Diminished Antiviral Innate Immune Gene Expression in the Placenta Following a Maternal SARS-CoV-2 Infection, 2022, Coler et al

Diminished Antiviral Innate Immune Gene Expression in the Placenta Following a Maternal SARS-CoV-2 Infection
Coler B, Tsung-Yen WU, Carlson L, Burd N, Munson J, Dacanay M, Cervantes O, Esplin S, Kapur RP, Feltovich H, Adams Waldorf KM

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with critical illness requiring hospitalization, maternal mortality, stillbirth, and preterm birth. SARS-CoV-2 has been shown to induce placental pathology, however, substantial gaps exist in our understanding of the pathophysiology of COVID-19 disease in pregnancy and the long-term impact of SARS-CoV-2 on the placenta and fetus. To what extent a SARS-CoV-2 infection of the placenta alters the placental antiviral innate immune response is not well understood. A dysregulated innate immune response in the setting of maternal COVID-19 disease may increase risk for inflammatory tissue injury or placental compromise and contribute to deleterious pregnancy outcomes.

Objective: We sought to determine the impact of a maternal SARS-CoV-2 infection on placental immune response by evaluating gene expression of a panel of six antiviral innate immune mediators that act as biomarkers of the antiviral and interferon cytokine response. Our hypothesis was that a SARS-CoV-2 infection during pregnancy would result in an upregulated placental antiviral innate immune response.

Study design: We performed a case control study on placental tissues [chorionic villous (CV) tissues and chorioamniotic membrane (CAM)] collected from pregnant patients with (N=140) and without (N=24) COVID-19 disease. We performed real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Placental histopathology was evaluated. Clinical data was abstracted. Fisher's exact test, Pearson correlations, and linear regression models were used to examine proportions and continuous data between patients with active (<10 days since diagnosis) versus recovered COVID-19 (>10 days since diagnosis) at time of delivery. Secondary regression models adjusted for labor status as a covariate and evaluated potential correlation between placental innate immune gene expression and other variables.

Results: SARS-CoV-2 vRNA was detected in placental tissues from 5 women with COVID-19 and from no controls (0/24, 0%). Only 1 of 5 cases with detectable SARS-CoV-2 vRNA in placental tissues was confirmed to express SARS-CoV-2 nucleocapsid and spike proteins in syncytiotrophoblast cells. We detected a significantly lower gene expression of five critical innate immune mediators (IFNB, IFIT1, MXA, IL6, IL1B) in CV and CAM from women with active or recovered COVID-19 compared to controls, which remained significant after adjustment for labor status. There were minimal correlations between placental gene expression and other studied variables including: gestational age at diagnosis, time interval from COVID-19 diagnosis and delivery, pre-pregnancy body mass index, COVID-19 disease severity or placental pathology.

Conclusion: A maternal SARS-CoV-2 infection was associated with an impaired placental innate immune response in chorionic villous tissues and chorioamniotic membranes that was not correlated with gestational age at COVID-19 diagnosis, timer interval from COVID-19 diagnosis to delivery, maternal obesity, disease severity or placental pathology.

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Research Implications

Our results present several important research questions and generate new hypotheses.

First, we hypothesize that impaired innate immunity is only one aspect of placental function that is impaired following a SARS-CoV-2 infection, likely due to the placental host response to control the infection. Certainly, histopathologic evidence of placental injury is well documented to occur in some cases of COVID-19 that manifest as SARS-CoV-2 placentitis, chronic histiocytic villitis, intervillous fibrin deposition, trophoblast necrosis, maternal vascular malperfusion and deposition of intervillous thrombi. As the canonical receptors for SARS-CoV-2 are not typically co-expressed in the placenta and viral infection of syncytiotrophoblast cells appears rare, it is more probable that innate immune mediators released during an acute infection are the source of placental injury than a primary viral infection itself. Regardless of the mechanism of placental injury, an impairment of placental immune functioning is likely to parallel other defects in metabolic and biological pathways that should be defined in order to understand SARS-CoV-2 pathogenesis in the placenta. Interestingly, several reports have highlighted a reduction in SARS-CoV-2 antibody transfer after a natural SARS-CoV-2 infection, which may be due to an impairment in placental function.

 

Clinical Implications

This data has several implications for clinical care. First, our observations that the placental innate immune response was impaired regardless of disease severity suggest that even a mild COVID-19 disease course can impair innate immunity in the [chorioamniotic membranes] and [chorionic villous tissues]. Whether an impaired placental innate immune response increases a pregnant individual's susceptibility to chorioamnionitis is unknown. A meta-analysis of approximately 1,500 pregnancies with COVID-19 revealed a higher-than-expected rate of chorioamnionitis (26%) compared to historical published studies from unexposed placentas (4-20%). Large studies evaluating rates of chorioamnionitis after a natural COVID-19 infection are needed to determine if rates are higher than expected in an uninfected population.