title: Immune Cell Regulatory Pathways Unexplored as Host-Directed Therapeutic Targets for Mycobacterium tuberculosis: An Opportunity to Apply Precision Medicine Innovations to Infectious Diseases.
abstract: The lack of novel antimicrobial drugs in development for tuberculosis treatment has provided an impetus for the discovery of adjunctive host-directed therapies (HDTs). Several promising HDT candidates are being evaluated, but major advancement of tuberculosis HDTs will require understanding of the master or "core" cell signaling pathways that control intersecting immunologic and metabolic regulatory mechanisms, collectively described as "immunometabolism." Core regulatory pathways conserved in all eukaryotic cells include poly (ADP-ribose) polymerases (PARPs), sirtuins, AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) signaling. Critical interactions of these signaling pathways with each other and their roles as master regulators of immunometabolic functions will be addressed, as well as how Mycobacterium tuberculosis is already known to influence various other cell signaling pathways interacting with them. Knowledge of these essential mechanisms of cell function regulation has led to breakthrough targeted treatment advances for many diseases, most prominently in oncology. Leveraging these exciting advances in precision medicine for the development of innovative next-generation HDTs may lead to entirely new paradigms for treatment and prevention of tuberculosis and other infectious diseases.
authors.affiliation: Division of AIDS-Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Contractor to the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Mahon
authors.affiliation: Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Hafner
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000995:Antitubercular Agents / Q000627:therapeutic use*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D037761:Sirtuins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D000995:Antitubercular Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D037761:Sirtuins
keywords: host-directed therapy; immunometabolism; precision medicine; signaling pathways; tuberculosis