NK Cells in Pathogenesis of Congenital Cytomegalovirus Infection (NKconCMV)

Full title: NK Cells in Pathogenesis of Congenital Cytomegalovirus Infection

Grantors: Croatian Science Foundation

Grantor’s website:   http://www.hrzz.hr/

Duration: 2018-2022

Coordinator: Dr. Ilija Brizic

Research team: Prof. Dr. Ester Pernjak Pugel.

                                Prof. Dr. Jelena Tomac

                                Dr. Berislav Lisnic

                                Dr. Durdica Cekinovic Grbesa

                                Dr. Vanda Juranic Lisnic

                                Jelena Materljan, dr. med.

                                Daria Kvestak mag. biol. mol.

                                Carmen Rozmanic mag. biol. mol.

Total funding: 993.520,00 HRK

Brief description:

Congenital human cytomegalovirus (HCMV) infection is the most common viral cause of long-term neurodevelopmental sequelae, including mental retardation, microcephaly and sensorineural hearing loss. As HCMV does not cross species barrier, we employ a mouse model in which newborn mice are infected with mouse cytomegalovirus (MCMV). In many aspects newborn mice are developmentally equivalent to the human fetus during 2nd trimester of gestation, a time period when HCMV infection in humans is most frequently acquired during pregnancy. NK cells play an important role in control of CMV infection, and adaptive features of NK cells in response to CMV infection are recently being increasingly recognized. However, the extent to which congenital CMV infection affects and shapes NK-cell mediated immunity is largely unknown. To address this issue, we will use MCMV infected newborn mice and follow the impact of infection on the maturation and functional properties of NK cells. Our preliminary results indicate that MCMV infection strongly affects the maturation of NK cells and induces NK cell exhaustion characterized by downregulation of transcription factor Eomes. The goal of this project is to characterize functional, phenotypic and transcriptional changes in NK cells following perinatal MCMV infection. Furthermore, the goal is to characterize the factors and mechanisms that induce NK cell exhaustion and to determine if NK cell exhaustion can be prevented or reverted. In addition, in the proposed study we will determine the role of NK cells in MCMV control and virus induced pathology in newborn mice. The proposed research is an important step towards better understanding of pathogenesis of congenital CMV infection, but will as well contribute to better understanding of NK cell biology in general, and especially in pathological conditions.