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.

Keywords: SARS-CoV-2 infection; glycocalyx; micro-thrombosis; platelet activation; toll-like receptors.

Figure 1

TLR-4-mediated pathways. Abbreviations: AKT—protein kinase B, ATF2—activating transcription factor 2, AP-1—activator protein 1, Bax/Bcl-2 ratio—regulator protein ratio known to be responsible for apoptosis, GSK3ß—glycogen synthase kinase 3 beta, HO-1—heme oxygenase 1, IKKα/β—IκB kinase alpha/beta, IKK ε—IκB kinase epsilon, IRAK—interleukin receptor associated kinase, IRFs—interferon regulator factor, TAK—transforming growth factor-β-activated kinase, TBK1—TANK binding kinase, TIR—toll interleukin receptor, TIRAP—TIR domain-containing adaptor protein, TRAM—TRIF-related adaptor molecule, TRAF—tumor necrosis associated factor, TRIF—TIR domain-containing adaptor protein inducing interferon, MAPK—mitogen-activated protein kinases, MyD88—myeloid differentiation primary response protein 88, NEMO—NF-kappa-B essential modulator/inhibitor of nuclear factor kappa-B kinase subunit gamma, NF-κB—nuclear factor k light chain enhancer of activated B cells, NRF2—nuclear factor erythroid-2-related factor 2, PKR—double-stranded RNA-dependent protein kinase, PI3K—phosphoinositide 3-kinase, ROS—reactive oxygen species, SARM—selective androgen receptor modulators, SOD1—superoxide dismutase 1.

Figure 2

Platelets as drivers of leukocyte-mediated immunity and immuno-thrombosis via toll-like receptors (TLRs).