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Principal Investigator: Micah Alan Luftig
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $457,736
Funding agency: National Institute of Dental and Craniofacial Research
ABSTRACT
Our ultimate goal to define the molecular mechanisms for EBV latency establishment and reactivation in the oral
cavity. In this proposal, we aim to characterize how EBV usurps B-cell maturation programs for cell survival and
the establishment of a continuum of cell states balancing latency-driven proliferation, differentiation, and lytic
reactivation. It is our central hypothesis that EBV establishes B-cell latent infection through mimicry of the
germinal center (GC) reaction and subsequently promotes a continuum of activation and differentiation that is
balanced to enable access to a cell state supporting lytic reactivation. We have formulated our central hypothesis
based on preliminary data including single-cell gene expression, chromatin conformation of tonsillar B cells and
EBV-immortalized cells as well as characterization of new spontaneously lytic strains of EBV. We found that
EBV latent infection promotes GC mimicry through temporal regulation of anti-apoptotic MCL-1 and BFL-1. Using
scRNA-seq of LCLs, we discovered a continuum of gene expression where NFB signaling/activation (e.g.
NFKB2, MYC, IRF8) is strongly anti-correlated with plasmablast differentiation (e.g. CD38, PRDM1, XBP1).
Furthermore, EBV lytic genes were expressed in cells most similar to the high differentiation state suggesting a
model whereby EBV-infected cells constantly sample this differentiated state to enable a switch to lytic
reactivation. Finally, using new strains of EBV we describe a paradigm of a persistent, spontaneous switch to
productive infection that is transient and reversible. Therefore, the rationale for this proposed research is that
understanding how EBV establishes latency and reactivates to productive infection provides insight into
therapeutic modalities to eliminate EBV-infected cells from the oral cavity. The underlying molecular circuitry
controlling these cell fate decisions may also provide important new information regarding the plasticity of B-cell
maturation states. We plan to test our central hypothesis and complete the objectives in this proposal through
the following three specific aims: i) to determine the molecular mechanisms by which EBV promotes B-cell
survival mimicking tonsillar B-cell maturation, ii) to define the underlying molecular circuitry supporting a novel
activation/differentiation continuum within individual EBV-immortalized B cells, and iii) to define the biochemical
and cell biological features of a newly described EBV recurrence phenotype in which latently infected cells
produce virions and return to their basal latent state.
Terms: <12-20 years old><21+ years old><Adolescence><Adult><Adult Human><Antibody-Secreting Cells><Apoptotic><Architecture><B blood cells><B cell><B cell immortalization><B cells><B lymphocyte immortalization><B-Cell Activation><B-Cells><B-Lymphocytes><B-cell><BAG3><BAG3 gene><BCL2-Associated Athanogene 3><BLIMP1><Basal Transcription Factor><Basal transcription factor genes><Benign><Biochemical><Biological><Biology><Blood Plasma Cell><Buccal Cavity><Buccal Cavity Head and Neck><Burkitt Herpesvirus><Burkitt Lymphoma Virus><Cancers><Cavitas Oris><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Fate Control><Cell Fate Regulation><Cell Lineage><Cell Maturation><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Metabolic Process><Chaperone><Chromatin><Class Switching><Class Switchings><Data><Delta transcription factor><EB virus><EBV><EBV latency><Engineering / Architecture><Epithelial Cells><Epstein Barr Virus><Epstein-Barr Virus latency><F-ACT1 protein><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Germinal Center><Glandular Fever><Goals><HHV-4><HHV4><Herpesviridae><Herpesviruses><Human><Human Herpesvirus 4><Immune><Immunes><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin-Secreting Cells><Individual><Infection><Infectious Mononucleosis><Infectious Mononucleosis Virus><Intracellular Communication and Signaling><Isotype Switching><Isotype Switchings><LYT-10 Gene><LYT10 Gene><Latent virus infection phase><Life Cycle><Life Cycle Stages><Link><Lymphatic Tissue><Lymphoid Tissue><Lytic><Lytic Virus><MCL-1><MCL1><MCL1 gene><Malignant Neoplasms><Malignant Tumor><Mediating><Memory><Memory B Cell><Memory B-Lymphocyte><Mitochondria><Modality><Modeling><Modern Man><Molecular><Molecular Chaperones><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mouth><NF-D nuclear factor><NF-E1 protein><NFKB2><NFKB2 gene><NMP-1 protein><Nuclear Factor of Kappa Light Chain Gene Enhancer in B-Cells 2><Oral><Oral cavity><PRDI-BF1><PRDM1><PRDM1 gene><Phenotype><Plasma Cells><Plasmablast><Plasmacytes><Primary Infection><Productivity><Proliferating><Proteins><RNA Expression><Reaction><Recurrence><Recurrent><Regulation><Research><Rest><Saliva><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Structure of germinal center of lymph node><Testing><Therapeutic><Tonsil><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transmission><UCRBP protein><Viral><Viral Burden><Viral Genes><Viral Load><Viral Load result><Virion><Virus><Virus Particle><XBP1><XBP1 gene><YY1><YY1 Transcription Factor><YY1 protein><Yin-Yang-1 protein><activated B cells><adolescence (12-20)><adulthood><biologic><biological signal transduction><cell immortalization><cell metabolism><cellular differentiation><cellular metabaolism><conformation><conformational><conformational state><conformationally><conformations><delta factor><herpes virus><in vivo><insight><latency/reactivation><latent infection><latent viral infection><latent virus infection><life course><malignancy><mimicry><mitochondrial><mononucleosis><myeloid cell leukemia 1><myeloid cell leukemia sequence 1><myeloid leukemia cell differentiation protein><neoplasm/cancer><novel><nuclear matrix protein 1><peripheral blood><plasma cell differentiation><plasmocyte><programs><reactivation from latency><recruit><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><tonsillar><transcription factor><transmission process><virtual><yin-yang-1>