Thursday, 15 December 2016 14:13

Zika virus placental infection differs in maternal- and fetal-derived tissues

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Published in mBiosphere

The World Health Organization downgraded the spread of Zika virus from a Public Health Emergency of International Concern on November 22nd, but Zika virus infection remains an important emerging infection with an incompletely understood infection cycle. The better scientists understand how the virus infects its human hosts, the more likely they are to understand and control the long-term effects of infection, including microcephaly. A new report in the Journal of Virology demonstrates that Zika virus can infect the maternal uterine lining, and that this infection has a distinct effect on the immune response from other viral infections.

Click here to read the Journal of Virology report.

JVI Fig 1Schematic of maternal-fetal interface in the placenta, with potential Zika virus route of transmission. Source.

The study, performed by Yiska Weisblum, Esther Oiknine-Dijan, and a large team of scientists led by Dana Wolf, was designed to better understand the transmission of Zika from infected mother to fetus. The placenta is a complex environment made of both maternal and fetal tissues (referred to as decidua, or uterine lining/implantation site, and chorionic-villi, respectively; see figure, right). While other scientists have looked at in vitro cell lines to show that Zika virus can infect placental cell types, including placental macrophages and chorionic villi cytotrophoblasts, these previous studies haven’t demonstrated the potential of maternal decidua for transmitting Zika virus to the fetal tissue.

To address this issue, the scientific team studied Zika virus infection in an ex vivo three-dimensional organ culture, a model that has helped scientists better understand congenital viral transmission of other viruses, including human cytomegalovirus (HCMV). Viral genomic measurements showed that Zika virus spread efficiently through both first-trimester decidual tissue and chorionic-villi. Rates for viral replication were similar between both African and Asian lineages of the virus (the current epidemic is being caused by the Asian lineage). The same tissue types supported HCMV infection as well, though with different kinetics thought to be due to viral replication time and mechanisms.

The scientists then investigated viral replication in mid-gestational tissues, which showed different replication patterns: while the maternal decidual tissue supported similar levels of Zika virus replication, the chorionic villi from this stage were less susceptible to infection. Zika-infected tissue patterns differed from HCMV-infected tissues, in which robust viral replication was observed at both early- and mid-gestational timepoints.

Why might gestational time be a factor for infection outcome? Zika virus infection is most strongly associated with adverse pregnancy outcomes in early pregnancy, but infection during later pregnancy can also impact fetal health. Understanding the cell type to support viral infection, and when these cell types are susceptible, can help scientists better target the source of infection and prevent fetal infection.

Exactly how Zika virus crosses the placental barrier is still uncertain. As previous groups have observed, the scientific team found no Zika virus replication in the syncytiotrophoblast cell layer that directly interacts with maternal blood, failing to explain how Zika virus infection in maternal tissue could transfer to fetal cells. The authors suggest that maternal decidual tissue interactions with fetal tissue could transfer the virus, and their suggestion is supported by the robust viral replication observed in the maternal decidua. This could be especially important at later gestational stages, when decidual tissues support greater virus reproduction than fetal chorionic villi tissues.

JVI Fig 2Differential induction of interferons by Zika and HCMV infection in maternal and placental tissue. Source.

The team next addressed the question of how viral infection in different tissues could affect the immune response through gene expression experiments. The experiment compared uninfected tissues to tissues infected with either Zika or HCMV, using both the decidual and chorionic-villi tissues. In maternal decidual tissue, HCMV infection increased the expression of a number of immune-associated genes that were not increased in Zika virus-infected tissues, including interferon-related genes. IFNγ expression increased 78-fold with HCMV infection but not at all following Zika virus infection; Zika infection increased IFNα, IFNβ, and IFNλ expression while HCMV had little effect.

In chorionic-villi tissues, similar divergent cytokine responses were upregulated, with Zika virus again increasing expression of IFNα, IFNβ, and IFNλ (but not IFNγ) and HCMV increasing expression of other cytokines. Additionally, chorionic villi responses to Zika infection were enriched for transcripts associated with apoptosis, cell death, and necrosis, compared to the HCMV-upregulated transcripts associated with leukocyte migration, mobilization, and homing functions.

These experiments lay out the groundwork for future experiments into the mechanism of Zika infection-mediated birth defects. Zika virus-infected tissues fail to induce the key antiviral cytokine IFNγ as well as other key markers of immune cell activation and proliferation that were induced by HCMV infection, and in fetal-derived chorionic villi, Zika virus induced apoptosis and cell death pathways. While this research doesn’t draw a straight line to clinical outcomes, this direct damage due to viral infection may be part of the reason Zika manifests in fetal damage.

Importantly, this research also establishes the ex vivo model as a way to investigate Zika virus interaction in complex tissues composed of multiple cell types. With luck, it will help future research discoveries about the poorly understood transmission of Zika virus and other vertically transmitted viruses to build better treatment and prevention measures. 

Photo credit: Zika virus 3D model

Last modified on Thursday, 15 December 2016 14:28
Julie Wolf

ASM Communications Social Media Specialist Julie Wolf spent her research career focused on medical mycology and infectious disease. Broadly interested in microbiology and scientific communication, she has taught at Long Island University and the community biolab Genspace and has written for the Scientista Foundation and Scholastic’s Science World magazine. Follow her on Twitter for more ASM and Microbiology highlights at @JulieMarieWolf.

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