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Drugs to limit Zika virus infection and implication for maternal-fetal health.

ABSTRACT: Although the placenta has robust defense mechanisms that protect the fetus from a viral infection, some viruses can manipulate or evade these mechanisms and disrupt physiology or cross the placental barrier. It is well established that the Zika virus is capable of vertical transmission from mother to fetus and can cause malformation of the fetal central nervous system (i.e., microcephaly), as well as Guillain-Barre syndrome in adults. This review seeks to gather and assess the contributions of translational research associated with Zika virus infection, including maternal-fetal vertical transmission of the virus. Nearly 200 inhibitors that have been evaluated in vivo and/or in vitro for their therapeutic properties against the Zika virus are summarized in this review. We also review the status of current vaccine candidates. Our main objective is to provide clinically relevant information that can guide future research directions and strategies for optimized treatment and preventive care of infections caused by Zika virus or similar pathogens.

SUBMITTER: Kumar A

PROVIDER: S-EPMC10104533 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Drugs to limit Zika virus infection and implication for maternal-fetal health.

Kumar Ankur A Kumar Deepak D Jose Joyce J Giri Rajanish R Mysorekar Indira U IU

Frontiers in virology (Lausanne, Switzerland) 20220805

Although the placenta has robust defense mechanisms that protect the fetus from a viral infection, some viruses can manipulate or evade these mechanisms and disrupt physiology or cross the placental barrier. It is well established that the Zika virus is capable of vertical transmission from mother to fetus and can cause malformation of the fetal central nervous system (i.e., microcephaly), as well as Guillain-Barre syndrome in adults. This review seeks to gather and assess the contributions of t ...[more]

PMID: 37064602

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Project description:Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in vitro and in vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titers and caused more-severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here, we infected four pregnant rhesus macaques with a low-passage-number strain of African-lineage ZIKV and compared its pathogenesis to those for a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. The viral replication kinetics for the two experimental groups were not significantly different, and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1 to 1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV viral RNA (vRNA) was found in the maternal-fetal interface tissues of the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015 to 2016. In its most recent update, the WHO stated that improved understanding of African-lineage ZIKV pathogenesis during pregnancy must be a priority. The recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here, we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational nonhuman primate model. We show that African-lineage isolates replicate with kinetics similar to those of Asian-lineage isolates and can infect the placenta. However, there was no evidence of more-severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for epidemiological and translational in vivo studies with African-lineage ZIKV.

Project description:The maternal decidua is an immunologically complex environment that balances maintenance of immune tolerance to fetal paternal antigens with protection of the fetus against vertical transmission of maternal pathogens. To better understand host immune determinants of congenital infection at the maternal-fetal tissue interface, we performed a comparative analysis of innate and adaptive immune cell subsets in the peripheral blood and decidua of healthy rhesus macaque pregnancies across all trimesters of gestation and determined changes after Zika virus (ZIKV) infection. Using one 28-color and one 18-color polychromatic flow cytometry panel we simultaneously analyzed the frequency, phenotype, activation status and trafficking properties of αβ T, γδ T, iNKT, regulatory T (Treg), NK cells, B lymphocytes, monocytes, macrophages, and dendritic cells (DC). Decidual leukocytes showed a striking enrichment of activated effector memory and tissue-resident memory CD4+ and CD8+ T lymphocytes, CD4+ Tregs, CD56+ NK cells, CD14+CD16+ monocytes, CD206+ tissue-resident macrophages, and a paucity of B lymphocytes when compared to peripheral blood. t-distributed stochastic neighbor embedding (tSNE) revealed unique populations of decidual NK, T, DC and monocyte/macrophage subsets. Principal component analysis showed distinct spatial localization of decidual and circulating leukocytes contributed by NK and CD8+ T lymphocytes, and separation of decidua based on gestational age contributed by memory CD4+ and CD8+ T lymphocytes. Decidua from 10 ZIKV-infected dams obtained 16-56 days post infection at third (n=9) or second (n=1) trimester showed a significant reduction in frequency of activated, CXCR3+, and/or Granzyme B+ memory CD4+ and CD8+ T lymphocytes and γδ T compared to normal decidua. These data suggest that ZIKV induces local immunosuppression with reduced immune recruitment and impaired cytotoxicity. Our study adds to the immune characterization of the maternal-fetal interface in a translational nonhuman primate model of congenital infection and provides novel insight in to putative mechanisms of vertical transmission.

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Drugs to limit Zika virus infection and implication for maternal-fetal health.

Publications

Drugs to limit Zika virus infection and implication for maternal-fetal health.

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