A new preprint study on the Preprints with The Lancet*server has found that transforming growth factor (TGF)-β2 levels may be linked to asymptomatic and mild disease in both recovering mothers and women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the time of birth. A protective role of TGF-β2 was depicted in the setting of SARS-CoV-2 infection during pregnancy – expressed as pro-inflammatory cytokine release and lower viral loads, in vitro†
Background
The ongoing 2019 coronavirus disease (COVID-19) has had devastating effects on the lives of millions of people around the world. However, data on the effects on pregnant women remain limited.
Some research suggests that pregnant women who develop SARS-CoV-2 infection have an increased risk of severe symptoms, preterm birth and the need for intensive care and/or mechanical ventilation compared to non-pregnant women. In addition, maternal SARS-CoV-2 infection increases the likelihood of maternal and fetal death.
On the other hand, studies have shown that pregnant SARS-CoV-2 infected patients do not have a greater preference for developing critical pneumonia than non-pregnant women. Moreover, racial inequalities also alter the effects of COVID-19 during pregnancy, and more so because of the social divide.
In addition, studies of maternal immune response after SARS-CoV-2, placental infection and vertical transmission have mainly been conducted in women who had COVID-19 symptoms in their third trimester.
The study and findings
The new study examined the clinical and obstetric outcomes after SARS-CoV-2 infection in two groups of pregnant women, along with their association with the immunological parameters.
This prospective cohort study was conducted between March-October 2020. Pregnant women with a positive polymerase chain reaction (PCR) test result for SARS-CoV-2 during their pregnancy were included. The first group was the recovering cohort – infected during early pregnancy, and the second group was the actively infected cohort – mothers diagnosed with SARS-Cov-2 at the time of delivery.
Maternal (M) blood and vaginal secretion samples were collected from participants in both study groups on admission. After that samples of amniotic fluid (AF) – in cases with cesarean section; umbilical segment; amniotic; chorion; umbilical cord blood (CB); neonatal blood; and throat swab were collected at the time of delivery or one day after delivery. In addition, breast milk was sampled one or two days after delivery.
Patient demographics were recorded along with SARS-CoV-2 infection status, COVID-19 disease severity, infection during delivery, recovery status, antepartum and postpartum complications, and neonatal outcomes. The COVID-19 status was scored as 0 – asymptomatic; 1 – mild with few symptoms, no need for ventilation; 2 – moderate, requiring hospitalization or ventilation; 3 – severe, requiring intensive care and discharge; and 4 – Criticism, needing intensive care and near-death or deceased.
Of the 33 participants selected for biospecim analysis, 23 were African, 48.5% had an active SARS-CoV-2 infection during delivery, while 51.5% were recovering.
The results did not elicit the presence of the virus in any biospecimen; there was no incidence of vertical transmission. In maternal plasma and convalescent blood antibody measurements, a significant dichotomy was detected in the antibody profiles of amniotic fluid between the two cohorts.
A total of six antibody clusters were identified. Clusters 2 and 5 consisting of the viral anti-receptor binding domain (RBD) and anti-N-terminal domain (NTD)/Spike (S) protein antibodies were significantly higher in the recovering pregnant women. Cluster 3 showed positive associations with disease severity, while cluster 6 in this cohort was correlated with disease severity.
AF profiling outlined lower antibody levels than those on the plasma samples, in both study groups, while escalations in non-SARS-CoV-2 antibodies were recorded during active infection that exceeded the elevations in the SARS-CoV-2 specific antibodies. Non-SARS-CoV-2 antibody titers correlated with COVID-19 disease severity in the convalescent blood and maternal plasma samples during active SARS-Cov-2 infection.
The recovering samples showed elevated antibodies to SARS-CoV-2 and other coronaviruses. Correlations were found in almost all antibodies; the HKU1 was an exception as it did not correlate with other antibody titers.
It was also noted that cytokines and chemokines stimulated migration and cell differentiation, mediating inflammation, effector function, and tissue and immune homeostasis. The TGF-β2 and TGF-β3 levels were also significantly increased in the AF compared to plasma samples. While fractalkine levels in the convalescent plasma were inversely associated with disease severity, while the inducible protein (IP)-10, granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-1β were positively associated with COVID-19 severity of the disease.
In the maternal plasma, TGF-β2 levels and IL-21 were inversely related to disease severity. Note that Fractalkine was remarkably enriched in restorative plasma, while IL-27 and IL-15 were enriched in the maternal samples.
Furthermore, in the restorative plasma, GM-CSF, TGF-β2, and monocyte chemotactic protein 3 (MCP-3), macrophage inflammatory protein-1α (MIP-1α), and IL-10 were inversely related to disease severity. It was concluded that the interferon (IFN) pathways such as IP-10 were positively associated with the severity of COVID-19, while anti-inflammatory markers, for example -TGF-β2, correlated with absent or mild symptoms. In addition, cytokines were inversely associated with disease severity.
In neonates, markers of asymptomatic disease during active SARS-CoV-2 infection, e.g. – TGF-β2 and IL-21, were inversely associated with neonatal intensive care unit (NICU) admissions and preeclampsia. Immunological parameters indicating moderate or severe infection, such as IP-10, IL-1β, and non-SARS-CoV-2 antibodies, were positively correlated with NICU admissions, basal metabolic rate (BMI), anemia, asthma, and need for additional O2 therapy.
about testing a in vitro model of SARS-CoV-2 infection in normal human bronchial epithelial (NHBE) cells, TGF-β2 treatment elicited a clear profile of cytokines at both 0 and 72 h after the viral challenge, compared to untreated cells. These findings suggested that TGF-β2 might confer sustained and enhanced antiviral immunity.
When human tracheobronchial epithelial cells were pretreated with TGF-β2, a significant decay in SARS-CoV-2 viral loads and suppressed cytokine release was documented – in the setting of COVID-19. Therefore, a common anti-inflammatory environment could influence the appropriate antiviral response and prevent the overwhelming inflammation seen in the cytokine storm – characteristic of severe COVID-19 cases.
Therefore, the anti-inflammatory cytokine – TGF-β2, which was inversely related to the cytokines indicating the hyperimmune response in severe COVID-19, improved outcomes in pregnant COVID-19 patients. The results show that TGF-β2 impedes SARS-CoV-2 replication in NHBE cells by maintaining a non-inflammatory environment and suppressing cytokines.
*Important announcement
Lancet preprints publish preliminary scientific reports that have not been peer reviewed and therefore should not be considered conclusive, should guide clinical practice/health related behavior or be treated as established information.
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