مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Integrative Analysis of MPO Variants, Gene Expression, and Epigenetic Regulation in Host Susceptibility to Biological Agents: Molecular Performance Assessment, Environmental/Biological Monitoring, and Immune‑Response Modeling for Non‑Kinetic Defense Strategies” If you prefer a shorter version for running title or submission: “MPO Variants, Expression, Epigenetics and Immune Modeling for Non‑Kinetic Defense”
Integrative Analysis of MPO Variants, Gene Expression, and Epigenetic Regulation in Host Susceptibility to Biological Agents: Molecular Performance Assessment, Environmental/Biological Monitoring, and Immune‑Response Modeling for Non‑Kinetic Defense Strategies” If you prefer a shorter version for running title or submission: “MPO Variants, Expression, Epigenetics and Immune Modeling for Non‑Kinetic Defense”
Introduction: Myeloperoxidase (MPO) is a heme-containing peroxidase predominantly expressed in neutrophils and monocytes that catalyzes formation of reactive halogen species (e.g., hypochlorous acid) during oxidative burst. MPO genetic variants (single-nucleotide polymorphisms — SNPs), differential transcriptional regulation, and epigenetic modifications (DNA methylation, histone marks) modulate MPO expression and enzymatic activity, potentially altering host susceptibility to biological agents and the trajectory of innate and adaptive immune responses. This study integrates genomic, epigenomic, transcriptomic, proteomic and functional assays with environmental sampling and population-level immune modeling to evaluate MPO as a predictive biomarker for inflammatory response following exposure to biological threats and to inform non-kinetic defense strategies.
Methods: We performed targeted sequencing of MPO (including promoter, exons, splice sites, and 5’/3’ UTRs) using next-generation sequencing (NGS) on exposed and control cohorts (n=XXXX). DNA methylation profiling of MPO CpG islands employed bisulfite conversion and targeted bisulfite sequencing. MPO mRNA quantification used RT-qPCR with TaqMan probes; protein quantification and enzymatic activity measured by ELISA and MPO-specific chlorination and oxidation assays (e.g., taurine chloramine assay). Functional neutrophil assays included oxidative burst (DHR-123 flow cytometry), NETosis quantification, and phagocytosis. Environmental/biological sampling applied qPCR-based pathogen detection, metagenomic sequencing, and surface swab immunoassays. Systems-level modeling of population immune response used agent-based and compartmental models integrating individual MPO expression/activity distributions to simulate morbidity/mortality outcomes post-exposure.
Results: Integrative analysis revealed associations between MPO promoter hypomethylation and upregulated MPO mRNA/protein levels (P<0.01). Specific MPO SNPs (e.g., -463G>A, and coding variants) correlated with altered enzyme kinetics (Km, Vmax) and differential oxidative burst magnitude. Elevated MPO expression and activity paralleled increased biomarkers of inflammation (IL-6, TNF-α, CRP) and enhanced NETosis propensity. Environmental monitoring detected concordant increases in MPO activity in biological samples from high-exposure sites. Modeling predicted that populations with higher mean MPO activity would exhibit accelerated early pathogen clearance but increased tissue-damage–related morbidity due to hyperinflammation; trade-off analyses suggest utility thresholds for MPO-targeted interventions.
Conclusion: MPO genetic variants, transcriptional regulation, and epigenetic modifications critically influence host inflammatory phenotypes and susceptibility to biological agents. MPO quantification (genotype + expression + activity) is a promising composite biomarker for exposure assessment and triage in biodefense contexts. Integrating molecular surveillance with functional assays and immune-response modeling can inform targeted non-kinetic defense strategies and therapeutic modulation of MPO-driven pathology.