Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 205, Issue 5, Pages 550-562Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.202010-3880OC
Keywords
idiopathic pulmonary fibrosis; TLR3 L412F; viral and bacterial coinfection; lung microbiome; acute exacerbations
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Funding
- Kermanshah University Medical School
- Science Foundation Ireland (SFI)
- National Institute for Health Research Clinician Scientist Fellowship [CS-2013-13-017]
- British Lung Foundation Chair in Respiratory Research [C17-3]
- Health Research Board of Ireland
- Irish Lung Foundation
- Trinity College Dublin-Wellcome Trust Institutional Strategic Support Fund award
- Health Research Board
- Action for Pulmonary Fibrosis Mike Bray fellowship
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The study on the association between TLR3 L412F polymorphism and acute exacerbation-related death in idiopathic pulmonary fibrosis (IPF) reveals that this polymorphism attenuates the immune responses of IPF lung cells to bacteria and dysregulates the lung microbiome in IPF patients.
Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular antiviral responses and is associated with accelerated disease progression in idiopathic pulmonary fibrosis (IPF). The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objectives: To characterize the association between TLR3 L412F and AE-related death in IPF. To determine the effect of TLR3 L412F on the lung microbiome and on antibacterial TLR responses of primary lung fibroblasts from patients with IPF. Methods: TLR-mediated antibacterial and antiviral responses were quantitated in L412F wild-type and 412F-heterozygous primary lung fibroblasts from patients with IPF using ELISA, Western blot analysis, and quantitative PCR Hierarchical heatmap analysis was employed to establish bacterial and viral clustering in nasopharyngeal lavage samples from patients with AE-IPF. 16S ribosomal RNA quantitative PCR and pyrosequencing were used to determine the effect of TLR3 L412F on the IPF lung microbiome. Measurements and Main Results: A significant increase in AE-related death in patients with 412F-variant IPF was reported. We established that 412F-heterozygous IPF lung fibroblasts have reduced antibacterial TLR responses to LPS (TLR4), Pam3CYSK4 (TLR1/2), flagellin (TLR5), and FSL-1 (TLR6/1) and have reduced responses to live Pseudomonas aeruginosa infection. Using 16S ribosomal RNA sequencing, we demonstrated that 412F-heterozygous patients with IPF have a dysregulated lung microbiome with increased frequencies of Streptococcus and Staphylococcus spp. Conclusions: This study reveals that TLR3 L412F dysregulates the IPF lung microbiome and reduces the responses of IPF lung fibroblasts to bacterial TLR agonists and live bacterial infection. These findings identify a candidate role for TLR3 L412F in viral- and bacterial-mediated AE death.
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