STUDIES OF INNATE-IMMUNE RESPONSES IN THE MATERNAL-FETAL INTERFACE REVEAL DISTINCT MECHANISMS OF DEFENSE AGAINST CONGENITAL HCMV AND ZIKV INFECTIONS
2Department of Biochemistry and the Chanock center for Virology, IMRIC, Hadassah Hebrew University Medical Center, Jerusalem
3The Lautenberg Center for General and Tumor Immunology, IMRIC, Hadassah Hebrew University Medical Center, Jerusalem
4Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem
5Bioinformatics Unit of the I-CORE Computation Center, Hadassah Hebrew University Medical Center, Jerusalem
6Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan
In view of the severe outcome associated with congenital human cytomegalovirus (HCMV) infection, there is an urging need to better understand the innate mechanisms acting to limit trans-placental viral transmission. The placenta, given its critical function in protecting the developing fetus, has evolved effective, yet largely uncharacterized, innate immune barriers against invading pathogens. Recent studies, further facilitated by the Zika virus (ZIKV) epidemic, have begun to uncover the importance of these local-placental innate immune responses in the defense against congenital infections. To gain a global insight into these earliest events of viral-tissue interplay within the authentic environment of the maternal-fetal interface, we have employed HCMV infection and genome-wide transcriptome analysis in maternal-decidual (the maternal aspect of the placenta) and chorionic villi (the fetal aspect of the placenta) tissues, maintained as integral 3D organ cultures. We further compared the innate tissue-response patterns following parallel infections with HCMV and ZIKV. Notably, HCMV and ZIKV induced divergent innate responses in both maternal and fetal-derived tissues. While HCMV response was predominated by upregulation of immune-cells activation, proliferation, and cell trafficking pathways, these pathways were not significantly altered by ZIKV. Specifically, interferon (IFN)γ, that was profoundly upregulated by HCMV, was not affected by ZIKV, which rather induced the expression of type I and III IFNs. Interestingly, focusing on the most profoundly upregulated genes in the HCMV-infected decidual tissues, we have identified the activation of previously unexplored anti-HCMV innate immune mechanisms. We are currently characterizing their biological function in the defense against HCMV transmission. These studies provide a novel insight into front-line placental tissue innate responses which could mediate the outcome of congenital infection.
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