Small-molecule screening identifies Syk kinase inhibition and rutaecarpine as modulators of macrophage training and SARS-CoV-2 infection
Sinu P. John,
Anju Singh,
Jing Sun,
Makheni Jean Pierre,
Lulwah Alsalih,
Crystal Lipsey,
Ziann Traore,
Shenavia Balcom-Luker,
Clinton J. Bradfield,
Jian Song,
Tovah E. Markowitz,
Margery Smelkinson,
Marc Ferrer,
Iain D.C. Fraser
Affiliations
Sinu P. John
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA; Corresponding author
Anju Singh
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Rockville, MD 20850, USA
Jing Sun
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Makheni Jean Pierre
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Lulwah Alsalih
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Crystal Lipsey
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Ziann Traore
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Shenavia Balcom-Luker
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Clinton J. Bradfield
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA
Jian Song
Bioinformatics Group, Laboratory of Immune Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Tovah E. Markowitz
NIAID Collaborative Bioinformatics Resource, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Axle Informatics, Bethesda, MD 20892, USA
Margery Smelkinson
Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Marc Ferrer
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Rockville, MD 20850, USA
Iain D.C. Fraser
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA; Corresponding author
Summary: Biologically active small molecules can impart modulatory effects, in some cases providing extended long-term memory. In a screen of biologically active small molecules for regulators of tumor necrosis factor (TNF) induction, we identify several compounds with the ability to induce training effects on human macrophages. Rutaecarpine shows acute and long-term modulation, enhancing lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibits β-glucan-induced H3K4Me3 marks at the promoters of several pro-inflammatory cytokines, highlighting the potential of this molecule to modulate chromosomal topology. Syk kinase inhibitor (SYKi IV), another screen hit, promotes an enhanced response to LPS similar to that previously reported for β-glucan-induced training. Macrophages trained with SYKi IV show a high degree of resistance to influenza A, multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and OC43 coronavirus infection, highlighting a potential application of this molecule and other SYKis as prophylactic treatments for viral susceptibility.
