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Genetic variation in IL18R1 and IL18 genes and Inteferon ? ELISPOT response to smallpox vaccination: an unexpected relationship.

ABSTRACT: Genetic association studies demonstrated a role for cytokine proteins and cytokine or cytokine receptor gene polymorphisms in smallpox vaccine-induced adaptive immunity.We examined the association of genetic polymorphisms with cellular (interferon [IFN] ? enzyme-linked immunospot assay [ELISPOT]) immune response to smallpox vaccine in 1076 immunized individuals.The majority of significant associations were discovered between single-nucleotide polymorphisms/haplotypes in IL18R1 and IL18 genes, in which we previously reported an association with vaccinia virus-induced neutralizing antibody titers in this study cohort. A functional coding IL18R1 polymorphism (rs1035130/Phe251Phe; P = .01) was significantly associated with an allele dose-related increase in IFN-? production and was also associated with vaccinia-specific neutralizing antibody titers. Significant associations were also found between IL18R1 haplotypes and variations in IFN-? ELISPOT responses (global P < .0001).Our data suggest the importance of variants in the IL18R1 and IL18 genetic loci for broad-based smallpox vaccine-induced adaptive immunity.

SUBMITTER: Ovsyannikova IG

PROVIDER: S-EPMC3789570 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Genetic variation in IL18R1 and IL18 genes and Inteferon γ ELISPOT response to smallpox vaccination: an unexpected relationship.

Ovsyannikova Inna G IG Haralambieva Iana H IH Kennedy Richard B RB O'Byrne Megan M MM Pankratz V Shane VS Poland Gregory A GA

The Journal of infectious diseases 20130730 9

<h4>Background</h4>Genetic association studies demonstrated a role for cytokine proteins and cytokine or cytokine receptor gene polymorphisms in smallpox vaccine-induced adaptive immunity.<h4>Methods</h4>We examined the association of genetic polymorphisms with cellular (interferon [IFN] γ enzyme-linked immunospot assay [ELISPOT]) immune response to smallpox vaccine in 1076 immunized individuals.<h4>Results</h4>The majority of significant associations were discovered between single-nucleotide po ...[more]

PMID: 23901078

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Project description:ObjectivesCurrently, cardiovascular risk associated with COVID-19 has been brought to people's attention, but the mechanism is not clear. The aim of this study is to elucidate the mechanisms based on multiple omics data.MethodologyWeighted gene co-expression network analysis (WGCNA) was used to identify key pathways. Combination analysis with aneurysm and atherosclerosis related pathways, hypoxia induced factor-1 (HIF-1) signaling were identified as key pathways of the increased cardiovascular risk associated with COVID-19. ScMLnet algorithm based on scRNA-seq was used to explore the regulation of HIF-1 pathway by intercellular communication. Proteomic analysis was used to detect the regulatory mechanisms between IL18 and HIF-1 signaling pathway. Pseudo time locus analysis was used to study the regulation of HIF1 signaling pathway in macrophages and vascular smooth muscle cells (VSMC) phenotypic transformation. The Virtual Inference of protein-activity by Enriched Regulon (VIPER) analysis was used to study the activity of regulatory proteins. Epigenetic analysis based on methylation revealed epigenetic changes in PBMC after SARS-CoV-2 infection. Potential therapeutic compounds were explored by using Cmap algorithm.ResultsHIF-1 signaling pathway is a common key pathway for aneurysms, atherosclerosis and SARS-CoV-2 infection. Intercellular communication analysis showed that macrophage-derived interleukin-18 (IL-18) activates the HIF-1 signaling pathway through IL18R1. Proteomic analysis showed that IL18/IL18R1 promote NF-κB entry into the nucleus, and activated the HIF-1 signaling pathway. Macrophage-derived IL18 promoted the M1 polarization of macrophages and the syntactic phenotype transformation of VSMCs. MAP2K1 mediates the functional regulation of HIF-1 signaling pathway in various cell types. Epigenetic changes in PBMC after COVID-19 infection are characterized by activation of the type I interferon pathway. MEK inhibitors are the promising compounds for the treatment of HIF-1 overactivation.ConclusionsThe IL18/IL18R1/HIF1A axis is expected to be an therapeutic target for cardiovascular protection after SARS-CoV-2 infection. MEK inhibitors may be an choice for cardiovascular protection after SARS-COV-2 infection.

Project description:Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination. As vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In this study, we examined 1442 genetic variables (single nucleotide polymorphisms) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests (RF) method to filter the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein and protein-protein interactions we hypothesize to be involved in the development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study shows the utility of RF for such analytical tasks, while both enhancing and reinforcing our working model of AE development after smallpox vaccination.

Dataset Information

Genetic variation in IL18R1 and IL18 genes and Inteferon ? ELISPOT response to smallpox vaccination: an unexpected relationship.

Publications

Genetic variation in IL18R1 and IL18 genes and Inteferon γ ELISPOT response to smallpox vaccination: an unexpected relationship.

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