Within dyads, whole-virus IgG binding avidity was low in paired cord blood versus maternal sera in transmitting but not non-transmitting dyads (Physique 2B). were associated with reduced risk of congenital HCMV contamination. We also decided that HCMV-specific IgG activation of FcRI and FcRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcRI and FcRIIA expressed on human monocytes. These findings suggest that engagement of FcRI/FcRIIA and Fc effector functions including ADCP may protect against congenital HCMV contamination. Taken together, these data can guideline future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development. Keywords:Immunology, Infectious disease Keywords:Adaptive immunity, Immunoglobulins == Introduction == Human cytomegalovirus (HCMV) is the most common congenital contamination worldwide, affecting 1 of 200 births or nearly 1 million newborns annually (1,2). Most congenital HCMV (cCMV) infections are asymptomatic, yet serious disease outcomes can occur, including stillbirth, intrauterine growth restriction, neonatal multi-organ disease, neurodevelopmental impairment, and sensorineural hearing loss (3,4) Moreover, cCMV contamination has recently been linked to an elevated risk of acute lymphoblastic leukemia (57). Newborn screening for and public awareness of cCMV remain limited, leaving most cases undiagnosed and Diphenyleneiodonium chloride the true burden of disease underestimated (5,8,9). You will find no licensed vaccines or therapeutics to prevent cCMV, and an improved understanding of protective immunity against cCMV transmission is urgently needed to guideline novel interventions. HCMV is usually a ubiquitous, host-restricted -herpesvirus with multiple envelope glycoproteins and complexes, including glycoprotein B (gB) and gH/gL dimer; these can associate with gO to form the gH/gL/gO trimer or pUL128/130/131 to form the pentamer complex (10). HCMV envelope glycoproteins mediate viral access, and following main contamination, the host remains latently infected for life (1012). Over 80% of women of reproductive age worldwide are latently infected with HCMV, and congenital transmission occurs in maternal main and nonprimary contamination (i.e., reactivation from latency or reinfection with new strains) (2,1216). Mothers with main contamination have a 30% risk of fetal transmission, whereas those with nonprimary contamination have a 1%4% risk (2,1719), suggesting that preexisting maternal immunity partially protects against cCMV. In maternal main contamination, high-avidity IgG binding to HCMV and Diphenyleneiodonium chloride antipentamer IgG levels are correlated with decreased congenital transmission risk (2023). However, in maternal nonprimary contamination, protective immunity remains unclear, as HCMV-specific IgG levels and neutralizing antibody titers do not usually correlate with reduced congenital transmission (2426). Identifying protective immune responses in maternal main and nonprimary contamination is necessary for developing effective Diphenyleneiodonium chloride interventions to prevent cCMV. High-avidity HCMV-specific IgG Diphenyleneiodonium chloride binding and neutralizing antibodies have been the main targets of vaccines and therapeutics (10,27). Yet maternal treatment with HCMV hyperimmune globulin a pooled preparation of high-avidity, neutralizing antibodies to prevent fetal transmission following main contamination has had limited efficacy (2833). Emerging evidence indicates that non-neutralizing antibody functions also protect against HCMV contamination, but to our knowledge, these have not been targeted in HCMV vaccines or immunotherapeutics (3437). Moreover, whether Fc-mediated non-neutralizing antibody functions (e.g., antibody-dependent cellular phagocytosis [ADCP] and antibody-dependent cellular cytotoxicity [ADCC]) protect against cCMV has not been explored. In this study, we focused on ADCP, since vaccine trials suggest that Fc effector functions impartial of ADCC mediate protection against HCMV (34,38). We hypothesized that ADCP may protect against cCMV contamination, as ADCP can eliminate virus:IgG immune complexes and virally infected cells; and this could prevent systemic maternal viral replication, dissemination, and transmission across the maternal-fetal interface (39). To identify protective immune responses against cCMV transmission, we compared antibody profiles in HCMV-seropositive transmitting and non-transmitting mother-infant dyads identified as donors to a US-based public cord blood bank. In our main analysis, we compared 13 predefined IgG binding, neutralizing, and non-neutralizing antibody responses in transmitting versus non-transmitting women. In an exploratory analysis, we used systems serology to define differences between transmitting and non-transmitting dyads and examined the role of Fc-mediated immunity in cCMV transmission. Insights from this study could inform vaccine and therapeutic development to prevent cCMV contamination, a major cause of perinatal and pediatric morbidity worldwide. == Results == == Baseline characteristics of HCMV transmitting and non-transmitting mother-infant dyads. == Our study included sera from 81 mother-infant dyads recognized retrospectively as donors to the Carolinas Cord Blood Lender (CCBB), a large US-based public cord blood lender (Supplemental Physique 1; Rabbit Polyclonal to CRABP2 supplemental material available online with this short article;https://doi.org/10.1172/JCI156827DS1). cCMV contamination was defined based on the presence of HCMV viremia in the donated cord blood plasma. Forty-one dyads with cCMV contamination (HCMV transmitting) were matched to 40 dyads with HCMV IgGseropositive mothers who gave birth to cCMV-uninfected infants (HCMV non-transmitting). Matching criteria included infant sex, infant race, maternal age, and delivery 12 months. Only women with healthy, uncomplicated pregnancies that gave birth at term were included in our.