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

PLoS Pathog. 2016 Oct 13;12(10):e1005891. doi: 10.1371/journal.ppat.1005891. eCollection 2016 Oct.

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.

MeSH terms

  • Adult
  • Aged
  • Aging / immunology*
  • Animals
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • Chikungunya Fever / immunology*
  • Chikungunya virus
  • Disease Models, Animal
  • Disease Susceptibility
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Polymerase Chain Reaction
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / immunology*

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Transforming Growth Factor beta