Selective blockade of TNFR1 improves clinical disease and bronchoconstriction in experimental RSV infection

Dorothea R. Morris, Maria Ansar, Teodora Ivanciuc, Yue Qu, Antonella Casola, Roberto P. Garofalo

Research output: Contribution to journalArticlepeer-review

Abstract

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in infants and young children. Although some clinical studies have speculated that tumor necrosis factor (TNF)-α is a major contributor of RSV-mediated airway disease, experimental evidence remains unclear or conflicting. TNF-α initiates inflammation and cell death through two distinct receptors: TNF-receptor (TNFR)1 and TNFR2. Here we delineate the function of TNF-α by short-lasting blockade of either receptor in an experimental BALB/c mouse model of RSV infection. We demonstrate that antibody-mediated blockade of TNFR1, but not TNFR2, results in significantly improved clinical disease and bronchoconstriction as well as significant reductions of several inflammatory cytokines and chemokines, including IL-1α, IL-1β, IL-6, Ccl3, Ccl4, and Ccl5. Additionally, TNFR1 blockade was found to significantly reduce neutrophil number and activation status, consistent with the concomitant reduction of pro-neutrophilic chemokines Cxcl1 and Cxcl2. Similar protective activity was also observed when a single-dose of TNFR1 blockade was administered to mice following RSV inoculation, although this treatment resulted in improved alveolar macrophage survival rather than reduced neutrophil activation. Importantly, short-lasting blockade of TNFR1 did not affect RSV peak replication in the lung. This study suggests a potential therapeutic approach for RSV bronchiolitis based on selective blockade of TNFR1.

Original languageEnglish (US)
Article number1176
JournalViruses
Volume12
Issue number10
DOIs
StatePublished - Oct 17 2020

Keywords

  • BALF
  • Bronchiolitis
  • Bronchoconstriction
  • Macrophages
  • Neutrophils
  • RSV
  • Respiratory syncytial virus
  • TNF
  • TNFR1
  • TNFR2
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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