Small molecule screening identifies Syk kinase inhibition and Rutaecarpine as modulators of macrophage training and SARS CoV-2 infection

Biologically active small molecules can impart modulatory effects in immune cells, in some cases, providing extended long-term memory. In a screen of biologically active small molecules for regulators of TNF induction, we identified several compounds with the ability to induce training effects on human macrophages. Rutaecarpine was identified both as an acute and long-term modulator, enhancing LPS-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibited ß-glucan-induced H3K4Me3 marks at the promoters of several proinflammatory cytokines, highlighting the potential of this molecule to modulate 47 epigenetic topology. In further work, a Syk kinase inhibitor (SYKi IV) screen hit promoted an enhanced response to LPS similar to that previously reported for ß-glucan-induced training. Macrophages trained with SYKi IV showed a high degree of resistance to influenza A, multiple variants of SARS CoV-2 and OC43 coronavirus infection, highlighting a potential application of this molecule and other Syk kinase inhibitors as a prophylactic treatment for viral susceptibility. Overall design: Primary macrophage cells treated with Syk inhibitor IV, rutaecarpine, or DMSO for 0, 4, or 2h followed by LPS unless otherwise indicated. mRNA-seq on all samples was completed in triplicate.