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Pathogenesis of cytomegalovirus infection in the ovaries, impact on fertility and pregnancy maintenance

Project title: Pathogenesis of cytomegalovirus infection in the ovaries, impact on fertility and pregnancy maintenance

Grantor: Croatian Science Foundation

Grantor’s website:

Coordinator: Dr. Vanda Juranić Lisnić

Research team:
Prof. Jelena Tomac
Mijo Golemac, MD
Daria Kveštak, MA

Marija Mazor, PhD

Total funding: 1.000.000,00 HRK

Brief description:

Human cytomegalovirus (HCMV) is a herpes virus that infects the majority of the world’s population. Despite efficient immune control of the virus in immunocompetent individuals, the virus permanently persists in its host in a latent state from which it can cause productive infection. Infection during pregnancy can cause pregnancy-loss or numerous long-term developmental disabilities (such as permanent hearing-loss or damage to the central nervous system). There is no effective vaccine.
Research of HCMV pathogenesis is hindered by the virus’ strict species specificity. Infection of mice with MCMV is the most widely used model for studying the biology and pathogenesis of CMV, especially in the type of research that is impossible to conduct in humans thanks to biological similarities between human and mouse CMV (MCMV). Although CMV’s ability to pass the placenta is well established, very little is known about the CMV infection of reproductive organs and its consequences. Since the major portion of the world’s population of fertile age is CMV-infected, the aim of this research proposal is to investigate the impact of CMV infection on reproductive organs and reproductive capacity. In our preliminary research we have observed strong infection of the ovary in MCMV-infected sexually mature female mice. Upon closer inspection we have observed strong infection of the ovarian stroma and corpora lutea while follicles were completely devoid of the virus. The follicles remained resistant to infection even in severely immunocompromised mice which poorly control the CMV infection and whose ovarian stroma and corpora lutea were almost completely infected. While infection of corpora lutea can negatively impact pregnancy, infection of the follicle may endanger fertility in general. Understanding the mechanisms that protect the follicle from the infection is of utmost importance as disruption of these mechanisms by infection might cause infertility. We propose to investigate resistance of ovarian follicles to CMV by investigating possible morphological and immune response factors. We plan to provide a detailed phenotypical and functional analysis of innate and adaptive immune responses of the CMV infection in the ovary. Cytokine-mediated interactions between immune cells will be investigated using transgenic and knock-out mice lacking individual components of the signalling pathways. Better understanding of immune responses and viral immune evasion strategies in the ovary is a prerequisite for the development of new treatments and for better understanding of immune responses in general.
Following ovulation, follicular granulosa cells differentiate into lutein granulosa cells that comprise corpus luteum, structure secreting progesterone, a hormone essential for pregnancy maintenance. In fact, corpora lutea are the main source of progesterone in early pregnancy while the placenta is still developing. We show that strong infection of corpora lutea and ovarian stroma results in strong reduction of serum progesterone levels and could thus negatively impact pregnancy maintenance. We thus propose to research mechanisms behind reduction in progesterone after CMV infection, impact of this reduction on the maintenance of early and late pregnancy and possibility of pregnancy rescue with exogenous progesterone application.
The proposed research is an important new step towards better understanding of pathogenesis of CMV in reproductive organs and its impact on fertility in reproductive age. Infertility is a growing problem of modern societies and thus this research is relevant from public health perspective as well.