title: An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens.
abstract: The healthy lung maintains a steady state of immune readiness to rapidly respond to injury from invaders. Integrins are important for setting the parameters of this resting state, particularly the epithelial-restricted αVβ6 integrin, which is upregulated during injury. Once expressed, αVβ6 moderates acute lung injury (ALI) through as yet undefined molecular mechanisms. We show that the upregulation of β6 during influenza infection is involved in disease pathogenesis. β6-deficient mice (β6 KO) have increased survival during influenza infection likely due to the limited viral spread into the alveolar spaces leading to reduced ALI. Although the β6 KO have morphologically normal lungs, they harbor constitutively activated lung CD11b+ alveolar macrophages (AM) and elevated type I IFN signaling activity, which we traced to the loss of β6-activated transforming growth factor-β (TGF-β). Administration of exogenous TGF-β to β6 KO mice leads to reduced numbers of CD11b+ AMs, decreased type I IFN signaling activity and loss of the protective phenotype during influenza infection. Protection extended to other respiratory pathogens such as Sendai virus and bacterial pneumonia. Our studies demonstrate that the loss of one epithelial protein, αVβ6 integrin, can alter the lung microenvironment during both homeostasis and respiratory infection leading to reduced lung injury and improved survival.
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Victoria A
authors: VA
authors: Meliopoulos
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Lee-Ann
authors: LA
authors: Van de Velde
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Nicholas C
authors: NC
authors: Van de Velde
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Erik A
authors: EA
authors: Karlsson
authors: The Hartwell Center, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Geoff
authors: G
authors: Neale
authors: Department of Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Peter
authors: P
authors: Vogel
authors: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Cliff
authors: 0000-0001-7486-7107
authors: C
authors: Guy
authors: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Shalini
authors: S
authors: Sharma
authors: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Susu
authors: S
authors: Duan
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Sherri L
authors: SL
authors: Surman
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Bart G
authors: BG
authors: Jones
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Michael D L
authors: MD
authors: Johnson
authors: Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America.
authors: Catharine
authors: C
authors: Bosio
authors: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors: Lisa
authors: L
authors: Jolly
authors: Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.
authors: R Gisli
authors: RG
authors: Jenkins
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Julia L
authors: JL
authors: Hurwitz
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Jason W
authors: JW
authors: Rosch
authors: Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, UCSF Medical Center, San Francisco, California, United States of America.
authors: Dean
authors: D
authors: Sheppard
authors: Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Paul G
authors: PG
authors: Thomas
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.|Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Peter J
authors: PJ
authors: Murray
authors: Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Stacey
authors: S
authors: Schultz-Cherry
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D016023:Integrins / Q000276:immunology*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D012141:Respiratory Tract Infections / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D007370:Interferon Type I; C073878:integrin alphavbeta6