TLRs in COVID-19: How they drive immunopathology and the rationale for modulation

Abstract

COVID-19 is both a viral illness and a disease of immunopathology. Proximal events within the innate immune system drive the balance between deleterious inflammation and viral clearance. We hypothesize that a divergence between the generation of excessive inflammation through over activation of the TLR associated myeloid differentiation primary response (MyD88) pathway relative to the TIR-domain-containing adaptor-inducing IFN-β (TRIF) pathway plays a key role in COVID-19 severity. Both viral elements and damage associated host molecules act as TLR ligands in this process. In this review, we detail the mechanism for this imbalance in COVID-19 based on available evidence, and we discuss how modulation of critical elements may be important in reducing severity of disease.

Keywords: CD14; COVID-19; TLR; innate immunity; interferon.

Figure 1.

(a) Schematic detailing the innate immune response in COVID-19 beginning with viral infection of type II pneumocytes. Viral elements (PAMPs) and DAMPs are generated and act as ligands for TLR activation. Several cell surface and endosomal TLRs are activated. Through MyD88-dependent and TRIF-dependent pathways, an NF-κB derived inflammatory response and an IFN response are generated. (b) NF-κB derived inflammation generates DAMPs and initiates a cycle of innate immune activation. This inflammation may drive organ injury. The IFN response is critical for viral clearance. As both pathways are active, a race between viral clearance and host injury ensue. In severe disease, the balance is shifted toward injurious NF-κB derived inflammation.