The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense (preprint)

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles surfactant deficient RDS. Using a novel multi-cell type, human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system, validated against primary lung cells, we found that inflammatory cytokine/chemokine production and interferon (IFN) responses are dynamically regulated autonomously within the lung following SARS-CoV-2 infection, an intrinsic defense mechanism mediated by surfactant proteins (SP). Single cell RNA sequencing revealed broad infectability of most lung cell types through canonical (ACE2) and non-canonical (endocytotic) viral entry routes. SARS-CoV-2 triggers rapid apoptosis, impairing viral dissemination. In the absence of surfactant protein B (SP-B), resistance to infection was impaired and cytokine/chemokine production and IFN responses were modulated. Exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion restored resistance to SARS-CoV-2 and improved viability.

Pharmacological inhibition of TBK1/IKKε blunts COVID-19 immunopathology (preprint)

TANK-binding kinase 1 (TBK1) is a key signalling component that drives the production of type-I interferons (IFNs), which have essential antiviral activities including against SARS-CoV-2. TBK1 and its homolog IκB kinase-ε (IKKε) can also induce the production of pro-inflammatory factors that contribute to pathogen clearance. While initially protective, delayed engagement of type-I IFN is associated with lethal hyper-inflammation seen in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to this response is unknown. We have discovered that the small molecule idronoxil inhibits both IRF3 and NF-κB-driven inflammation by disrupting the formation of TBK1/IKKε signalling complexes following STING activation. Leveraging this unique activity, we show that therapeutic administration of idronoxil suppresses cellular and molecular lung inflammation in K18-hACE2 mice challenged with SARS-CoV-2, resulting in reduced pro-inflammatory cytokine production and decreased airway fibrosis in experimental COVID-19. Our results indicate a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation and identify a novel therapeutic intervention to limit disease severity in COVID-19 patients.