Evidence for Proinflammatory ?-1,6 Glucans in the Pneumocystis carinii Cell Wall.

ABSTRACT: Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall ?-glucans in stimulating inflammatory responses. Fungal ?-glucans are comprised of d-glucose homopolymers containing ?-1,3-linked glucose backbones with ?-1,6-linked glucose side chains. Prior studies in Pneumocystis carinii have characterized ?-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for ?-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize ?-1,6 glucans in the cell wall of Pneumocystis and to establish their activity in lung cell inflammation. Immune staining revealed specific ?-1,6 localization in P. carinii cyst walls. Homology-based cloning facilitated characterization of a functional P. carinii kre6 (Pckre6) ?-1,6 glucan synthase in Pneumocystis that, when expressed in kre6-deficient Saccharomyces cerevisiae, restored cell wall stability. Recently synthesized ?-1,6 glucan synthase inhibitors decreased the ability of isolated P. carinii preparations to generate ?-1,6 carbohydrate. In addition, isolated ?-1,6 glucan fractions from Pneumocystis elicited vigorous tumor necrosis factor alpha (TNF-?) responses from macrophages. These inflammatory responses were significantly dampened by inhibition of host cell plasma membrane microdomain function. Together, these studies indicate that ?-1,6 glucans are present in the P. carinii cell wall and contribute to lung cell inflammatory activation during infection.

SUBMITTER: Kottom TJ 

PROVIDER: S-EPMC4468544 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature