Biology subjects

Sevak, J. K.

Publications and source records attributed to Sevak, J. K..

2 recordsLinked to original sources

bioRxiv2023

Epigenetic mediated functional reprogramming of immune cells leads to HBsAg seroconversion in Hepatitis B Virus Reactivation patients

BackgroundHepatitis B virus (HBV) modulates epigenetic landscape by epigenetic regulators. HBsAg seroconversion is possible with immune activation, therefore we aimed to investigate epigenetic modulation in HBV reactivation (rHBV) for viral clearance and seroconversion. MethodsSixteen retrospectively collected rHBV patients [Seroconverters (SC, n=7, HBsAg loss and anti-HBs>10 IU/ml), non- seroconverters (NSC, n=9)], chronic hepatitis B treatment naive (nCHBV, n=7) patients and healthy controls (HC, n=7) were included in this study. Genome methylation, gene expression, plasma-cytokines, and immune cell profiling was analysed by Reduced Representation Bisulfite Sequencing (RRBS), QRT-PCR, multiplex-cytokine-bead array and flow-cytometry. ResultsrHBV patients having high HBV DNA and ALT showed epigenetic remodellers; KDM2B, NCOR2 and GATA6, immune and metabolic genes; TGF-{beta}, IL-6, IRF8, RPTOR, HK3 significantly (p<0.05) hypomethylated at specific CpG islands compared to nCHBV. TOX was hypomethylated in nCHBV suggesting immune-exhaustion. At-baseline, seroconverters showed hypomethylation of KDM2B, COX19, IRF8, TLR5 and hypermethylation of LAG3 compared to non-seroconverters. Further, in seroconverters at week-24, IL17RA, IFN-{gamma}, TGF-{beta}, and STAT5B (p<0.05) were additionally hypomethylated at specific CpG islands suggesting immune activation. Cytokine-bead analysis revealed increased IL-6 (p=0.009) and decreased LAG3 plasma levels (p=0.01) also imply on significantly differentiated HBV specific CD8, Tfh and Th1/17 cells in seroconverters at baseline and week-24. However, both nCHBV and non-seroconverters had consistent hypomethylation of LAG3 and TOX, which leads to immune exhaustion. ConclusionIn rHBV, seroconversion is driven by position specific CpG islands methylation in epigenetic remodellers, immune and metabolic genes. Immune metabolic reprograming is reflected by Th1/17 differentiation, extensive interleukin production for HBsAg seroconversion. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/554133v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@48e206org.highwire.dtl.DTLVardef@ef0fa7org.highwire.dtl.DTLVardef@ecb710org.highwire.dtl.DTLVardef@e6b34e_HPS_FORMAT_FIGEXP M_FIG C_FIG Lay summaryEpigenetic landscape in nCHBV depicts exhaustion and immune dysfunction. Out of many hypermethylated CpG islands of nCHBV, few become hypomethylated in rHBV and drives immune and metabolic reprogramming. This study provides insights into the cellular and molecular basis of epigenomic programs that regulate the differentiation and activation of immune cells leading to viral clearance and seroconversion. Targeting epigenetic mechanism could be promising strategy for the treatment of nCHBV and non-seroconverters.

immunology↗

bioRxiv2023

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

BackgroundPregnancy 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. MethodsCOVID-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. Mothers 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. ResultsIn 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-, IFN-, IFN-{gamma}, IL-6 cytokine storm, IL-9 was increased in both mothers and neonates. Pyruvate and NAD+ metabolic pathways along with IL-9 and IFN-{gamma} had impact on non-classical monocytes, increased CD4 T cells and B cells but depleted CD8+ T cells. Cord blood mimicked the mothers metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in asymptomatic and NAD+ and riboflavin metabolism in mild and moderate disease subjects. ConclusionsOur 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- {gamma} regulated pyruvate, lactate TCA metabolism and riboflavin metabolism with context to disease severity are hall marks of this materno-fetal metabolome. HighlightsO_LISARS-CoV-2 infection alters energy consumption metabolic pathways during pregnancy. C_LIO_LIPregnant women with mild to moderate COVID-19 show increased energy demands, and consume stored glucose by upregulating pyruvate and NAD+ metabolism. C_LIO_LIIncreased TNF- 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. C_LIO_LIWith mild to moderate disease, raised IL-9 and TNF-, decreased riboflavin pathway, exhaustion of T and B cells cause pathogenesis. C_LIO_LICord blood mimics the metabolic profile of mothers peripheral blood, SARS- CoV-2 infection reshapes immune-metabolic profiles of mother-infant dyad. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=141 HEIGHT=200 SRC="FIGDIR/small/540101v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@657cc3org.highwire.dtl.DTLVardef@e1e76forg.highwire.dtl.DTLVardef@12153f2org.highwire.dtl.DTLVardef@10e5332_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗