Forsythe, Marshaleen Henriques

Abstract Glycosphingolipid (GSL) Lactosyl Ceramide (LacCer) is thought to be involved in Pneumocystis interaction with the host. Our previous results show that treatment with glycosphingolipid synthesis inhibitor PDMP reduces the fungus lung burden as well as symptoms of inflammation in mice with Pneumocystis pneumonia (PCP). Experiments were set up to resolve whether anti-inflammatory effects were due to the specific mechanisms involved in innate immune responses to Pneumocystis, or to some general anti-inflammatory property of PDMP. Animals were infected with live organisms, or challenged with either beta-glucan (the pro-inflammatory component of Pneumocystis cell wall) or LPS (inducer of lung inflammation unrelated to Pneumocystis). At the experimental endpoint the following inflammatory parameters were assessed: leukocyte recruitment to the lungs, production of pro-inflammatory cytokines and chemokines, histopathology and lung damage. Results show that glucan-induced acute inflammation partially mimics the inflammation caused by the whole organism, and PDMP suppresses some of the inflammatory parameters affected in PCP. In contrast, although LPS induces comparable intensity of inflammation as live Pneumocystis or glucan, PDMP does not suppress any inflammatory parameters measured in this group. These results suggest that the mechanism of PDMP action is related to the features specific to Pneumocystis and host recognition of the microorganism. Further studies will attempt to determine the role of LacCer in these processes. Supported by NIH-RO1-HL62150 and Mayo Clinic