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Defining the roles of an enhancer long non-coding RNA eIncRNA-ID2 in rickettsial pathogenesis and immunity

定义增强子长链非编码 RNA eIncRNA-ID2 在立克次体发病机制和免疫中的作用

基本信息

批准号：
10323675
负责人：
Abha Sahni
金额：
$ 19.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-04 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323675
关键词：
Address Affect Agreement Animal Model Anti-Infective Agents Area B-Lymphocytes Bacteria Biogenesis Biological Biological Process Biology Blood Brain C3H/HeN Mouse CD8-Positive T-Lymphocytes Cells Cellular Immunity Cerebral Edema ChIP-seq Chemosensitization Code Communicable Diseases DNA Data Set Dendritic Cells Deoxyribonuclease I Development Disease Disease Progression E protein EP300 gene Edema Elements Encyclopedia of DNA Elements Endothelial Cells Enhancers Epigenetic Process Functional disorder Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genomics Goals Helix-Loop-Helix Motifs Human Human Genome Hypersensitivity ID2 gene Immune Immune System Diseases Immune response Immune system Immunity Immunology In Vitro Infection Inflammation Inhibitor of Differentiation Proteins Investigation Knowledge Link Lung Lysine Maintenance Mediating Messenger RNA Microbiology Modification Molecular Mus Natural Killer Cells Nucleotides Organ Outcome POLR2A gene Pathogenesis Pathogenicity Physiological Poly(A) Tail Predisposition Proteins Publishing RNA RNA Polymerase II RNA Splicing Regulation Regulator Genes Rickettsia Rickettsia Infections Rickettsia conorii Role Shapes Site Spleen System T memory cell T-Lymphocyte Testing Therapeutic Tissues Transcript Transcription Initiation Site Transcriptional Regulation Untranslated RNA Up-Regulation Vaccine Adjuvant Vascular Permeabilities alpha helix antagonist base body system cell mediated immune response cell type dark matter defined contribution follow-up histone methylation human disease human model immune activation in vivo Model insight macrophage mammalian genome microbial migration monolayer mouse model novel novel strategies pathogenic microbe polypeptide prevent programs promoter response spotted fever therapeutic development therapeutic target tick-borne transcription factor transcriptome sequencing vascular inflammation

项目摘要

PROJECT SUMMARY Precise and dynamic alterations in gene expression are critical determinants of the regulation of host immunity to microbial pathogens. Pathogenic rickettsiae in the spotted fever group cause some of the most severe infectious diseases in humans, characterized by microvascular inflammation and dysfunction attributed to disseminated infection of endothelial cells and increased vascular permeability resulting in pulmonary/cerebral edema. Long non-coding (lnc) RNAs of ≥ 200 nucleotides regulate a panoply of biological responses through an array of mechanisms and changes in their expression levels are now intricately linked to the determination of innate as well as cell-mediated immune responses. As an important subset of lncRNAs, enhancer lncRNAs implement their regulatory roles by enhancing protein coding genes (PCGs) in a cis- or trans-acting manner. We performed RNA-sequencing on the lungs as one of the predominantly affected target organs of susceptible mice infected with R. conorii to identify up-regulation of 179 lncRNAs. Via follow-up analysis to differentiate enhancer (elnc) from promoter-associated (plnc) RNAs based on the ratio of single- versus tri-methylation of histone 3 at lysine 4 (H3K4Me1:H3K4Me3) and other active enhancer signatures based on POLR2A, p300, DNase I hypersensitivity sites, CTCF, and Hi-3C ChIP-Seq datasets, we further determined significantly higher expression of an active elncRNA013718 and its target PCG Inhibitor of DNA binding 2 (ID2) in the mouse lungs, spleen, and CD8+ T-cells during Rickettsia conorii infection. Our preliminary findings further suggest that elncRNA013718 positively regulates the expression of ID2, a protein antagonist of E protein transcription factors and a regulator of T cells in the immune system. Accordingly, we refer to elncRNA013718 as elncRNA- ID2 and hypothesize novel contributory roles for elncRNA-ID2:Id2 interplay in the regulation of protective host immunity during rickettsial infections. We propose to test this hypothesis via two independent yet thematically interlinked specific aims. Aim 1 will distinguish cell type-specific expression and functional roles of elncRNA- ID2 and ID2 in the host lungs and spleen in experimental murine models of R. conorii and R. australis infection. In Aim 2, we will determine the modulatory effects of both global and cell-specific interference with elncRNA- ID2 on host immune responses and disease progression/outcome. Given the complexity of cellular immune responses, we will employ two independent and established in vivo models of infection closely mimicking the pathophysiology of human rickettsioses and cutting-edge approaches of cellular microbiology and immunology to determine the regulatory potential of elncRNA-ID2 as a novel elncRNA in the molecular circuitry underlying regulation of host immunity. The acquired insights will enhance our knowledge of context-specific physiological roles of elncRNA-ID2 in the determination of host responses to pathogenic rickettsiae and reveal potentially unique entry points for novel strategies to enhance host immunity against intracellular microbial infections.

项目总结