The efficacy of complement‐mediated phagocytosis of <i>Cryptococcus neoformans</i> is dependent on the location of C3 in the polysaccharide capsule and involves both direct and indirectC3‐mediated interactions

TLDR

Complement component 3 is the primary opsonin for *Cryptococcus neoformans*, yet its effectiveness varies among strains due to unknown mechanisms. The study investigates how capsule size and C3 deposition location enable some *Cryptococcus* strains to evade phagocytosis. Phagocytic uptake decreases with larger capsule volume, correlates with C3 positioned at the capsule edge, occurs through CR3, and is only partially dependent on C3, while antibody‑mediated uptake increases with capsule size.

Abstract

Abstract Complement component 3 (C3) is the major opsonin for the pathogenic fungus Cryptococcus neoformans in the non‐immune host. However, the efficiency of complement‐mediated opsonization varies, depending on the strain, through mechanisms that are not understood. Analysis of complement‐mediated phagocytosis for 12 strains grown in Sabouraud medium revealed that phagocytic indices were inversely correlated with capsule volume. In contrast, there was no correlation between phagocytic index and capsule volume for IgG1‐opsonized cells. When capsule size was increased, the efficacyof complement‐mediated phagocytosis decreased, whereas that of antibody‐mediated phagocytosis increased. C3 localized inside the capsule and at the outer capsule edge for poorly phagocytozed and well‐phagocytozed strains, respectively. Blocking experiments revealed that complement‐mediated phagocytosis occurred through complement receptor 3 (CR3), without significant involvement of CR1 or CR4. Blocking experiments with antibodies to C3 did not completely abrogate yeast cell uptake, consistent with phagocytosis through glucuronoxylomannan–CR3 interactions. Our data explain how some large encapsulated cells avoid phagocytosis and suggest a novel strategy for immune evasion whereby a microbial capsule interferes with phagocytosis by modifying the location of C3 deposition.