Virus-specific Activating NK Cell Receptors and Their Viral Immunoevasion

Virus-specific Activating NK Cell Receptors and Their Viral Immunoevasion



Project title: Virus-specific Activating NK Cell Receptors and Their Viral Immunoevasion

Grantor: Croatian Science Foundation

Grantor’s website:

Coordinator: ProfDr. Astrid Krmpotić

Research team:

Dr. Berislav Lisnić

Dr. Vanda Juranić Lisnić

Dr. Irena Slavuljica

Dr. Johana Julia Reichel (until November 2015)

Branka Popović

Ilija Brizić

Daria Kveštak

Jelena Železnjak

Total funding: 991.460,00 HRK


Brief description:

The infection of mice with mouse cytomegalovirus (MCMV) as a model of human CMV (HCMV) infection has been particularly informative in elucidating the role of antiviral immune response. NK cells are essential in early control of CMV infection. An evolutionary struggle between NK cells and CMVs can be inferred from a numerous viral mechanisms designed to compromise NK cell function. A deeper insight was gained by studying MCMV evasion of ‘missing-self’ mechanisms and host response to this immunoevasion, illustrated by several MCMV-specific NK cell activating receptors. The work on Ly49H receptor emphasized the selective pressure imposed on the virus to generate variants no longer recognized by this receptor. Another example can be seen from the function of viral m04 protein, which binds to newly synthesized MHC-I molecules and escorts them to the cell surface to engage inhibitory Ly49 receptors. However, while m04 prevents NK cell activation by escaping ‘missing-self’ recognition, several activating Ly49 receptors also depend on its presence for their own recognition of infected cells. Beside m04, another so far unidentified viral factor is required for turning on the activating Ly49 receptors. In addition to characterization of this new viral gene, the aim of this study is to elucidate the functional significance of MCMV-specific activating Ly49 receptors and their interaction with inhibitory counterparts during primary and latent infection. Ly49 receptors in mice are functional homologues of KIR receptors in humans. Recent studies also indicate a strong impact of HCMV on the repertoire and frequency of activating KIR-expressing NK cells, suggesting their specific response to this virus. Therefore, in addition to the MCMV genes involved in ligation of activating Ly49 receptors, here we also propose study aimed to characterize HCMV gene(s) involved in ligation of activating KIRs. We expect these studies to provide new data of groundbreaking potential in the field.