Journal
VIRUSES-BASEL
Volume 12, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/v12101176
Keywords
tumor necrosis factor; TNF; TNFR1; TNFR2; respiratory syncytial virus; RSV; bronchiolitis; bronchoconstriction; neutrophils; macrophages; BALF
Categories
Funding
- NIH [AI25434, AI062885, ES026782]
- Clinical and Translational Science Award [(NRSA (TL1) Training Core)] [TL1TR001440]
- McLaughlin fellowship
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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)-alpha is a major contributor of RSV-mediated airway disease, experimental evidence remains unclear or conflicting. TNF-alpha initiates inflammation and cell death through two distinct receptors: TNF-receptor (TNFR)1 and TNFR2. Here we delineate the function of TNF-alpha 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-1 alpha, IL-1 beta, 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.
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