The Role of Toll-like Receptors and Viral Infections in the Pathogenesis and Progression of Pulmonary Arterial Hypertension—A Narrative Review

Aberrant activation of innate immunity promotes the development of pulmonary arterial hypertension (PAH); however, the role of pattern recognition by Toll-like receptors (TLRs) within the pulmonary vasculature remains unclear. To consolidate knowledge (as of June 2025) about TLRs and their interactions with viruses in PAH and to identify therapeutic implications. A narrative review of experimental and clinical studies investigating ten TLRs in the context of the pulmonary vascular microenvironment and viral infections. Activation of TLR1/2, TLR4, TLR5/6, TLR7/8, and TLR9 converges on the MyD88-NF-κB/IL-6 axis, thereby enhancing endothelial-mesenchymal transition, smooth muscle proliferation, oxidative stress, thrombosis, and maladaptive inflammation, ultimately increasing pulmonary vascular resistance. Conversely, TLR3, through TRIF-IFN-I, preserves endothelial integrity and inhibits vascular remodeling; its downregulation correlates with PAH severity, and poly (I:C) restitution has been shown to improve hemodynamics and right ventricular function. HIV-1, EBV, HCV, endogenous retrovirus K, and SARS-CoV-2 infections modulate TLR circuits, either amplifying pro-remodeling cascades or attenuating protective pathways. The "TLR rheostat" is shaped by polymorphisms, ligand biochemistry, compartmentalization, and biomechanical forces. The balance between MyD88-dependent signaling and the TRIF-IFN-I axis determines the trajectory of PAH. Prospective therapeutic strategies may include TLR3 agonists, MyD88/NF-κB inhibitors, modulation of IL-6, and combination approaches integrating antiviral therapy with targeted immunomodulation in a precision approach.