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Considering Differences Between Hormone Stages in Research of the Female Reproductive Tract

The Female Reproductive System

Every month, the female reproductive system is responsible for the maturation and of an egg from one of the two ovaries. During this time, the inner lining of the uterus (or womb), called the endometrium, thickens to prepare for implantation of an embryo. Once mature, the egg is released from the ovary in a process called ovulation, and travels through the associated fallopian tube to reach the uterus where it can be fertilized. In the absence of fertilization and implantation, the endometrium and unfertilized egg are shed through the cervix (the lower portion of the uterus) and vagina in the process of menstruation.

The entire human menstrual cycle (egg maturation, ovulation, and menstruation) is tightly regulated by hormones, including estrogen, follicle-stimulating hormone, luteinizing hormone, and progesterone, which fluctuate in a well-orchestrated manner to ensure the cycle operates properly every month. Any dysfunction in this hormone cycle can lead to disruption of ovulation, which may in turn, affect fertility.

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Lifeline® Human Vaginal and Cervical Epithelial Cells in Zika Virus Research

Zika virus (ZIKV) is a mosquito-borne and sexually transmitted virus that causes birth defects in fetuses of infected pregnant women. ZIKV has become a significant health concern, with the prevalence of birth defects rising about 20-fold in 2016 from 2013-20141. A better understanding of how ZIKV infection occurs will aid the development of effective preventative measures against infection. In a new study this year in Nature Communications, Caine and colleagues set out to characterize ZIKV infection of the female reproductive tract and anti-infection responses of infected tissues. In particular, based on previous studies demonstrating that IFN-l had anti-viral activity against ZIKV in the placenta, the group focused on ZIKV-induced effects on IFN-l and IFN-l-dependent anti-viral effects in the tissues of the female reproductive tract.

            The researchers first pre-treated Lifeline® human vaginal epithelial cells and human cervical epithelial cells with IFN-l and IFN-b before infecting the cell cultures with ZIKV. They found that pre-treatment with either IFN caused a significant reduction in ZIKV infection in both cell types. Reduced infection was associated with an IFN response, confirmed by whole-genome RNA-Seq analysis of Lifeline® human vaginal epithelial cells pre-treated with IFN-l or IFN-b.

            Previous studies show that mice are more resistant to ZIKV infection during the estradiol-high estrous phase. Unlike humans, mice do not have a menstrual cycle, but an estrous cycle, which can be modeled by researchers. Using hormone-synchronized, non-pregnant, female mice lacking ovaries (OVX mice) and OVX mice with genetic deletion of the IFN-l receptor (Ifnlr1-/-), the researcher mimicked the estrous and diestrous phases of the murine estrous cycle by treating mice with estradiol (a form of estrogen) or progesterone, respectively. They found that loss of the IFN-l receptor in Ifnlr1-/- mice did not affect resistance to ZIKV infection during the estrous phase, suggesting that IFN-l signaling does not contribute to estrous phase resistance to ZIKV infection.

            To determine how IFN-l might protect the female reproductive tract against ZIKV infection, the authors measured ZIKV infection of the vagina of wild-type and Ifnlr1-/- OVX mice. Following intravaginal ZIKV infection of mice treated with progesterone or progesterone and estradiol, the authors found that progesterone-treated Ifnlr1-/- mice had increased ZIKV infection in vaginal fluid and vaginal tissue compared with wild-type mice; ZIKV infection of non-vaginal tissues (cervix, uterus, serum, brain, and spleen) was similar between the two genotypes.

In contrast, no differences in ZIKV infection of vaginal and non-vaginal tissues were observed between wild-type and Ifnlr1-/- OVX mice treated with progesterone and estradiol. This suggests that the anti-viral effects of IFN-l are hormone stage-dependent. To determine whether the hormone stage-dependent effects of IFN-l on ZIKV infection were due to differential expression of IFN-l itself, the group measured IFN-l transcripts (Ifnl2 and Ifnl3) in the vagina of OVX mice in either the diestrous (progesterone only) or proestrous (progesterone and estradiol) phases. Ifnl3 mRNA was found in mice treated with vehicle or progesterone only, suggesting that, in the absence of estradiol (which alone induces ZIKV infection resistance), IFN-l is stimulated to combat infection.

            Finally, to test whether exogenous IFN-l could temper ZIKV infection, the researchers treated wild-type OVX mice with progesterone and estradiol, as well as exogenous intravaginal pegylated IFN-l2. They showed that exogenous IFN-l2 resulted in decreased ZIKV infection in the vagina, vaginal fluid, cervix, and uterus. In addition, ZIKV infection in other non-reproductive tissues (serum, spleen, and brain) was lower in IFN-l-treated mice, suggesting that exogenous IFN-l may ameliorate the spread of ZIKV to distant tissues.

            Together, the results of this study demonstrate that IFN-l has hormone stage-dependent anti-viral activity against ZIKV infection in the vagina. Further study is needed to determine whether exogenous IFN-l can be used as a preventative intervention, but this study illustrates the importance of considering the differences between hormone stages in research related to the female reproductive tract.

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