Imperial College London
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ProfessorPhilipMolyneaux

Faculty of Medicine, National Heart & Lung Institute

Professor of Interstitial Lung Disease
 
 
 
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Contact

 

p.molyneaux

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{McElroy:2022:10.1164/rccm.202010-3880OC,
author = {McElroy, AN and Invernizzi, R and Laskowska, JW and O'Neill, A and Doroudian, M and Moghoofei, M and Mostafaei, S and Li, F and Przybylski, AA and O'Dwyer, DN and Bowie, AG and Fallon, PG and Maher, TM and Hogaboam, CM and Molyneaux, PL and Hirani, N and Armstrong, ME and Donnelly, SC},
doi = {10.1164/rccm.202010-3880OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
title = {Candidate role for toll-like receptor 3 L412F polymorphism and infection in acute exacerbation of idiopathic pulmonary fibrosis},
url = {http://dx.doi.org/10.1164/rccm.202010-3880OC},
volume = {205},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular anti-viral responses and is associated with accelerated disease progression in IPF. The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objective: 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 anti-bacterial TLR-responses of primary lung fibroblasts from IPF patients. Methods: TLR-mediated anti-bacterial and anti-viral responses were quantitated in L412F-wild-type and 412F-heterozygous primary lung fibroblasts from IPF patients using ELISA, western blot analysis and qPCR. Hierarchical heatmap analysis was employed to establish bacterial and viral clustering in nasopharyngeal lavage (NPL) samples from AE-IPF patients. 16S rRNA qPCR 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 412F-variant IPF patients was reported. We established that 412F-heterozygous IPF lung fibroblasts have reduced anti-bacterial 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 rRNA sequencing, we demonstrated that 412F-heterozygous IPF patients 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.
AU  - McElroy,AN
AU  - Invernizzi,R
AU  - Laskowska,JW
AU  - O'Neill,A
AU  - Doroudian,M
AU  - Moghoofei,M
AU  - Mostafaei,S
AU  - Li,F
AU  - Przybylski,AA
AU  - O'Dwyer,DN
AU  - Bowie,AG
AU  - Fallon,PG
AU  - Maher,TM
AU  - Hogaboam,CM
AU  - Molyneaux,PL
AU  - Hirani,N
AU  - Armstrong,ME
AU  - Donnelly,SC
DO  - 10.1164/rccm.202010-3880OC
PY  - 2022///
SN  - 1073-449X
TI  - Candidate role for toll-like receptor 3 L412F polymorphism and infection in acute exacerbation of idiopathic pulmonary fibrosis
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.202010-3880OC
UR  - https://www.ncbi.nlm.nih.gov/pubmed/34985402
UR  - https://www.atsjournals.org/doi/10.1164/rccm.202010-3880OC
UR  - http://hdl.handle.net/10044/1/93701
VL  - 205
ER  -
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