title: Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis.
abstract: Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Although some degree of inflammation is required for protection, progressive inflammation may worsen disease and ultimately prevents pathogen eradication. To define molecular pathways leading to or diverting from pathogenic inflammation in infection, we resorted to dendritic cells (DCs), known to activate distinct signaling pathways in response to pathogens. We found that distinct intracellular pathways mediated the sensing of conidia and hyphae by lung DCs in vitro, which translate in vivo in the activation of protective Th1/Treg responses by conidia or inflammatory Th2/Th17 responses by hyphae. In vivo targeting inflammatory (PI3K/Akt/mTOR) or anti-inflammatory (STAT3/IDO) DC pathways by intranasally delivered small interfering RNA (siRNA) accordingly modified inflammation and immunity to infection. Thus, the screening of signaling pathways in DCs through a systems biology approach may be exploited for the development of siRNA therapeutics to attenuate inflammation in respiratory fungal infections and diseases.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bonifazi
authors.forename: C
authors.initials: C
authors.lastname: D'Angelo
authors.forename: S
authors.initials: S
authors.lastname: Zagarella
authors.forename: T
authors.initials: T
authors.lastname: Zelante
authors.forename: S
authors.initials: S
authors.lastname: Bozza
authors.forename: A
authors.initials: A
authors.lastname: De Luca
authors.forename: G
authors.initials: G
authors.lastname: Giovannini
authors.forename: S
authors.initials: S
authors.lastname: Moretti
authors.forename: R G
authors.initials: RG
authors.lastname: Iannitti
authors.forename: F
authors.initials: F
authors.lastname: Fallarino
authors.forename: A
authors.initials: A
authors.lastname: Carvalho
authors.forename: C
authors.initials: C
authors.lastname: Cunha
authors.forename: F
authors.initials: F
authors.lastname: Bistoni
authors.forename: L
authors.initials: L
authors.lastname: Romani
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001228:Aspergillosis / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D015153:Blotting, Western; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000276:immunology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000276:immunology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse