Candidate role for TLR3 L412F in disease progression in Idiopathic Pulmonary Fibrosis (IPF) during bacterial and viral infection
Citation:MCELROY, AOIFE NORA, Candidate role for TLR3 L412F in disease progression in Idiopathic Pulmonary Fibrosis (IPF) during bacterial and viral infection, Trinity College Dublin.School of Medicine, 2019
In this thesis, we investigated the mechanisms by which TLR3 Leu412Phe (L412F) promotes disease progression in idiopathic pulmonary fibrosis (IPF) patients. IPF is a fatal interstitial lung disease of unknown aetiology and currently no cure or specific treatments are available for IPF patients. To date, lung transplant remains the best clinical option for IPF patients. Historically, viral and bacterial infections have been associated with accelerated disease progression and poorer outcomes in patients. Our research group previously established that TLR3 L412F increased mortality and accelerated lung decline in IPF patients. These findings were associated with a reduced ability of lung fibroblasts from TLR3 L412F-variant IPF patients to induce pro-inflammatory or anti-viral, type I interferon responses to TLR3-activation in cells. In this thesis, we expand on these original findings. Here, we demonstrated that TLR3 L412F-heterozygous lung fibroblasts from IPF patients have attenuated responses to additional TLR agonists, including: LPS (TLR4), Pam3CSK4 (TLR2), flagellin (TLR5), FSL-1 (TLR6) and CpG (TLR9). Furthermore, we demonstrated that variant-TLR3 L412F attenuates responses of IPF lung fibroblasts to non-TLR agonists including: Poly(dA:dT), HT-DNA and PMA. These effects may increase TLR3 L412F-heterozygous IPF patients susceptibility to viral and bacterial infections. We additionally investigated the role of autophagy in viral clearance in primary lung fibroblasts from IPF and pulmonary sarcoidosis patients. We demonstrated that TLR3 L412F-homozygous sarcoidosis patients have increased transcription of autophagy proteins following IAV H1N1 viral infection. Furthermore, lung fibroblasts from TLR3 L412F-heterozygous IPF patients exhibited increased transcription of autophagy proteins in response to nutrient-starvation. These effects correlated with defective induction of autophagy in IPF fibroblasts following TLR3- and TLR4-activation, and rapamycin treatment, respectively. We also observed persistent mTOR activation in TLR3 L412F-heterozygous IPF fibroblasts, which may play a role in dysregulated autophagy in IPF patients. In future studies, we will model these TLR3 L412F-mediated effects in vivo using our novel TLR3 L413F knock-in mice, which we have characterised at a cellular level in this thesis. We believe that our current data provides supportive evidence for the potential use of TLR3 L412F as a biomarker in IPF patients.
Author: MCELROY, AOIFE NORA
Publisher:Trinity College Dublin. School of Medicine. Discipline of Clinical Medicine
Type of material:Thesis
Availability:Full text available