Targeting CARD9 with Small-Molecule Therapeutics Inhibits Innate Immune Signaling and Inflammatory Response to Pneumocystis carinii β-Glucans

Theodore J. Kottom, Eva M. Carmona, Andrew H. Limper

Research output: Contribution to journalArticlepeer-review

Abstract

Pneumocystis jirovecii, the opportunistic fungus that causes Pneumocystis pneumonia (PCP) in humans, is a significant contributor to morbidity and mortality in immunocompromised patients. Given the profound deleterious inflammatory effects of the major β-glucan cell wall carbohydrate constituents of Pneumocystis through Dectin-1 engagement and downstream caspase recruitment domain-containing protein 9 (CARD9) immune activation, we sought to determine whether the pharmacodynamic activity of the known CARD9 inhibitor BRD5529 might have a therapeutic effect on macrophage innate immune signaling and subsequent downstream anti-inflammatory activity. The small-molecule inhibitor BRD5529 was able to significantly reduce both phospho-p38 and phospho-pERK1 signaling and tumor necrosis factor alpha (TNF-α) release during stimulation of macrophages with Pneumocystis cell wall β-glucans.

Original languageEnglish (US)
Article numbere01210
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number11
DOIs
StatePublished - Oct 2020

Keywords

  • CARD9
  • Inflammation
  • Inhibitor
  • Macrophages
  • Pneumocystis carinii

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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