Metabolic Alterations Unravel the Materno–fetal Immune Responses with Disease Severity in Pregnant Women Infected with SARS-CoV-2

Pregnancy being an immune compromised state, coronavirus disease of 2019 (COVID-19) disease poses high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses, therefore we aimed to analyze the change in plasma secretome, metabolome, and immune cells with disease severity in COVID-19 positive pregnant females and their cord blood. COVID-19 reverse transcriptase-polymerase chain reaction positive pregnant females (n = 112) with asymptomatic (Asy) (n = 82), mild (n = 21), or moderate (n = 9) disease, healthy pregnant (n = 18), COVID-19 positive nonpregnant females (n = 7) were included. Eighty-two cord blood from COVID-19 positive and seven healthy cord blood were also analyzed. Mother's peripheral blood and cord blood were analyzed for untargeted metabolome profiling and cytokines by using high-resolution mass spectrometry and cytokine bead array. Immune scan was performed only in mothers' blood by flow cytometry. In Asy severe acute respiratory syndrome coronavirus 2 infection, the amino acid metabolic pathways such as glycine, serine, l-lactate, and threonine metabolism were upregulated with downregulation of riboflavin and tyrosine metabolism. However, with mild-to-moderate disease, the pyruvate and nicotinamide adenine dinucleotide (NAD(+)) metabolism were mostly altered. Cord blood mimicked the mother's metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in Asy and NAD(+), riboflavin metabolism in mild and moderate. Additionally, with disease severity tumor necrosis factor-alpha, interferon (IFN)-alpha, IFN-gamma, interleukin (IL)-6 cytokine storm, IL-9 was raised in both mothers and neonates. Pyruvate, NAD metabolism and increase in IL-9 and IFN-gamma had an impact on nonclassical monocytes, exhausted T and B cells. Our results demonstrated that immune-metabolic interplay in mother and fetus is influenced with increase in IL-9 and IFN-gamma regulated pyruvate, lactate tricarboxylic acid, and riboflavin metabolism with context to disease severity.