title: Fine-tuning of macrophage activation using synthetic rocaglate derivatives.
abstract: Drug-resistant bacteria represent a significant global threat. Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. As IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using an interferon-inducible nuclear protein Ipr1 as a biomarker of macrophage activation, we performed a high-throughput screen and identified molecules that synergized with low concentration of IFNγ. Several active compounds belonged to the flavagline (rocaglate) family. In primary macrophages a subset of rocaglates 1) synergized with low concentrations of IFNγ in stimulating expression of a subset of IFN-inducible genes, including a key regulator of the IFNγ network, Irf1; 2) suppressed the expression of inducible nitric oxide synthase and type I IFN and 3) induced autophagy. These compounds may represent a basis for macrophage-directed therapies that fine-tune macrophage effector functions to combat intracellular pathogens and reduce inflammatory tissue damage. These therapies would be especially relevant to fighting drug-resistant pathogens, where improving host immunity may prove to be the ultimate resource.
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, 02118, USA.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Bhattacharya
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, 02118, USA.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, 02215, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Devine
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA, 02115, USA.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.affiliation: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, 02215, USA.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Beeler
authors.affiliation: Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, 02215, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, 02118, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D005604:Francisella tularensis / Q000187:drug effects; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007370:Interferon Type I / Q000037:antagonists & inhibitors; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010865:Pilot Projects; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; C494258:Irf1 protein, mouse; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II