◽  
Viral Persistence ◽  
The Body ◽  
Therapeutic Approaches ◽  
Zikv Infection ◽  
Congenital Zika Syndrome ◽  
Early Case ◽  
The Impact

For the first 60 years following its isolation, Zika virus (ZIKV) remained a relatively poorly described member of the Flaviviridae family. However, since 2007, it has caused a series of increasingly severe outbreaks and is now associated with neurological symptoms such as Guillain-Barré syndrome and congenital Zika syndrome (CZS). A number of reports have improved our understanding of rare complications that may be associated with ZIKV infection in adults, the areas of the body to which it spreads, and viral persistence in various tissues. Likewise, studies on the effect of ZIKV infection during pregnancy have identified risk factors for CZS and the impact this syndrome has on early childhood. Understanding these outcomes and the factors that drive ZIKV pathogenesis are key to developing vaccination and therapeutic approaches to avoid these severe and potentially debilitating symptoms.

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