Toll-like receptor 3 Leu412Phe (TLR3 L412F) gene mutations may increase the risk of death from acute exacerbations (AE) in patients with idiopathic pulmonary fibrosis (IPF), according to a new study published in the American Journal of Respiratory and Critical Care Medicine.

The study found that AE-related deaths were significantly higher (P =.03) in patients with IPF with the L412F mutation compared to patients with IPF with L412-wild type (L412-WT). A total of only 1 out of 66 deaths were due to AE in the L412-WT group compared to 7 out of 63 deaths in the L412F group.

The authors also found that fibroblasts from patients with IPF from a different cohort with heterozygous L412F mutations had attenuated antibacterial responses in several toll-like receptors. This included TLR1/2, TLR4, TLR5, and TLR6/1 which led to reduced responses to lipopolysaccharides, Pam3CYSK4, flagellin, and FSL-1 commonly found on bacteria, respectively.

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“These findings illustrate the broader role which TLR3 plays in pathogen recognition in the host,” the authors said. They also demonstrated that these fibroblasts have a reduced response to Pseudomonas aeruginosa infections.

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Analysis of lower lung samples collected using bronchoalveolar lavage (BAL) showed a change in the microbiome of patients with heterozygous L412F compared to patients with L412-WT. The study found that the bacterial burden was significantly lower in patients with L412F compared to patients with L412-WT (P =.0024), however, the distributions of bacterial species had shifted between the 2 groups.

The BAL samples of the patients with heterozygous L412F had significantly higher percentages of Streptococcus spp and Staphylococcus spp while the patients with wild-type had higher levels of Prevotella spp.

“These results demonstrate the TLR3 L412F polymorphism acts to dysregulate the lung microbiome in 412F-heterozygous IPF patients and may predispose these patients to AE-IPF,” the authors concluded.

During the study, deaths were investigated in a cohort of 228 patients with IPF who attended the Edinburgh Lung Fibrosis Clinic in the UK. Another cohort of 47 patients with IPF was also enrolled from the Royal Brompton Hospital in London, UK to collect BAL and investigate the distribution of bacteria in the lungs.


McElroy AN, Invernizzi R, Laskowska JW, et al. Candidate role for Toll-like receptor 3 L412F polymorphism and infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. Published online January 5, 2022. doi:10.1164/rccm.202010-3880OC