Discrimination of primary and chronic cytomegalovirus infection based on humoral immune profiles in pregnancy.

Abstract

Background: Most humans have been infected by Cytomegalovirus (CMV) by the time they reach forty years of age. Whereas most of these CMV infections are well controlled by the immune system, congenital infection can lead to serious health effects and death for the fetus and neonate. Most humans have been infected bywith cytomegalovirus (CMV) by the time they reach mid-life without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled, and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus is lower during chronic maternal infection, and varies in association with gestational age at the time of primary maternal infection, further research on humoral immune responses to primary CMV infection during pregnancy is needed.

Methods: Here, systems serology tools were applied to characterize antibody responses to CMV infection inamong pregnant and non-pregnant women experiencing either primary or chronic infection.

Results: Whereas strikingly different antibody profiles were observed depending on infection status, more limited differences were associated with pregnancy status. Beyond known differences in IgM responses that are used clinically for identification of primary infection, distinctions observed in IgA and FcγR- binding antibodiesy responses and among viral antigen specificities accurately predicted infection status in a cross-sectional cohort. Leveraging machine Machine learning, longitudinal samples were also was used to define an immunological clock of CMV infectionthe transition from primary to chronic states and predict time since primary infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as is typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection.

Conclusion: In sum, this work provides new insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics and to support clinical trials of interventions to reduce mother-to-fetus transmission of CMV.

Trial registration: Not applicable Funding. CYMAF consortium and National Institutes of Health.