The capsule is closely associated with the virulence of Cryptococcus neoformans. The capsule inhibits phagocytosis of the yeast by macrophages, monocytes, and neutrophils. More recent studies in our laboratory have shown that incubation of encapsulated cryptococci with normal human serum leads to deposition of large amounts of C3 and C3 fragments and lesser amounts of IgG within the capsule and at the capsular surface. Thus, the capsule mediates two biological functions with opposing effects. It is our current view that phagocytosis of the yeast is dependent upon a balance between the antiphagocytic action of cryptococcal polysaccharide and the ability of the yeast to focus opsonically active complement fragments and IgG at the capsular surface. The proposed studies will 1) determine the function and antigenic specificity of IgG that is deposited from normal human serum into the capsule; 2) determine the mode of activation, mechanism of binding, molecular form, and molecular activator of C3 that binds to the capsule; 3) determine whether cryptococcal isolates differ in ability to localize opsonic fragments of C3 and/or IgG at the capsular surface; 4) examine the influence of phagocyte activation on phagocytosis of C. neoformans; and 5) determine the influence of neutrophil oxidative metabolites on complement activation by cryptococcal polysaccharide. The significance of the proposed study lies in our ability to understand the mechanism of action of a major virulence factor of a medically important yeast. Cryptococcosis is of increasing clinical importance in patients whose immune systems are compromised by cancer chemotherapy or AIDS. The capsule is the interface between C. neoformans and the defense mechanisms of the body. An understanding of the molecular mechanisms of this interaction is fundamental to understanding the pathobiology of the disease and provides a framework for therapeutic modification of host-parasite interaction.
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