Article Alert: TBK1/IKKε Inhibition Attenuates SARS-CoV-2-induced Pulmonary Hyper-inflammation

TANK-binding kinase 1 (TBK1) and IκB kinase-ε (IKKε) represent a point of convergence for several pattern recognition receptor pathways that lead to the production of Type I interferons. Acting redundantly, these kinases are crucial components of the innate immune response to viruses and other pathogens mediated by RIG-I/MAVS, cGAS-STING, and TLR4-TRIF signaling. Nevertheless, anomalous or sustained activation of this signaling can result in destructive hyper-inflammatory states, with severe SARS-CoV-2 infection being a recent example. Thus, there has been significant interest in identifying agents that can mitigate the immunopathology associated with SARS-CoV-2 (or other virus) infection, with particular focus on TBK1/IKKε inhibition.

A new study by Ullah et al. compares the effects of different inhibitors of TBK1/IKKε on the inflammatory response after SARS-CoV-2 infection in mouse models (1). The authors first used in vitro techniques to show that the synthetic flavonoid Idronoxil (IDX) and the TBK1/IKKε kinase inhibitor MRT67307 (MRT) can inhibit downstream signaling by the STING, TRIF, and MAVS pathways. They then demonstrated that IDX acts by disrupting the formation of TBK1/IKKε signaling complexes (which distinguishes it from MRT) thereby highlighting its distinct mechanism-of-action. In addition, IDX was able to decrease both NF-κB- and IRF3-driven inflammatory signaling subsequent to STING/TLR3/TLR4/RIG-I activation. Moving on to an in vivo model, the authors utilized SARS-CoV-2-infected K18-hACE2 mice to reveal that IDX reduces viral-induced hyper-inflammation. Significantly, their results further argue that TBK1/IKKε inhibition is potentially a more effective approach to minimize SARS-CoV-2-triggered pulmonary hyper-inflammation than is direct STING inhibition. In summary, this study by Ullah et al. establishes a foundation for further work on IDX, or its derivative(s), as a new agent to lessen virus-induced hyper-inflammation.

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