Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus

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 ar...

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Bibliographic Details
Published in:PLoS pathogens 2016-10, Vol.12 (10), p.e1005891-e1005891
Main Authors: Uhrlaub, Jennifer L, Pulko, Vesna, DeFilippis, Victor R, Broeckel, Rebecca, Streblow, Daniel N, Coleman, Gary D, Park, Byung S, Lindo, John F, Vickers, Ivan, Anzinger, Joshua J, Nikolich-Žugich, Janko
Format: Article
Language:English
Subjects:
Adult
Aged
Aging - immunology
Animals
Antibodies, Neutralizing - blood
Antibodies, Neutralizing - immunology
Antibodies, Viral - blood
Antibodies, Viral - immunology
Biology and life sciences
Chikungunya Fever - immunology
Chikungunya virus
Disease Models, Animal
Disease Susceptibility
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Humans
Male
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
Polymerase Chain Reaction
Research and Analysis Methods
Transforming Growth Factor beta - biosynthesis
Transforming Growth Factor beta - immunology
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1005891