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Principal Investigator: Abha Sahni
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2022
Award: $197,500
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Active Follow-up><Address><Affect><Agreement><Allergy><Animal Model><Animal Models and Related Studies><Anti-Infective Agents><Anti-Infective Drugs><Anti-Infectives><Anti-infective Preparation><AntiInfective Drugs><AntiInfectives><Antiinfective Agents><Area><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Biogenesis><Biological><Biological Function><Biological Process><Biology><Blood><Blood Reticuloendothelial System><Body Tissues><Brain><Brain Nervous System><C3H/HeN Mouse><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Cerebral Edema><ChIP Sequencing><ChIP-seq><Chemosensitization><Chemosensitization/Potentiation><Code><Coding System><Communicable Diseases><Cytotoxic cell><DNA><DNA Directed RNA Polymerase II Polypeptide A><DNA Endonuclease><DNA binding protein inhibitor><DNA-Dependent RNA Polymerase II><DNA-Directed RNA Polymerase II Largest Subunit><DNA-binding protein inhibitor ID-2><DNase I><Data Set><Dataset><Dendritic Cells><Deoxyribonuclease I><Deoxyribonucleic Acid><Development><Disease><Disease Progression><Disorder><Dropsy><Dysfunction><E protein><E1A Binding Protein p300><EP300><EP300 gene><Edema><Elements><Encephalon><Encyclopedia of DNA Elements><Endothelial Cells><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Functional RNA><Functional disorder><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Transcription><Genomics><Goals><HLH Motifs><Helix-Loop-Helix Domain><Helix-Loop-Helix Motifs><Human><Human Genome><Hydrops><Hypersensitivity><ID DNA Binding Protein Inhibitor><ID2><ID2 gene><Id protein><Id-2 protein><Id2 protein><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immune system><Immunes><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunology><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inhibitor of DNA Binding 2><Inhibitor of Differentiation 2><Inhibitor of Differentiation Protein 2><Inhibitor of Differentiation Proteins><Investigation><K lymphocyte><KAT3B><Knowledge><L-Lysine><Link><Lung><Lung Respiratory System><Lysine><MGC26389><Maintenance><Mediating><Messenger RNA><Mice><Mice Mammals><Microbiology><Modern Man><Modification><Molecular><Murine><Mus><Mφ><NK Cells><Natural Killer Cells><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleotides><Organ><Organ System><Origin of Life><Outcome><POLR2A><POLR2A gene><Pancreatic DNase><Pathogenesis><Pathogenicity><Physiologic><Physiological><Physiopathology><Poly(A) Tail><Potentiation><Predisposition><Proteins><Publishing><R conorii><R. conorii><RNA><RNA Expression><RNA Gene Products><RNA Polymerase B><RNA Polymerase II><RNA Polymerase II 220 kD Subunit><RNA Seq><RNA Splicing><RNA sequencing><RNAseq><RPO2><RPOL2><Regulation><Regulator Genes><Ribonucleic Acid><Rickettsia><Rickettsia Infections><Rickettsia conorii><Rickettsial Infectious Disease><Rickettsial Infectious Disorder><Rickettsiales><Rickettsiales disease><Rickettsiosis><Role><Shapes><Site><Spleen><Spleen Reticuloendothelial System><Splicing><Susceptibility><System><T memory cell><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Thymonuclease><Tissues><Transcript><Transcription><Transcription Factor Proto-Oncogene><Transcription Initiation Site><Transcription Regulation><Transcription Start Site><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transcriptional Regulatory Elements><Untranslated RNA><Up-Regulation><Upregulation><Vaccine Adjuvant><Vascular Permeabilities><Veiled Cells><active followup><allergic/immunologic body system><allergic/immunologic organ system><alpha helix><antagonist><base><biologic><body system><cell mediated immune response><cell type><chromatin immunoprecipitation-sequencing><communicable disease control agent><dark matter><defined contribution><developmental><follow up><follow-up><followed up><followup><helix-loop-helix protein differentiation inhibitor><histone acetyltransferase p300><histone methylation><host response><hsRPB1><hsRPB2><human disease><human model><human whole genome><immune activation><immune system response><immunoresponse><in vivo Model><inhibitor of DNA binding 2 protein><inhibitor of differentiation 2 protein><insight><mRNA><macrophage><mammalian genome><memory T lymphocyte><microbe pathogen><microbial><microbial pathogen><migration><model of animal><model of human><model organism><monolayer><mouse model><murine model><new approaches><noncoding><novel><novel approaches><novel strategies><novel strategy><p300><pathogenic microbe><pathophysiology><polypeptide><prevent><preventing><programs><promoter><promotor><pulmonary><regulatory gene><response><rickettsial disease><social role><spotted fever><therapeutic agent development><therapeutic development><therapeutic target><thymus derived lymphocyte><tick-borne><tickborne><trans acting element><transcription factor><transcriptome sequencing><vascular inflammation><α-helix>