Metabolic alterations unravel the materno–fetal immune responses with disease severity in pregnant women infected with SARS-CoV-2

Background Pregnancy being immune compromised state, COVID-19 disease poses high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses and we aimed to analyze the plasma secretome, metabolome and immune cells in COVID-19 positive pregnant mother and cord blood. Methods COVID-19 RT-PCR positive pregnant females (n=112) asymptomatic (n=82), or with mild (n=21) or moderate (n=9) disease and control healthy pregnant (n=10) females were included. Mother’s blood and cord blood (n=80) was analysed for untargeted metabolome profiling and plasma cytokines by high-resolution mass spectrometry (MS) and multiplex cytokine bead array. Immune scan in mothers was done using flow cytometry. Results In asymptomatic SARS-CoV-2 infection, --the amino acid metabolic pathways such as glycine, serine, L-lactate and threonine metabolism was upregulated, riboflavin and tyrosine metabolism, downregulated. In mild to moderate disease, the pyruvate and NAD + metabolism (energy metabolic pathways) were mostly altered. In addition to raised TNF-α, IFN-α, IFN-γ, IL-6 cytokine storm, IL-9 was increased in both mothers and neonates. Pyruvate and NAD + metabolic pathways along with IL-9 and IFN-γ had impact on non-classical monocytes, increased CD4 T cells and B cells but depleted CD8 + T cells. Cord blood mimicked the mother’s metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in asymptomatic and NAD + and riboflavin metabolism in mild and moderate disease subjects. Conclusions Our results demonstrate a graduated immune-metabolomic interplay in mother and fetus in pregnant females with different degrees of severity of COVID-19 disease. IL-9 and IFN- γ regulated pyruvate, lactate TCA metabolism and riboflavin metabolism with context to disease severity are hall marks of this materno-fetal metabolome. Highlights SARS-CoV-2 infection alters energy consumption metabolic pathways during pregnancy. Pregnant women with mild to moderate COVID-19 show increased energy demands, and consume stored glucose by upregulating pyruvate and NAD + metabolism. Increased TNF-α and IL-9 in mild COVID-19 disease involve TCA cycle to produce lactate and consume stored glucose by up regulating pyruvate and nicotinamide and nicotinate metabolism. With mild to moderate disease, raised IL-9 and TNF-α, decreased riboflavin pathway, exhaustion of T and B cells cause pathogenesis. Cord blood mimics the metabolic profile of mother’s peripheral blood, SARS- CoV-2 infection reshapes immune-metabolic profiles of mother-infant dyad. Graphical Abstract