Fc-mediated Immunity in Congenital Human Cytomegalovirus Infection

Permar, Sallie R

Semmes, Eleanor Caldwell

2023-06-08T18:19:36Z

2023

Molecular Genetics and Microbiology

Human cytomegalovirus (HCMV) is a ubiquitous, host-restricted β-herpesvirus that has co-evolved with humans over millennia. In healthy individuals, HCMV infection is usually mild or potentially beneficial, as seropositivity can boost host heterologous immunity. Conversely, infection in immunocompromised individuals or in utero can cause severe disease. Congenital HCMV infection (cCMV), acquired via transplacental transmission from mother to fetus, is the most common vertically transmitted infection worldwide and is associated with stillbirth, neurodevelopmental impairment, hearing loss, and childhood leukemia. There are no vaccines or therapeutics to prevent cCMV and our knowledge of the impacts of infection on neonatal immunity remain limited. In my dissertation work, we aimed to discover protective immune responses against cCMV infection and to define how cCMV modulates neonatal immunity. To investigate these aims, we established a case-control cohort of mother-infant dyads with and without cCMV infection using the Carolinas Cord Blood Bank. We leveraged paired maternal and cord blood samples to define 1) how HCMV modifies placental IgG transfer, 2) protective antibody responses against cCMV transmission, and 3) the impact of cCMV on neonatal cellular immunity. First, we found that placental IgG transfer efficiency was reduced in cCMV infection because HCMV transmitting mothers had high rates of hypergammaglobulinemia, leading to saturation of the neonatal Fc receptor (FcRn) and decreased IgG transfer ratios. However, neonates with and without cCMV infection had similar levels of antigen-specific IgG, suggesting equivalent protection conferred by FcRn-mediated IgG transfer. When comparing HCMV transmitting to HCMV seropositive non-transmitting dyads, we observed that placental transfer of high avidity HCMV-specific IgG was reduced in cCMV infection but that cCMV-infected infants had high levels of neutralizing, HCMV-specific IgG. Next, we found that antibody-dependent cellular phagocytosis (ADCP), a Fc-mediated antibody effector function, was associated with protection against cCMV transmission. We determined that HCMV-specific IgG activation of FcγRI and FcγRIIA, which mediate ADCP and other innate immune cell effector functions by binding to the Fc region of IgG, was enhanced in mothers who did not transmit HCMV in utero. Finally, we compared cord blood immunophenotypes in infants with and without cCMV infection. We found that activated CD8+ and CD4+ T cells were increased and that regulatory T cells were reduced in cCMV infection. Moreover, we discovered that a unique population of “NKT-like” CD8+ T cells expressing NK cell markers such as FcγRIIIA/CD16 and NKG2A/C was significantly expanded in cord blood from cCMV-infected neonates. Cumulatively, our data highlights the important role of Fc-mediated immunity in cCMV infection and reveals that HCMV is a powerful immunomodulator in utero, which can guide future vaccination strategies against HCMV and other infectious diseases.

https://hdl.handle.net/10161/27569

Immunology

Virology

Fc-mediated Immunity in Congenital Human Cytomegalovirus Infection

Dissertation

24

2025-05-24T00:00:00Z