The role of placental macrophages in cytomegalovirus infection at the maternal-fetal interface - Human cytomegalovirus (HCMV) is the most common cause of congenital infection, affecting an estimated 0.6- 0.7% of newborns in the USA. Depending on the timing of maternal primary infection, congenital infection can result in severe clinical consequences and neurodevelopmental sequelae, making HCMV the leading cause of sensorineural hearing loss in newborns. The monocyte-macrophage lineage plays a vital role in HCMV infection in humans. Placental macrophages, known as Hofbauer cells (HBCs), therefore likely serve as a crucial barrier to HCMV transmission to the fetus, but their role in this process is largely underexplored. The role of humoral immunity in controlling HCMV and preventing congenital infection is complex. Anti-HCMV antibodies can perform both neutralizing and cell activation functions, but even in the presence of specific antibody, latent HCMV has the ability to reactivate, and patients can become reinfected with new strains. Nonetheless, reactivation and reinfection are both associated with a much lower risk of congenital infection, suggesting that humoral immunity is at least partly effective at preventing transmission to the fetus. With CMV vaccines now in Phase 3 trials, it is important that we improve our understanding of HCMV antibody functioning in the placenta, including via HBCs, which express Fc receptors, and like other macrophages, are able to perform neutralising and non-neutralising anti-HCMV functions. The role of viral glycoproteins in HCMV entry and infection is another critical area of investigation with profound implications for both basic virology and clinical therapeutics. These glycoproteins serve as the mediators of virus-host cell interactions, facilitating attachment, fusion, and internalization processes. Moreover, they play a pivotal role in immune evasion strategies employed by HCMV. Viral glycoprotein interactions with host cells are at least partly mediated by their interaction with lectins, proteins that recognize endogenous and/or pathogen-associated glycans. While the role of lectins in HCMV infection at the maternal-fetal interface is poorly understood, it could offer innovative targets for therapeutic intervention. Understanding the precise molecular mechanisms by which these glycoproteins orchestrate the entry process, including at the maternal-fetal interface, is of paramount importance for developing targeted antiviral interventions and can inform the design of vaccines and therapeutics. To help attain these goals, the specific aims of our proposal are to: 1) Interrogate the temporal response of HBCs to human cytomegalovirus infection, 2) Elucidate the role of maternal Ab in HCMV infection of HBC, 3) Identify lectin-glycan interactions involved in HCMV infection of HBCs. Through combining several methodologies including Quantitative Temporal Viromics, functional antibody assays, a human lectin binding array, glycomics/glycoproteomics/glycolipidomics and glycan-binding arrays, complemented by functional in vitro investigations, performed in HBCs across gestation, we will provide an unprecedented and overdue insight into HBC responses to viral infection.
