title: Autophagy, TGF-β, and SMAD-2/3 Signaling Regulates Interferon-β Response in Respiratory Syncytial Virus Infected Macrophages.
abstract: Human respiratory syncytial virus (RSV) is a lung tropic virus causing severe airway diseases including bronchiolitis and pneumonia among infants, children, and immuno-compromised individuals. RSV triggers transforming growth factor-β (TGF-β) production from lung epithelial cells and TGF-β facilitates RSV infection of these cells. However, it is still unknown whether RSV infected myeloid cells like macrophages produce TGF-β and the role of TGF-β if any during RSV infection of these cells. Our study revealed that RSV infected macrophages produce TGF-β and as a consequence these cells activate TGF-β dependent SMAD-2/3 signaling pathway. Further mechanistic studies illustrated a role of autophagy in triggering TGF-β production from RSV infected macrophages. In an effort to elucidate the role of TGF-β and SMAD-2/3 signaling during RSV infection, we surprisingly unfolded the requirement of TGF-β-SMAD2/3 signaling in conferring optimal innate immune antiviral response during RSV infection of macrophages. Type-I interferon (e.g., interferon-β or IFN-β) is a critical host factor regulating innate immune antiviral response during RSV infection. Our study revealed that loss of TGF-β-SMAD2/3 signaling pathway in RSV infected macrophages led to diminished expression and production of IFN-β. Inhibiting autophagy in RSV infected macrophages also resulted in reduced production of IFN-β. Thus, our studies have unfolded the requirement of autophagy-TGF-β-SMAD2/3 signaling network for optimal innate immune antiviral response during RSV infection of macrophages.
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University Pullman, WA, USA.
authors.forename: Swechha M
authors.initials: SM
authors.lastname: Pokharel
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University Pullman, WA, USA.
authors.forename: Niraj K
authors.initials: NK
authors.lastname: Shil
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University Pullman, WA, USA.
authors.forename: Santanu
authors.initials: S
authors.lastname: Bose
mesh_terms: D000818:Animals; D000998:Antiviral Agents; D001343:Autophagy / Q000502:physiology; D000071186:Beclin-1 / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D000067996:RAW 264.7 Cells; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D000071186:Beclin-1; D007370:Interferon Type I; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D016899:Interferon-beta
keywords: SMAD; TGF-β; autophagy; interferon-β; macrophages; respiratory syncytial virus