Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

ABSTRACT The new epidemic of Zika virus infection raises grave concerns, especially with the increasingly-recognized link between emerging cases of microcephaly and this infectious disease. Besides small cranial dimensions, there are striking morphologic anomalies in the fetal brain. Key anomalies include cortical developmental malformations and a peculiar distribution of pathologic calcifications. These potentially indicate a new pattern of congenital central nervous system infection. Methods: Eight women underwent fetal MRI. Four infants also underwent postnatal CT. Five of the women underwent amniocentesis. Results: All neonates were born with microcephaly. On fetal MRI, ventriculomegaly, marked reduction of white matter thickness, severe sylvian fissure simplification, abnormal sulcation, and diffuse volumetric loss of cerebellar hemispheres were consistently seen. On postnatal CT, diffuse subcortical and basal ganglia calcifications were observed. The Zika virus was detected in two amniocenteses by polymerase chain reaction assays. Conclusion: We hope to assist the medical community in recognizing the spectrum of encephalic changes related to congenital Zika virus infection.

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

10.1101/331108 ◽

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.

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Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities

New England Journal of Medicine ◽

10.1056/nejmoa1601824 ◽

2016 ◽

Vol 374 (22) ◽

pp. 2142-2151 ◽

Cited By ~ 547

Author(s):

Rita W. Driggers ◽

Cheng-Ying Ho ◽

Essi M. Korhonen ◽

Suvi Kuivanen ◽

Anne J. Jääskeläinen ◽

...

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Fetal Brain ◽

Brain Abnormalities ◽

Zika Virus Infection

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Placenta, Zika Virus Infection and Fetal Brain Abnormality

American Journal of Reproductive Immunology ◽

10.1111/aji.12521 ◽

2016 ◽

Vol 76 (2) ◽

pp. 97-98 ◽

Cited By ~ 14

Author(s):

Viroj Wiwanitkit

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Fetal Brain ◽

Brain Abnormality ◽

Zika Virus Infection

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Congenital Zika Virus Infection Paradigm: What is in the Wardrobe? A Narrative Review

East Africa Science ◽

10.24248/easci.v1i1.4 ◽

2019 ◽

Vol 1 (1) ◽

pp. 49-56

Author(s):

Mariam M. Mirambo ◽

Lucas Matemba ◽

Mtebe Majigo ◽

Stephen E. Mshana

Keyword(s):

Virus Infection ◽

Neural Tube ◽

Zika Virus ◽

English Language ◽

Case Reports ◽

Case Series ◽

Epidemiological Studies ◽

Ocular Manifestations ◽

Zika Virus Infection ◽

N 93

Background: Zika virus infection during pregnancy has been recently associated with congenital microcephaly and other severe neural tube defects. However, the magnitude of confirmed cases and the scope of these anomalies have not been extensively documented. This review focuses on the magnitude of laboratory-confirmed congenital Zika virus cases among probable cases and describing the patterns of congenital anomalies allegedly caused by the Zika virus, information which will inform further research in this area. Methods: We conducted a literature search for English-language articles about congenital Zika virus infection using online electronic databases (PubMed/MEDLINE, POPLINE, Embase, Google Scholar, and Web of Knowledge). The search terms used were, “zika”, “pregnancy”, [year], “microcephaly”, “infants”, “children”, “neonates”, “foetuses”, “neural tube defect”, and “CNS manifestations” in different combinations. All articles reporting cases or case series between January 2015 and December 2016 were included. Data were entered into a Microsoft Excel database and analysed to obtain proportions of the confirmed cases and patterns of anomalies. Results: A total of 24 articles (11 case series, 9 case reports, and 4 others) were found to be eligible and included in this review. These articles reported 919 cases, with or without microcephaly, presumed to have congenital Zika virus infection. Of these cases, 884 (96.2%) had microcephaly. Of the 884 cases of microcephaly, 783 (88.6%) were tested for Zika virus infection, and 216 (27.6%; 95% confidence interval, 24.5% to 30.8%) were confirmed to be Zika virus-positive. In addition to microcephaly, other common abnormalities reported – out of 442 cases investigated – were calcifications of brain tissue (n=240, 54.3%), ventriculomegaly (n=93, 20.8%), cerebellar hypoplasia (n=52, 11.7%), and ocular manifestations (n=46, 10.4%). Conclusion: Based on the available literature, Zika virus infection during pregnancy might lead to a wide array of outcomes other than microcephaly. There is a need for more epidemiological studies in Zika-endemic areas, particularly in Africa, to ascertain the role of Zika virus in causing congenital neurological defects.

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Congenital Zika Virus Infection Paradigm: What is in the Wardrobe? A Narrative Review

East Africa Science ◽

10.24248/easci.v1.iss1.4 ◽

2019 ◽

Vol 1 (1) ◽

pp. 49-56

Author(s):

Mariam M. Mirambo ◽

Lucas Matemba ◽

Mtebe Majigo ◽

Stephen E. Mshana

Keyword(s):

Virus Infection ◽

Neural Tube ◽

Zika Virus ◽

English Language ◽

Case Reports ◽

Case Series ◽

Epidemiological Studies ◽

Ocular Manifestations ◽

Zika Virus Infection ◽

N 93

Background: Zika virus infection during pregnancy has been recently associated with congenital microcephaly and other severe neural tube defects. However, the magnitude of confirmed cases and the scope of these anomalies have not been extensively documented. This review focuses on the magnitude of laboratory-confirmed congenital Zika virus cases among probable cases and describing the patterns of congenital anomalies allegedly caused by the Zika virus, information which will inform further research in this area. Methods: We conducted a literature search for English-language articles about congenital Zika virus infection using online electronic databases (PubMed/MEDLINE, POPLINE, Embase, Google Scholar, and Web of Knowledge). The search terms used were, “zika”, “pregnancy”, [year], “microcephaly”, “infants”, “children”, “neonates”, “foetuses”, “neural tube defect”, and “CNS manifestations” in different combinations. All articles reporting cases or case series between January 2015 and December 2016 were included. Data were entered into a Microsoft Excel database and analysed to obtain proportions of the confirmed cases and patterns of anomalies. Results: A total of 24 articles (11 case series, 9 case reports, and 4 others) were found to be eligible and included in this review. These articles reported 919 cases, with or without microcephaly, presumed to have congenital Zika virus infection. Of these cases, 884 (96.2%) had microcephaly. Of the 884 cases of microcephaly, 783 (88.6%) were tested for Zika virus infection, and 216 (27.6%; 95% confidence interval, 24.5% to 30.8%) were confirmed to be Zika virus-positive. In addition to microcephaly, other common abnormalities reported – out of 442 cases investigated – were calcifications of brain tissue (n=240, 54.3%), ventriculomegaly (n=93, 20.8%), cerebellar hypoplasia (n=52, 11.7%), and ocular manifestations (n=46, 10.4%). Conclusion: Based on the available literature, Zika virus infection during pregnancy might lead to a wide array of outcomes other than microcephaly. There is a need for more epidemiological studies in Zika-endemic areas, particularly in Africa, to ascertain the role of Zika virus in causing congenital neurological defects.

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