TGF-β2 is Associated with Asymptomatic/Mild SARS-CoV-2 Infection During Pregnancy and Lower SARS-CoV-2 Viral Loads in vitro

Background: COVID-19 is a major public health concern and recent studies have shown that pregnant women are more likely to get severely ill from COVID-19 compared to not pregnant women. Actively infected women or convalescents at time of delivery were recruited.Methods: This prospective cohort was enrolled at UHCMC, CCHS, and MHS, in Cleveland, Ohio (March-October 2020). Collected samples were maternal blood, amniotic fluid (if C-session), umbilical cord segment, cord blood, amnion, chorion and neonatal throat swab and breastmilk. Viral load and cytokines/antibodies level were determined by RT-qPCR and MSD, respectively. In vitro validation in SARS-CoV-2 infected NHBE cells was performed. Data analysis was performed in R, GraphPad Prism 9, and Microsoft Excel.Findings: Plasma TGF-β2 levels were significantly associated with asymptomatic/mild disease and inversely correlated with levels of IP-10, IL-6 and IL-8. Pre-treatment of human tracheobronchial epithelial cells with TGF-β2 led to significant increase of IL-6(IFN- β2) that led to the control of SARS-CoV-2 viral loads. Additionally, TGF-β2 pre-treatment suppressed the release of cytokines part of the in vivo cytokine storm such as IP-10, IL1b and IL-8 post-infection. Altogether this data suggests that TGF-β2 plays a protective role in SARS-CoV-2 infection by improving epithelial cells intrinsic antiviral function and by suppressing the expression of the cytokines associated with heightened inflammation in severe cases.Interpretation: Our study shows that TGF- β2 is a cytokine that has a protective role during SARS-CoV-2 infection in pregnancy and is associated with lower viral loads and pro-inflammatory cytokines release in in vitro infection.Funding: NIH NCATS CTSA Program grant UL1TR002548 to Case Western Reserve University andsupport from the Clinical Research Center of University Hospitals Cleveland Medical CenterDeclaration of Interest: The authors declare no conflict of interest. Ethical Approval: This was a prospective cohort study (March-October 2020) approved by the institutional review board at University Hospitals Cleveland Medical Center (UHCMC), the Cleveland Clinic Healthcare System (CCHS) and the Metro Health System (MHS) (Approval number: 20200479).