-glucans are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia

-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study we examined whether -1,3 glucans are masked by surface proteins in Pneumocystis, and what role -glucans play in Pneumocystis-associated inflammation. For 3 species, including P. jirovecii, which causes Pneumocystis pneumonia (PCP) in humans, P. carinii, and P. murina, -1,3 glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using Q-PCR and microarray techniques, we demonstrated in a mouse model of PCP that treatment with caspofungin, an inhibitor of -1,3 glucan synthesis, for 21 days, decreased expression of a broad panel of inflammatory markers, including IFN-, TNF-, IL-1, IL-6, and multiple chemokines/chemokine ligands. Thus, -glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses.

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Kutty G, Davis AS, Ferreyra GA, Qiu J, Huang da W, Sassi M, Bishop L, Handley G, Sherman B, Lempicki R, Kovacs JA