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

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: http://www.hrzz.hr/

Coordinator: Dr. Vanda Juranić Lisnić

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

Total funding: 1.000.000,00 HRK

Brief description:

Human cytomegalovirus (HCMV) is a herpesvirus that infects the majority of world’s population [1], attacking numerous tissues and organs. Congenital CMV infection is the main cause of trans-placentally transmitted congenital infections of newborns with annual prevalence of 0.1 to 2% and can cause a wide range of structural and functional disabilities and permanent neurological sequelae such as hearing-loss, mental retardation or cerebral palsy [2]. Primary infection in the first few weeks of pregnancy may cause abortions [3-5] with so far unknown mechanism [6, 7]. CMV is also associated with stillbirths [8, 9]. Unfortunately, there is no effective vaccine while available treatments are burdened with numerous side-effects and toxicities after long-term use [10-12].

Human CMV is strictly species-specific precluding infection of experimental animals. Luckily, murine cytomegalovirus (MCMV) shares numerous biological, pathological and genetic characteristics with human CMV. Infection of mice with MCMV is one of the most commonly used model for studying biology and pathogenesis of CMV infection in research that is impossible to conduct in humans. MCMV genome is sequenced and annotated and available in bacterial artificial chromosome (BAC) which facilitates genetic manipulation. Already numerous mutants are available. Mice are most widely used experimental animals due to their small size, well characterized genome and a plethora of transgenic and knock-out strains readily available.

CMV’s success as persistent pathogen is a consequence of its numerous viral subversion mechanisms. CMVs have dedicated large portions of their genome towards encoding immune-evasive genes targeting nearly every aspect and arm of the immune system [13]: from cells and mechanisms of innate immunity such are interferon responses [14], programmed cell death [15], myeloid cells [16] and NK cells [17] to various mechanisms targeting adaptive immune responses [18]. MCMV as a model for HCMV infection has played an immense role in the discovery of this virus’ numerous immune-evasive roles and in elucidation of pathogenesis of congenital CMV infection [19].

CMV readily infects numerous tissues and organs thanks to its wide cell tropism: the virus easily infects many parenchymal, connective and hematopoietic cells while epithelial, endothelial, smooth muscle and fibroblast cells support viral replication [20]. Although replication and pathogenesis of MCMV is well described for many organs, very little is known about infection and pathogenesis in the ovaries.

In this project we will provide the first and detailed information about CMV’s replication in the ovaries and impact of CMV infection on fertility and pregnancy maintenance and an in-depth analysis of the immune responses to infection and phenotype of the involved immune cells. The proposed research is important not only from clinical but also from a public health perspective considering that infertility is a growing problem of modern societies.

References

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