title: Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus.
abstract: Chikungunya virus (CHIKV) is a re-emerging global pathogen with pandemic potential, which causes fever, rash and debilitating arthralgia. Older adults over 65 years are particularly susceptible to severe and chronic CHIKV disease (CHIKVD), accounting for >90% of all CHIKV-related deaths. There are currently no approved vaccines or antiviral treatments available to limit chronic CHIKVD. Here we show that in old mice excessive, dysregulated TGFβ production during acute infection leads to a reduced immune response and subsequent chronic disease. Humans suffering from CHIKV infection also exhibited high TGFβ levels and a pronounced age-related defect in neutralizing anti-CHIKV antibody production. In vivo reduction of TGFβ levels minimized acute joint swelling, restored neutralizing antibody production and diminished chronic joint pathology in old mice. This study identifies increased and dysregulated TGFβ secretion as one key mechanism contributing to the age-related loss of protective anti-CHIKV-immunity leading to chronic CHIKVD.
authors.affiliation: Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, Arizona, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Uhrlaub
authors.affiliation: Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, Arizona, United States of America.
authors.forename: Vesna
authors.initials: V
authors.lastname: Pulko
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Victor R
authors.initials: VR
authors.lastname: DeFilippis
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Rebecca
authors.identifier: http://orcid.org/0000-0003-3740-5442
authors.initials: R
authors.lastname: Broeckel
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Streblow
authors.affiliation: Charles River, Ashland, Ohio, United States of America.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Coleman
authors.affiliation: Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Byung S
authors.identifier: http://orcid.org/0000-0003-3516-7516
authors.initials: BS
authors.lastname: Park
authors.affiliation: Department of Microbiology, University of the West Indies, Mona, Kingston, Jamaica.
authors.forename: John F
authors.initials: JF
authors.lastname: Lindo
authors.affiliation: Department of Microbiology, University of the West Indies, Mona, Kingston, Jamaica.
authors.forename: Ivan
authors.initials: I
authors.lastname: Vickers
authors.affiliation: Department of Microbiology, University of the West Indies, Mona, Kingston, Jamaica.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Anzinger
authors.affiliation: Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, Arizona, United States of America.
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Žugich
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D065632:Chikungunya Fever / Q000276:immunology*; D002646:Chikungunya virus; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D016212:Transforming Growth Factor beta