The role of CMV-encoded IgG binding glycoproteins in diaplacental virus transmission

• Applicant: Dr. Philipp Kolb
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524728597

Congenital HCMV infection (cCMV) is one of the most devastating complications during pregnancy worldwide. As there is no vaccine available and administration of antiviral chemotherapeutics against HCMV during pregnancy is fraught with safety problems, the development of antibody-based intervention strategies has been at the center of recent clinical studies aiming for the prevention or treatment of cCMV. One major roadblock in the efforts to develop an effective strategy against cCMV is our limited knowledge on the molecular mechanism(s) causing transplacental HCMV transmission followed by fetal infection. We recently identified the HCMV encoded IgG-Fc (Fcγ) binding glycoproteins gp34 (RL11) and gp68 (UL119-118) to cooperatively antagonize Fcγ mediated immune responses to protect infected cells from antibody-mediated cell killing. While this mechanism, together with cell-to-cell spread, explains how HCMV spreads in human tissues even in the presence of HCMV immune IgG, our most recent experiments also identify gp34 and gp68 as determinants for diaplacental virus transmission across the polarized fetal syncytiotrophoblast. Specifically, we demonstrate that HCMV virions undergo rapid IgG-dependent transport across the syncytiotrophoblast via FcRn-mediated transcytosis. Deletion of RL11 and UL119-118 from the HCMV genome completely abolishes transcytosis. The discovery of this infection-independent route of dissemination explains why neutralization of HCMV virions was not sufficient to prevent viral spread in previous studies. In the proposed research program, we aim to test a set of gp34- and gp68-specific monoclonal antibodies as potential inhibitors of HCMV transcytosis. As our preliminary data indicates that non-neutralizing HCMV-specific IgG might even enhance transcytosis, we also aim to combine this approach with human sera of varying neutralizing potential to identify synergistic or antagonistic effects. Rhesus CMV is the prime in vivo model for cCMV studies. We therefore aim to translate our findings to Rhesus CMV virion transcytosis. The spread of HCMV to specific organs and virus uptake and excretion at distinct mucosal surfaces implies directed routes of HCMV dissemination and shedding. To address this, we aim to explore the IgG mediated dissemination of HCMV across other cellular barriers expressing FcRn. Finally, we aim to uncover the intracellular route of virion transcytosis.

• DFG Programme: Research Grants