Trimester-specific Zika virus infection affects placental responses in women

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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Zika Virus Infection at Different Pregnancy Stages: Anatomopathological Findings, Target Cells and Viral Persistence in Placental Tissues

10.1101/370528 ◽

2018 ◽

Author(s):

Lucia de Noronha ◽

Camila Zanluca ◽

Marion Burger ◽

Andreia Akemi Suzukawa ◽

Marina Azevedo ◽

...

Keyword(s):

Zika Virus ◽

Congenital Malformations ◽

Acute Infection ◽

Histological Finding ◽

Placental Tissue ◽

Cell Types ◽

Target Cells ◽

Third Trimester ◽

Zikv Infection ◽

Hofbauer Cells

ABSTRACTZika virus (ZIKV) infection in humans has been associated with congenital malformations and other neurological disorders, such as Guillain-Barré syndrome. The mechanism(s) of ZIKV intrauterine transmission, the cell types involved, the most vulnerable period of pregnancy for severe outcomes from infection and other physiopathological aspects remain unknown. In this study, we analyzed placental samples obtained at the time of delivery from a group of twenty-four women diagnosed with ZIKV infection during the first, second or third trimesters of pregnancy. Villous immaturity was the main histological finding in the placental tissues, although placentas without alterations were also frequently observed. Significant enhancement of the number of syncytial sprouts was observed in the placentas of women infected during the third trimester, indicating the development of placental abnormalities after ZIKV infection. Hyperplasia of Hofbauer cells (HCs) was also observed in these third-trimester placental tissues, and remarkably, HCs were the only ZIKV-positive fetal cells found in the placentas studied that persisted until birth, as revealed by immunohistochemical (IHC) analysis. Thirty-three percent of women infected during pregnancy delivered infants with congenital abnormalities, although no pattern correlating the gestational stage at infection, the IHC positivity of HCs in placental tissues and the presence of congenital malformations at birth was observed. Placental tissue analysis enabled us to confirm maternal ZIKV infection in cases where serum from the acute infection phase was not available, which reinforces the importance of this technique in identifying possible causal factors of birth defects. The results we observed in the samples from naturally infected pregnant women may contribute to the understanding of some aspects of the pathophysiology of ZIKV.

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Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK-cell activity

10.1101/225102 ◽

2017 ◽

Cited By ~ 1

Author(s):

Fok Moon Lum ◽

David Lee ◽

Tze-Kwang Chua ◽

Jeslin J.L. Tan ◽

Cheryl Y.P. Lee ◽

...

Keyword(s):

Nk Cells ◽

Zika Virus ◽

Peripheral Blood ◽

Cellular Response ◽

Nk Cell ◽

Acute Infection ◽

Cell Activity ◽

Host Cells ◽

Nk Cell Activity ◽

Zikv Infection

AbstractZika virus (ZIKV) has re-emerged in the population and caused unprecedented global outbreaks. Here, the transcriptomic consequences of ZIKV infection were studied systematically firstly in human peripheral blood CD14+ monocytes and monocyte-derived macrophages with high density RNA-sequencing. Analyses of the ZIKV genome revealed that the virus underwent genetic diversification and differential mRNA abundance was found in host cells during infection. Notably, there was a significant change in the cellular response with crosstalk between monocytes and natural killer (NK) cells as one of the highly identified pathway. Immune-phenotyping of peripheral blood from ZIKV-infected patients further confirmed the activation of NK cells during acute infection. ZIKV infection in peripheral blood cells isolated from healthy donors led to the induction of IFNγ and CD107a — two key markers of NK-cell function. Depletion of CD14+ monocytes from peripheral blood resulted in a reduction of these markers and reduced priming of NK cells during infection. This was complemented by the immunoproteomic changes observed. Mechanistically, ZIKV infection preferentially counterbalances monocyte and/or NK-cell activity, with implications for targeted cytokine immunotherapies.

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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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Distinct cellular immune signatures in acute Zika virus infection are associated with high or low persisting neutralizing antibody titers

10.1101/2021.05.27.446054 ◽

2021 ◽

Author(s):

Elizabeth E. McCarthy ◽

Pamela M. Odorizzi ◽

Emma Lutz ◽

Carolyn P. Smullin ◽

Iliana Tenvooren ◽

...

Keyword(s):

Zika Virus ◽

Neutralizing Antibodies ◽

Viral Infections ◽

Immune Cell ◽

Acute Infection ◽

Neutralizing Antibody ◽

Natural Immunity ◽

Zikv Infection ◽

Antibody Titers ◽

Cellular Immune

Although the formation of a durable neutralizing antibody response after an acute viral infection is a key component of protective immunity, little is known about why some individuals generate high versus low neutralizing antibody titers to infection or vaccination. Infection with Zika virus (ZIKV) during pregnancy can cause devastating fetal outcomes, and efforts to understand natural immunity to this infection are essential for optimizing vaccine design. In this study, we leveraged the high-dimensional single-cell profiling capacity of mass cytometry (CyTOF) to deeply characterize the cellular immune response to acute and convalescent ZIKV infection in a cohort of blood donors in Puerto Rico incidentally found to be viremic during the 2015-2016 epidemic in the Americas. During acute ZIKV infection, we identified widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated innate immune subsets, as well as activated follicular helper CD4+ T cells and proliferating CD27-IgD- B cells, during acute infection were associated with high titers of ZIKV neutralizing antibodies at 6 months post-infection. On the other hand, low titers of ZIKV neutralizing antibodies were associated with immune features that suggested a cytotoxic-skewed immune "set-point." Our study offers insight into the cellular coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials for ZIKV and other acute viral infections aimed at inducing high titers of neutralizing antibodies.

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Embryotoxic impact of Zika virus in a rhesus macaque in vitro implantation model†

Biology of Reproduction ◽

10.1093/biolre/ioz236 ◽

2020 ◽

Vol 102 (4) ◽

pp. 806-816 ◽

Cited By ~ 4

Author(s):

Lindsey N Block ◽

Matthew T Aliota ◽

Thomas C Friedrich ◽

Michele L Schotzko ◽

Katherine D Mean ◽

...

Keyword(s):

Rhesus Macaque ◽

Pregnancy Outcomes ◽

Zika Virus ◽

Negative Impact ◽

Culture Media ◽

Blastocyst Formation ◽

Placental Development ◽

Zikv Infection ◽

The Impact

Abstract Zika virus (ZIKV) infection is associated with adverse pregnancy outcomes in humans, and infection in the first trimester can lead to miscarriage and stillbirth. Vertical and sexual transmissions of ZIKV have been demonstrated, yet the impact of infection during the initial stages of pregnancy remains unexplored. Here we defined the impact of ZIKV on early embryonic and placental development with a rhesus macaque model. During in vitro fertilization (IVF), macaque gametes were inoculated with a physiologically relevant dose of 5.48log10 plaque-forming units (PFU) of Zika virus/H.sapiens-tc/PUR/2015/PRVABC59_v3c2. Exposure at fertilization did not alter blastocyst formation rates compared to controls. To determine the impact of ZIKV exposure at implantation, hatched blastocysts were incubated with 3.26log10, 4.26log10, or 5.26log10 PFU, or not exposed to ZIKV, followed by extended embryo culture for 10 days. ZIKV exposure negatively impacted attachment, growth, and survival in comparison to controls, with exposure to 5.26log10 PFU ZIKV resulting in embryonic degeneration by day 2. Embryonic secretion of pregnancy hormones was lower in ZIKV-exposed embryos. Increasing levels of infectious virus were detected in the culture media post-exposure, suggesting that the trophectoderm is susceptible to productive ZIKV infection. These results demonstrate that ZIKV exposure severely impacts the zona-free blastocyst, whereas exposure at the time of fertilization does not hinder blastocyst formation. Overall, early stages of pregnancy may be profoundly sensitive to infection and pregnancy loss, and the negative impact of ZIKV infection on pregnancy outcomes may be underestimated.

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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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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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Persistence of Anti-Zika Virus Immunoglobulin M Antibodies in Children with Microcephaly up to Four Years after Primary Infection

10.1101/857847 ◽

2019 ◽

Author(s):

Gubio S. Campos ◽

Rejane H. Carvalho ◽

Maria da Glória Teixeira ◽

Giovanna F. Britto e Silva ◽

Carolina A. Rolo ◽

...

Keyword(s):

Zika Virus ◽

Primary Infection ◽

Immune Reaction ◽

Acute Infection ◽

Immunoglobulin M ◽

Zikv Infection ◽

Igm Antibodies ◽

Igm Antibody ◽

Antibody Persistence

AbstractZika virus (ZIKV) is a member of the flaviviridae family of virus, considered to cause acute self-limited infection in adults, though it may lead to severe complications. It is believed that ZIKV infection elicit a classical viral immune reaction, with primary IgM antibody response and secondary IgG immunity. Persistence of IgM antibodies has been identified for other viruses belonging to the same family as ZIKV. We investigated, therefore, the presence of anti-ZIKV IgM antibodies in children with microcephaly born between January 2015 and November 2018, and their parents. We have detected persistence of IgM in 22% of children with microcephaly up to four years after primary infection. Long term IgM persistence have implications for the diagnosis of acute infection. More investigation is needed in order to correctly construe the significance of anti-ZIKV IgM persistence in the population in general, and in children with microcephaly in particular. The dynamics of IgM antibody responses against ZIKV must be known and understood to avoid misinterpretation of diagnosis for acute infection, re-infection and antibody persistence.

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Fibroblast Growth Factor 2 Enhances Zika Virus Infection in Human Fetal Brain

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz073 ◽

2019 ◽

Vol 220 (8) ◽

pp. 1377-1387 ◽

Cited By ~ 10

Author(s):

Daniel Limonta ◽

Juan Jovel ◽

Anil Kumar ◽

Julia Lu ◽

Shangmei Hou ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Zika Virus ◽

Cellular Response ◽

Fetal Brain ◽

Fibroblast Growth Factor 2 ◽

Interferon Response ◽

Fibroblast Growth ◽

Human Fetal Brain ◽

Zikv Infection

Abstract Zika virus (ZIKV) is an emerging pathogen that can cause microcephaly and other neurological defects in developing fetuses. The cellular response to ZIKV in the fetal brain is not well understood. Here, we show that ZIKV infection of human fetal astrocytes (HFAs), the most abundant cell type in the brain, results in elevated expression and secretion of fibroblast growth factor 2 (FGF2). This cytokine was shown to enhance replication and spread of ZIKV in HFAs and human fetal brain explants. The proviral effect of FGF2 is likely mediated in part by suppression of the interferon response, which would represent a novel mechanism by which viruses antagonize host antiviral defenses. We posit that FGF2-enhanced virus replication in the fetal brain contributes to the neurodevelopmental disorders associated with in utero ZIKV infection. As such, targeting FGF2-dependent signaling should be explored further as a strategy to limit replication of ZIKV.

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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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