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

Jennifer L. Uhrlaub, Vesna Pulko, Victor De Filippis, Rebecca Broeckel, Daniel Streblow, Gary D. Coleman, Byung Park, John F. Lindo, Ivan Vickers, Joshua J. Anzinger, Janko Nikolich-Žugich

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005891
JournalPLoS Pathogens
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Chikungunya virus
Chronic Disease
Antibody Formation
Joints
Arthralgia
Pandemics
Virus Diseases
Exanthema
Neutralizing Antibodies
Antiviral Agents
Immunity
Fever
Vaccines
Pathology
Infection

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Uhrlaub, J. L., Pulko, V., De Filippis, V., Broeckel, R., Streblow, D., Coleman, G. D., ... Nikolich-Žugich, J. (2016). Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus. PLoS Pathogens, 12(10), [e1005891]. https://doi.org/10.1371/journal.ppat.1005891

Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus. / Uhrlaub, Jennifer L.; Pulko, Vesna; De Filippis, Victor; Broeckel, Rebecca; Streblow, Daniel; Coleman, Gary D.; Park, Byung; Lindo, John F.; Vickers, Ivan; Anzinger, Joshua J.; Nikolich-Žugich, Janko.

In: PLoS Pathogens, Vol. 12, No. 10, e1005891, 01.10.2016.

Research output: Contribution to journalArticle

Uhrlaub, JL, Pulko, V, De Filippis, V, Broeckel, R, Streblow, D, Coleman, GD, Park, B, Lindo, JF, Vickers, I, Anzinger, JJ & Nikolich-Žugich, J 2016, 'Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus', PLoS Pathogens, vol. 12, no. 10, e1005891. https://doi.org/10.1371/journal.ppat.1005891
Uhrlaub, Jennifer L. ; Pulko, Vesna ; De Filippis, Victor ; Broeckel, Rebecca ; Streblow, Daniel ; Coleman, Gary D. ; Park, Byung ; Lindo, John F. ; Vickers, Ivan ; Anzinger, Joshua J. ; Nikolich-Žugich, Janko. / Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus. In: PLoS Pathogens. 2016 ; Vol. 12, No. 10.
@article{e79ca1c45855405296f15e8f9a237a8f,
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.",
author = "Uhrlaub, {Jennifer L.} and Vesna Pulko and {De Filippis}, Victor and Rebecca Broeckel and Daniel Streblow and Coleman, {Gary D.} and Byung Park and Lindo, {John F.} and Ivan Vickers and Anzinger, {Joshua J.} and Janko Nikolich-Žugich",
year = "2016",
month = "10",
day = "1",
doi = "10.1371/journal.ppat.1005891",
language = "English (US)",
volume = "12",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus

AU - Uhrlaub, Jennifer L.

AU - Pulko, Vesna

AU - De Filippis, Victor

AU - Broeckel, Rebecca

AU - Streblow, Daniel

AU - Coleman, Gary D.

AU - Park, Byung

AU - Lindo, John F.

AU - Vickers, Ivan

AU - Anzinger, Joshua J.

AU - Nikolich-Žugich, Janko

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84992695872&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992695872&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1005891

DO - 10.1371/journal.ppat.1005891

M3 - Article

C2 - 27736984

AN - SCOPUS:84992695872

VL - 12

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 10

M1 - e1005891

ER -