Cytomegalovirus Evades Antibody Immunity Through UL16- Mediated Intracellular Sequestration Of The IgG Transport And Protection Receptor FcRn

Cytomegalovirus (CMV) is a β-herpes virus in the family Herpesviridae. Human cytomegalovirus (HCMV) is one of important viruses that cause congenital infection in humans worldwide. HCMV is also the leading viral cause of birth defects associated with infections and a major cause of morbidity and mortality in transplant patients. Recent studies showed that HCMV(human) can escape CD8+ T and natural killer cells by interfering the formation of antigen presenting complex among MHC class I, and MHC class I related molecules. However, it remains elusive how HCMV avoids antibody immunity. Neonatal Fc receptor for IgG (FcRn) is an Fc receptor having similar structure to MHC classl molecules. FcRn mainly facilitates IgG across the polarized mucosal epithelial cells to seed mucosal immunity and protect IgG from degradation throughout life so that increases the half-life of IgG in serum.Since HCMV infects epithelial cells, endothelial cells, macrophages and DCs where FcRn is present, HCMV may also have ways to interfere with FcRn structure, trafficking and fuction.By screening HCMV proteins, we found that viral glycoprotein UL16 binds to FcRn. The interaction was confirmed by reciprocal immunoprecipitations from transfected HeLa cells or FcRn pulling-down with GST-UL16 proteins from Caco-2 intestinal epithelial cells. Further, they were co-localized in Caco-2 cells infected with wild-type, but not UL16-deleted virus. By using b2m-null cells transfected with FcRn heavy chain alone, we showed that UL16 binding occurred within the endoplasmic reticulum (ER) prior to recruiting b2m. Confocal microscopy and endoglycosidase digestion revealed that UL16 selectively retained FcRn in the ER and reduced FcRn accumulation in endosome, an acidic compartment necessary for FcRn binding to IgG. HCMV infection or UL16 alone significantly decreased IgG transcytosis across Caco-2 intestinal epithelial monolayers.Because FcRn is expressed in the same population of cells capable of supporting HCMV replication, our results first suggest that by inhibiting the capacity of FcRn to bind IgG, the HCMV blocks IgG transcytosis and enhances IgG catabolism in infected cells or tissues. Hence, this study discovers a novel HCMV immune evasion mechanism against humoral immunity.In summary, our data suggested that HCMV membrane glycoprotein UL16 mediated the binding with FcRn inhibiting intracellular trafficking of FcRn that leaded to low IgG transcytosis, and reduced IgG half lifetime. UL16 may help HCMV to escape the cytotoxic T cell response and humoral immunity. This study at the first time confirmed the interactions among glycoprotein UL16, FcRn and IgG during HCMV infection. HCMV might evade cellular and humoral immunity by the mechanism by using UL16 proteins to bind FcRn that reduces or blocks IgG binding. Ligated intestine in vivo proved that HCMV could cause mucosa damage. This rabbit model could be used for HCMV pathogenesis study.