The legacy of maternal SARS-CoV-2 infection on the immunology of the neonate

Abstract

Despite extensive studies into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the effect of maternal infection on the neonate is unclear. To investigate this, we characterized the immunology of neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy. Here we show that maternal SARS-CoV-2 infection affects the neonatal immune system. Despite similar proportions of B cells, CD4 + T cells and CD8 + T cells, increased percentages of natural killer cells, Vδ2 + γδ T cells and regulatory T cells were detected in neonates born to mothers with recent or ongoing infection compared with those born to recovered or uninfected mothers. Increased plasma cytokine levels were also evident in neonates and mothers within the recent or ongoing infection group. Cytokine functionality was enhanced in neonates born to SARS-CoV-2-exposed mothers, compared to those born to uninfected mothers. In most neonates, this immune imprinting was nonspecific, suggesting vertical transmission of SARS-CoV-2 is limited, a finding supported by a lack of SARS-CoV-2-specific IgM in neonates despite maternal IgG transfer.

Maternal COVID-19 leaves a lasting immunological impression on the fetus

“…A polyfunctional cytokine response refers to the ability of a cell population to produce multiple cytokines at once (such as TNF, IFN-γ and IL-17) and represents a marker of cellular activation and maturation, as well as a correlate of protective immunity when specifically targeted to a virus 4 . The increased T cell cytokine functionality noted by Gee et al was evaluated in a subset of neonates and was found not to be specific for SARS-CoV-2 peptides in seven of eight neonates (88%) 3 . These data indicate that fetal immune imprinting due to a maternal SARS-CoV-2 infection during pregnancy is probably not a result of direct exposure to the virus and is instead a result of fetal exposure to an inflammatory environment.…”

“…A striking finding by Gee et al was that some changes in fetal immunity associated with maternal COVID-19 were time dependent 3 . Perturbations in the frequency of neonatal NK cells and Vδ2 + γδ T cells seemed to recover with a longer interval between maternal COVID-19 and birth.…”

“…Changes in immune effector cell activation and proinflammatory cytokine production can negatively affect fetal neurodevelopment. Alarmingly, Gee et al found that fetal cytokine levels were, in some cases, as high as those in the mother actively or recently infected with SARS-CoV-2 3 . In the absence of a control group of fetuses not exposed to SARS-CoV-2, the authors compared the umbilical cord plasma cytokines of infants born to women with a recent or ongoing SARS-CoV-2 infection with those of infants from women who had recovered from SARS-CoV-2 infection.…”

“…born to women with a recent or ongoing maternal SARS-CoV-2 infection at the time of birth -in the absence of a congenital infection -had increased frequencies of neonatal natural killer (NK) cells, Vδ2 + γδ T cells and FOXP3 + regulatory T cells, and greater quantities of plasma cytokines 3 (Fig. 1).…”

“…There is cause for concern, as activation of the maternal immune system has been shown to adversely affect fetal neurodevelopment and increase the long-term risk of neuropsychiatric disorders in mouse models and in humans 1,2 . In this issue, Gee et al provide the first evidence linking maternal COVID-19 with dysregulation of the fetal immune system and activation of multiple innate, innate-like and adaptive immune cells in neonatal cord blood 3 . Similar to other published studies showing a very low rate of vertical transmission of SARS-CoV-2, congenital infection in this neonatal cohort may have occurred in only a single case (1 of 30 (~3%)).…”