TLR3 absence confers increased survival with improved macrophage activity against pneumonia

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Abstract
Toll-like receptor 3 (TLR3) is a pathogen recognition molecule associated with viral infection with double-stranded RNA (dsRNA) as its ligand. We evaluated the role of TLR3 in bacterial pneumonia using Klebsiella pneumoniae ( KP ). WT and TLR3 –/– mice were subjected to a lethal model of KP . Alveolar macrophage polarization, bactericidal activity, and phagocytic capacity were compared. RNA-sequencing was performed on alveolar macrophages from the WT and TLR3 –/– mice. Adoptive transfers of alveolar macrophages from TLR3 –/– mice to WT mice with KP were evaluated for survival. Expression of TLR3 in postmortem human lung samples from patients who died from gram-negative pneumonia and pathological grading of pneumonitis was determined. Mortality was significantly lower in TLR3 –/– , and survival improved in WT mice following antibody neutralization of TLR3 and with TLR3/dsRNA complex inhibitor. Alveolar macrophages from TLR3 –/– mice demonstrated increased bactericidal and phagocytic capacity. RNA-sequencing showed an increased production of chemokines in TLR3 –/– mice. Adoptive transfer of alveolar macrophages from the TLR3 –/– mice restored the survival in WT mice. Human lung samples demonstrated a good correlation between the grade of pneumonitis and TLR3 expression. These data represent a paradigm shift in understanding the mechanistic role of TLR3 in bacterial pneumonia.
Funding Information
  • NIH/NIGMS (GM-111305)
  • National Institutes of Health (GM,111,305-,04)

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