Protection from cytomegalovirus infection by antibodies
Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital infection, which affects 0.5-2 % of all live births worldwide, and is a major cause of morbidity and mortality in transplant recipients. Hence, development of an HCMV vaccine has highest priority. The glycoprotein B (gB) was identified as the most immunogenic HCMV envelope protein, which induces up to 70 % of the total neutralizing antibody response following natural infection. In previous studies, this research group analysed the antibody responses against HCMV or murine CMV (MCMV) and demonstrated comparable target specificities of gB-specific neutralizing (nt) and non-neutralizing (nnt) monoclonal antibodies (mAbs). When administered prophylactically, both, nt and nnt mAbs were comparably effective in protecting immunodeficient RAG-/- mice from MCMV infection. It was as well shown that protection via polyvalent serum depends on expression of Fcγ receptors in recipients.
Therefore, the major aim of this project is to understand the role of IgG isotypes for protection. Since mainly cell-to-cell spread results in virus dissemination, the capacity of MCMV-specific mAbs for inhibition of cell-to-cell spread should be elucidated. MCMV gB specific antibodies were already characterized by this research group and mAbs with isotype switch and new mAbs will further be characterized in vitro with respect to target specificity, neutralization and inhibition of cell-to-cell spread. Those results will then be compared with in vivo investigation of the mAbs in the mouse model using MCMV. Finally, the major effector cells responsible for protection will be defined via depletion and/or ablation of different effector cell types and recombinant mAbs deficient for Fcγ-receptor and/or complement binding. Taken together this project aims to identify the mechanisms by which antibodies protect from MCMV infection, which will be important for future HCMV immunotherapy and vaccine development.
