Targeting CARD9 with Small-Molecule Therapeutics Inhibits Innate Immune Signaling and Inflammatory Response to Pneumocystis carinii β-Glucans.
Theodore J KottomEva M CarmonaAndrew H LimperPublished in: Antimicrobial agents and chemotherapy (2020)
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.
Keyphrases
- cell wall
- small molecule
- innate immune
- protein protein
- inflammatory response
- end stage renal disease
- rheumatoid arthritis
- chronic kidney disease
- ejection fraction
- social media
- peritoneal dialysis
- autism spectrum disorder
- patient reported outcomes
- extracorporeal membrane oxygenation
- intellectual disability
- cancer therapy
- respiratory failure
- acute respiratory distress syndrome
- lipopolysaccharide induced
- induced apoptosis
- signaling pathway