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Principal Investigator: Daniel Pearce Depledge
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2020
Award: $545,420
Funding agency: National Institute of Allergy and Infectious Diseases
7. PROJECT SUMMARY / ABSTRACT
Chemical modification of mRNA provides a powerful means to dynamically alter gene expression in eukaryotes
via epitranscriptomic changes. In particular, methylation of adenosine at the N6 position (m6A) constitutes the
most widespread internal base modification to mRNA. Modification of mRNA by m6A influences numerous
biological processes including development, differentiation, reprogramming, circadian rhythm, cell cycle,
disease pathogenesis, and stress responses including virus infection. Significantly, virus-encoded mRNAs are
also chemically modified by m6A, and a role for m6A in Human Cytomegalovirus (HCMV) infection biology is
emerging. As a canonical TORCH (T. gondii, other, rubella virus, HCMV, HSV) pathogen, primary HCMV
infection during pregnancy remains the leading viral cause of birth defects. While HCMV infection causes mild
if any maternal morbidity and is predominately asymptomatic in healthy individuals, it results in life-threatening
disease among the immunocompromised, including solid-organ or stem cell transplant recipients, and is a
significant source of congenital morbidity and mortality among newborn infants in the developed world.
Addressing HCMV congenital infection remains a serious unmet medical need as there is no HCMV vaccine to
prevent primary infection during pregnancy and no current treatment to prevent transmission from mother to
fetus. Our long-term objective is to understand how the chemical modification of host and/or viral RNA
by m6A impacts reproduction of HCMV, a common infection that remains the leading viral cause of
congenital abnormalities. Preliminary results demonstrate that cellular m6A methyltransferase subunits
METTL3/14, the m6A demethylase ALKBH5, and m6A recognition proteins regulate HCMV reproduction and
responses to double strand DNA (dsDNA) in uninfected cells. This is achieved in part through changes in
interferon b gene (IFNB1) expression. These findings establish that m6A RNA modification enzymes regulate
cellular responses to HCMV and dsDNA sensing, which shapes host immunity and contributes to autoimmune
disease. It further suggests that m6A epitranscriptomic changes play a fundamental role in cell-intrinsic innate
immune responses to the TORCH pathogen HCMV. Based upon our preliminary results, we hypothesize that
HCMV reproduction is differentially controlled by the host m6A modification machinery. Here, this hypothesis
will be tested in three specific aims designed to: (i) identify how the host m6A modification machinery is
regulated in response to HCMV infection; (ii) determine how cellular m6A modification enzymes regulate IFNB1
mRNA accumulation in HCMV-infected cells; and (iii) identify how HCMV gene expression is impacted by
differential m6A modification. The project is significant because it investigates how epitranscriptomic changes
impact HCMV reproduction and innate immunity. Understanding how HCMV infection is regulated by
epitranscriptomic RNA modification could lead to new opportunities for therapeutic intervention and possibly
new strategies for vaccine development.
Terms: <0-4 weeks old><Address><Adenosine><Autoimmune Diseases><Biological Function><Biological Process><Biology><Birth Defects><CMV><CMV infection><Cell Body><Cell Cycle><Cell Division Cycle><Cells><Chemicals><Circadian Rhythms><Congenital Abnormality><Congenital Anatomic Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Cytomegalic Inclusion Disease><Cytomegalovirus><Cytomegalovirus Infections><Data><Development><Disease><Disorder><Double-Stranded DNA><EC 2.1.1><Endogenous Interferon Beta><Enzyme Gene><Enzymes><Eukaryota><Eukaryote><Fetus><Fibroblast Interferon><Gene Expression><Genes><German Measles Virus><Gestation><HCMV><HHV 5><HHV5><HSV><Herpes Simplex Virus><Herpes labialis Virus><Human><Human Herpesvirus 5><IFN-Beta><IFN-β><IFNb><Immune response><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunosuppressed Host><Inclusion Disease><Individual><Infection><Infection specific to the perinatal period><Innate Immune Response><Innate Immunity><Interferon-beta><Interferon-β><Kinases><Lead><Life><Mediating><Medical><Messenger RNA><Methylation><Methyltransferase><Modern Man><Modification><Morbidity><Morbidity - disease rate><Mothers><Native Immunity><Natural Immunity><Natural Interferon Beta><Natural human interferon beta><Newborn Infant><Newborns><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nyctohemeral Rhythm><Organ><Pathogenesis><Pb element><Perinatal Infection><Phosphotransferase Gene><Phosphotransferases><Play><Position><Positioning Attribute><Pregnancy><Primary Infection><Process><Progenitor Cell Transplantation><Proteins><RNA><RNA Gene Products><Reader><Regulation><Reproduction><Ribonucleic Acid><Role><Rubella virus><Salivary Gland Virus Disease><Salivary Gland Viruses><Sepsis - perinatal><Shapes><Signal Pathway><Simplexvirus><Solid><Source><Stem Cell Transplantation><Stem cell transplant><T gondii><T. gondii><Testing><Therapeutic Intervention><Toxoplasma gondii><Transmission><Transphosphorylases><Transplant Recipients><Twenty-Four Hour Rhythm><Vaccine Design><Vaccines><Viral><Viral Diseases><Viral Genes><Virus><Virus Diseases><autoimmune disorder><base><biological adaptation to stress><circadian process><congenital infection><cytomegalovirus group><daily biorhythm><design><designing><develop a vaccine><development of a vaccine><developmental><ds-DNA><dsDNA><epitranscriptomics><heavy metal Pb><heavy metal lead><host response><immunoresponse><immunosuppressed patient><intervention therapy><mRNA><maternal morbidity><methylase><mortality><new drug treatments><new drugs><new therapeutics><new therapy><newborn child><newborn children><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathogen><prevent><preventing><reaction; crisis><recruit><response><social role><stress response><stress; reaction><transmethylase><transmission process><transplant patient><vaccine development><vaccine formulation><viral RNA><viral infection><virus RNA><virus infection><virus-induced disease>