Cryptococcosis is a serious infectious disease in the immunocompromised patient. It is the third most common serious infectious complication of AIDS. The capsule is arguably the most important virulence factor produced by Cryptococcus neoformans. Our studies focus on the manner in which the capsule influences phagocytosis of the yeast by human mononuclear phagocytes. Studies during the current grant period have shown that incubation of encapsulated cryptococci in normal human serum leads to deposition of large amounts of iC3b and smaller amounts of IgG within and at the surface of the capsule. iC3b and the IgG in normal human serum act synergistically to mediate phagocytosis of the yeast. Conversely, phagocyte receptors for iC3b (CR3) and IgG (FcR) are essential for optimal phagocytosis. These studies have also shown that encapsulated isolates are not all alike and differ with regard to their relative resistance to phagocytosis. An explanation of the cellular and molecular basis for these differences is central to this proposal. The overall hypothesis for this proposal is that phagocytosis of encapsulated cryptococci is critically dependent on the opsonic action of iC3b and IgG and their respective membrane receptors (CR3 and FcR). The proper functioning of these systems will determine whether or not the yeast is ingested. This hypothesis will be pursued by the study of three specific aims.
The first aim will characterize the anti-capsular antibody found in normal human serum.
The second aim will examine activation and binding of opsonic C3 fragments by the cryptococcal capsule.
The third aim will examine the mechanism for inhibition of phagocytosis by the cryptococcal capsule by comparing the properties of phagocytosis-resistant and phagocytosis-sensitive encapsulated isolates. These studies will contribute to understanding the mechanism by which capsules function as anti-phagocytic surface structures and will facilitate an understanding of the pathogenesis of an increasingly important opportunistic pathogen.
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