A role for Toll-like receptor 3 in lung vascular remodeling associated with SARS-CoV-2 infection.
A A Roger ThompsonSrimathi BogamuwaBryce PiperGeoffrey NewcombPranav GunturuJoseph S BednashJames D LondinoAjit ElhanceRichard NhoOscar Rosas MejiaJacob S YountJeffrey C HorowitzElena A GoncharovaRama K MallampalliRichard T RobinsonLaszlo FarkasPublished in: bioRxiv : the preprint server for biology (2023)
Cardiovascular sequelae of severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) disease 2019 (COVID-19) contribute to the complications of the disease. One potential complication is lung vascular remodeling, but the exact cause is still unknown. We hypothesized that endothelial TLR3 insufficiency contributes to lung vascular remodeling induced by SARS-CoV-2. In the lungs of COVID-19 patients and SARS-CoV-2 infected Syrian hamsters, we discovered thickening of the pulmonary artery media and microvascular rarefaction, which were associated with decreased TLR3 expression in lung tissue and pulmonary artery endothelial cells (ECs). In vitro , SARS-CoV-2 infection reduced endothelial TLR3 expression. Following infection with mouse-adapted (MA) SARS-CoV-2, TLR3 knockout mice displayed heightened pulmonary artery remodeling and endothelial apoptosis. Treatment with the TLR3 agonist polyinosinic:polycytidylic acid reduced lung tissue damage, lung vascular remodeling, and endothelial apoptosis associated with MA SARS-CoV-2 infection. In conclusion, repression of endothelial TLR3 is a potential mechanism of SARS-CoV-2 infection associated lung vascular remodeling and enhancing TLR3 signaling is a potential strategy for treatment.
Keyphrases
- toll like receptor
- sars cov
- pulmonary artery
- respiratory syndrome coronavirus
- inflammatory response
- endothelial cells
- coronary artery
- pulmonary hypertension
- pulmonary arterial hypertension
- nuclear factor
- immune response
- coronavirus disease
- poor prognosis
- risk assessment
- risk factors
- binding protein
- cell proliferation
- human health
- smoking cessation
- case report
- replacement therapy
- combination therapy