Targeting CARD9 With Small Molecule Therapeutics Inhibits Innate Immune Signaling and Inflammatory Response to Pneumocystis carinii β-glucans.

Pneumocystis jirovecii, the opportunistic fungi 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 potentially therapeutic effect on macrophage innate immune signaling and subsequent downstream anti-inflammatory activity. The small BRD5529 molecule inhibitor was able to significantly reduce both p-p38 and p-pERK1 signaling and TNF-alpha release during stimulation of macrophages with Pneumocystis cell wall β-glucans.