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

doi:10.1016/j.celrep.2022.111441

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

Cell Rep. 2022 Oct 4;41(1):111441. doi: 10.1016/j.celrep.2022.111441. Epub 2022 Sep 15.

Authors

Affiliations

¹ Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA. Electronic address: sinu.john@nih.gov.
² Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Rockville, MD 20850, USA.
³ Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA.
⁴ Bioinformatics Group, Laboratory of Immune Systems Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁵ NIAID Collaborative Bioinformatics Resource, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Axle Informatics, Bethesda, MD 20892, USA.
⁶ Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁷ Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20895, USA. Electronic address: fraseri@nih.gov.

Abstract

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.

Keywords: CP: Immunology; LPS tolerance; NFAT-2; SARS-CoV-2; Syk inhibition; innate immune training; rutaecarpine.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural

MeSH terms

COVID-19 Drug Treatment*
Cytokines
Humans
Indole Alkaloids
Lipopolysaccharides
Macrophages
Quinazolinones
SARS-CoV-2
Syk Kinase
Tumor Necrosis Factor-alpha
beta-Glucans*

Substances

Cytokines
Indole Alkaloids
Lipopolysaccharides
Quinazolinones
Tumor Necrosis Factor-alpha
beta-Glucans
rutecarpine
SYK protein, human
Syk Kinase