Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review

Abstract

Toll-like receptors (TLRs) have a critical role in the pathogenesis and disease course of viral infections. The induced pro-inflammatory responses result in the disturbance of the endovascular surface layer and impair vascular homeostasis. The injury of the vessel wall further promotes pro-thrombotic and pro-coagulatory processes, eventually leading to micro-vessel plugging and tissue necrosis. Moreover, TLRs have a direct role in the sensing of viruses and platelet activation. TLR-mediated upregulation of von Willebrand factor release and neutrophil, as well as macrophage extra-cellular trap formation, further contribute to (micro-) thrombotic processes during inflammation. The following review focuses on TLR signaling pathways of TLRs expressed in humans provoking pro-thrombotic responses, which determine patient outcome during viral infections, especially in those with cardiovascular diseases.

Myocardial Oedema as a Consequence of Viral Infection and Persistence – a Narrative Review with Focus on COVID-19 and Post COVID Sequelae

“…Viral infections lead to systemic inflammatory processes affecting (micro-) vascular homeostasis [28][29][30]296]. During the acute phase, rapid cellular entry is facilitated through the destabilization of the protective endothelial shield, the glycocalyx [296].…”

“…The breakdown of the endothelial barrier leads to enhanced permeability shifting inflammatory processes to adjacent tissues [296]. The chronic phase comprises viral persistence and sub-clinical inflammation triggering immunothrombosis, oedema formation, tissue necrosis and, more specifically, myocardial remodelling resulting in heart failure [1,4,28,29,183,269,365,380].…”

“…Consequently, dsRNA is recognized by cytosolic pattern recognition receptors (PRRs) triggering pro-inflammatory responses, which include protein kinase R (PKR) and oligoadenylate-ribonuclease L (OAS-RNase L) activation as well as interferon production [494]. PKR activation is also central in the signalling cascade mediated by TLR-4 after sensing of viral glycoproteins [28]. This pathway seems to have a regulatory function, while promoting the activation of the transcription factor nuclear factor erythroid-2-related factor 2 (NRF2), which enhances the expression of anti-oxidant enzymes, such as superoxide dismutase 1 (SOD-1) or heme oxygenase 1 (HO-1) [495,496].…”

“…As a consequence of glycocalyx degradation and excessive inflammation, platelets are more likely to adhere to the endothelium, provoking both micro-as well as macrovascular thrombosis [27,486,487]. In addition to degradation of the glycocalyx, TLR-4 dependent mechanisms are also thought to contribute to immunothrombosis in COVID-19 [28,488]. While anticoagulation as therapeutic measure was accepted consensus early on in the pandemic, the exact timing, dosage, and duration remain still a matter of debate [489][490][491].…”

“…Furthermore, the interaction of pathological processes initiated or exacerbated by MO, including inflammation, endothelial cell dysfunction, release of reactive oxygen species and proinflammatory cytokine signalling, contribute to a vicious circle of immunothrombosis, ultimately leading to tissue necrosis, fibrosis and organ failure [28][29][30].…”