Environmental arsenic, immunoregulation, and viral disease risk

环境砷、免疫调节和病毒性疾病风险

• 批准号: 10589936
• 负责人: JAMES A COFFMAN
• 金额: $ 19.48万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589936
• 关键词: Acute; Adrenal Glands; Adult; Affect; Animal Model; Anti-Inflammatory Agents; Arsenic; Biological Models; Bronchiectasis; Cells; Cessation of life; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Color; Development; Disease; Down-Regulation; Embryo; Endocrine Disruptors; Environmental Exposure; Epigenetic Process; Experimental Models; Exposure to; Failure; Fluorescence Microscopy; Food; Gene Dosage; Gene Expression; Gene Expression Profiling; Generations; Genes; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Heterozygote; Human; Hydrocortisone; Hypothalamic structure; Image; Immune; Immune response; Immune system; Inbreeding; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza A Virus, H1N1 Subtype; Influenza A virus; Innate Immune Response; Innate Immune System; Knock-out; Label; Larva; Leukocytes; Life; Macrophage; Measures; Mediating; Modeling; Morbidity - disease rate; NF-kappa B; Optics; Pathway interactions; Persons; Pituitary Gland; Predisposition; Public Health; Puerto Rico; Receptor Signaling; Reporter; Reporting; Repression; Research; Research Project Grants; Resolution; Respiratory Signs and Symptoms; Sampling; Severities; Severity of illness; Signal Pathway; Signal Transduction; Site; Study models; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Viral; Virus; Virus Diseases; Visualization; Zebrafish; cell type; circadian pacemaker; disorder risk; dosage; dynamic system; early life exposure; epidemiological model; flu; immunoregulation; in vivo; in vivo Model; influenza infection; intergenerational; knockout gene; lung injury; mortality; mortality risk; mutant; neutrophil; novel; pathogen; respiratory virus; response; tool; trafficking; transcription factor; transmission process; well water

PROJECT SUMMARY / ABSTRACT Arsenic exposure from well water and food is a major public health concern and is associated with increased morbidity and mortality from viral infections. Influenza A virus (IAV) annually infects ~5 million people causing acute respiratory symptoms and up to 646,000 deaths. The severity of viral disease varies between individuals and is likely to involve both genetic and environmental effects on immunoregulation. Epidemiological and animal model studies suggest that early life exposure to arsenic alters the immune response to pathogens, resulting in prolonged or excessive inflammation. Furthermore, available evidence indicates that arsenic is an endocrine disruptor that interferes with the glucocorticoid receptor (GR) signaling pathway, a critical regulator of inflammation, possibly with intergenerational epigenetic effects. However, significant gaps remain in our understanding of how arsenic disrupts GR signaling and promotes inflammation. This exploratory/ developmental research project will use zebrafish as a model system to test the novel hypothesis that arsenic exacerbates viral disease by downregulating the klf9-dependent anti-inflammatory GR signaling pathway. Preliminary studies indicate that Klf9 is a GR-responsive negative regulator of proinflammatory genes, and that basal and cortisol- induced klf9 activity is suppressed in zebrafish embryos exposed to very low levels of arsenic. Zebrafish larvae have a functional innate immune system and are a powerful model to study host-pathogen interactions during systemic or localized influenza (IAV) infection, as trafficking of macrophages and neutrophils to the site of IAV infection can be visualized using live imaging with transgenic lines with fluorescently labeled leukocytes as well as fluorescently labeled viruses. The proposed research will use those tools, as well as GR amd klf9 knockout lines that we recently created using CRISPR, to accomplish two specific aims. The first is to determine if arsenic dysregulates the inflammatory response to IAV infection by suppressing the anti-inflammatory GR-Klf9 signaling pathway, leading to excessive an/or prolonged pro-inflammatory gene expression and failure to resolve the response. This will be accomplished by asking how treatment of zebrafish larvae with arsenic affects expression of klf9 and downstream proinflammatory genes that we have identified as putative targets of Klf9-mediated repression, and assessing the effects of arsenic and klf9 dosage on the response dynamics of inflammatory cells (neutrophils and macrophages) and NF-kB activity following IAV infection. The second specific aim is to determine if arsenic exposure has intergenerational effects on the innate immune response to IAV infection that correlate with aberrant activity of the GR-Klf9 immunoregulatory pathway. To accomplish this, F0 arsenic- or vehicle-exposed wild-type larvae will be raised to adulthood and inbred through 2 generations without further exposure. In larvae from each generation (F1 and F2) we will assess immunoregulatory gene expression and larval survival after IAV infection. The project will elucidate a novel anti-viral immunoregulatory pathway impacted by arsenic, opening an avenue for future research focused on further elucidating the underlying mechanisms.

项目摘要/摘要