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Principal Investigator: CARL Francis NATHAN
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $211,875
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Mycobacterium tuberculosis (Mtb) was the world’s single leading cause of death from infection before COVID-
19. Direct-acting antimycobacterial regimens are long, often toxic and plagued by emergence of drug resistance.
Adjunctive therapies could potentially speed the cure of tuberculosis by targeting a process in the host that alters
the host-pathogen interaction to the advantage of the host. One potential form of host-directed therapy would be
to help macrophages better survive Mtb infection. In vitro, the death of Mtb-infected mouse macrophages is co-
dependent on a type I interferon (IFN), IFN-beta, that macrophages produce in response to Mtb, along with an
additional contribution by Mtb. This application seeks to identify specific molecular participants in Mtb-induced
macrophage death that are downstream of the type I IFN receptor. We have identified potential molecular
participants by two approaches—a CRISPR activation screen that restored Mtb-induced cell death to
macrophages lacking the type I IFN receptor, and an innovative biochemical pulldown approach using a probe
based on a small chemical compound that rescues Mtb-infected macrophages from Mtb-induced cell death
without impairing the growth of Mtb. This application aims to validate the candidates genetically, test the ability
of already existing inhibitors to recapitulate the effect of knocking them out, and then place the validated
candidates on a mechanistic path. That would set the stage for future studies, beyond the scope of this
application, to find, improve or develop drug-like inhibitors for tests in preclinical models of TB to see if they
mitigate pathology and hasten cure when used in combination with direct-acting antimycobacterial agents.
Terms: <(IFN) α><(IFN)-α><(IFN)α><1-Propene-1,2,3-tricarboxylic acid><Achilleic Acid><Aconitate><Aconitic Acid><Acontic Acid><Adonic Acid><Alferon><Alpha-Beta-Omega Interferon Receptor-1><Animal Model><Animal Models and Related Studies><Anti Mycobacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antimycobacterial Agents><Antiviral Protein Alpha Type><Apoptosis><Apoptosis Pathway><Basal Transcription Factor><Basal transcription factor genes><Binding><Biochemical><Biogenesis><COVID-19><CRISPR activation><CRISPR activator><CRISPR based activation><CRISPR gene activation><CRISPR transcription activation><CRISPR transcriptional activation><CRISPR-Cas-9-mediated gene activation><CRISPR-based gene activation><CRISPR-dCAS9 Activator><CRISPR-mediated transcriptional activation><CRISPR/CAS9 activation><CRISPR/CAS9 gene activation><CRISPR/dCas9 activation><CRISPR/dCas9-based transcriptional activation><CRISPRa><CV-19><Carboxy-Lyases><Carboxyglutaconic Acid><Cathepsins><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Death><Cell Death Induction><Cell Line><Cell Signaling><CellLine><Cells><Cessation of life><Chemicals><Citridic Acid><Citridinic Acid><Clinical Treatment Moab><Cods><Coronavirus Infectious Disease 2019><Death><Decarboxylases><Drug resistance><Drugs><Endogenous Interferon Beta><Enzyme Gene><Enzymes><Equisetic Acid><Esteroproteases><Fibroblast Interferon><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><GPR84><GPR84 gene><Gadidae><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Goals><Growth><HuIFN-Alpha-Rec><IFN Alpha><IFN α><IFN-Beta><IFN-α><IFN-β><IFNAR><IFNAR1><IFNAR1 gene><IFNBR><IFNa><IFNb><IFNα><IFRC><Immune Response Genes><Impairment><In Vitro><Individual><Infection><Inflammation><Interferon Alfa-n3><Interferon Alpha-Beta Receptor Alpha Chain><Interferon Type I><Interferon alpha><Interferon-beta><Interferon-α><Interferon-β><Intracellular Communication and Signaling><Ir Gene><Learning><Leukocyte Interferon><Link><Lymphoblast Interferon><Lymphoblastoid Interferon><Lysosomes><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Macrophage><Mediating><Medication><Medium chain fatty acid><Mice><Mice Mammals><Miscellaneous Antibiotic><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mφ><Natural Interferon Beta><Natural human interferon beta><Necrotic Lesion><Origin of Life><Orphan><Participant><Pathology><Pathway interactions><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Pre-Clinical Model><Preclinical Models><Process><Programmed Cell Death><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Pyrocitric Acid><Receptor Protein><Regimen><Resistance><Role><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Strains Cell Lines><TB infection><TB therapy><TB treatment><Testing><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Tuberculosis><Virulent><Virus><activating CRISPR technology><angiotensinase C><antimycobacterial><bactericidal><bactericide><biological signal transduction><candidate identification><candidate validation><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cultured cell line><cytokine><disseminated TB><disseminated tuberculosis><drug resistant><drug-like chemical><drug-like compound><drug-like molecule><drug/agent><experiment><experimental research><experimental study><experiments><gene product><genetic approach><genetic strategy><ifnar1 gene product><improved><infection due to Mycobacterium tuberculosis><inhibitor><innovate><innovation><innovative><lysosomal Pro-X carboxypeptidase><lysosomal carboxypeptidase C><mAbs><model of animal><monoclonal Abs><mtb><necrocytosis><ontogeny><overexpress><overexpression><pathogen><pathway><proline carboxypeptidase><prolylcarboxypeptidase><receptor><resistance to Drug><resistant><resistant to Drug><response><social role><success><transcription factor><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><type I IFN receptor><type I interferon receptor>