The Cellular Responses Induced by the Capsular Polysaccharide of Cryptococcus neoformans Differ Depending on the Presence or Absence of Specific Protective Antibodies

Abstract

The capsule of Cryptococcus neoformans, the principal virulence factor of this fungus, is composed primarily of polysaccharide. The predominant component of the polysaccharide capsule is glucuronoxylomannan (GXM), a compound with potent immunoregulatory properties. GXM is bound and internalized by natural immune cells affecting innate and subsequent adaptive immune response. The cellular pattern recognition receptors involved in GXM binding include toll-like receptor (TLR)4, CD14, TLR2, CD18, Fc gamma receptor II (FcgammaRPi). This multiple cross-linking leads to a suppressive outcome that is arrested and even reversed by protective antibodies to GXM. This review analyzes the immunosuppressive effects induced by capsular material, considering its pattern recognition receptors, and dissects the mechanism of monoclonal antibody shifting to immunoactivation.

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

“…Our studies, as well as others, demonstrated that the GXM-mAb complex counteracts the suppression exerted by GXM (20,37,42). This suggests an essential role for macrophages in acquiring and storing GXM in various organs and is consistent with previous observations of GXM accumulation inside tissue macrophages in vivo (43,44).…”

“…7). It is noteworthy that Fc␥RIIA senses the GXM-mAb complex, providing an explanation for the previously reported extraordinary activation of innate and adaptive immune response documented for this Ab (37). This is consistent with phosphorylation of IB␣; however, it is plausible that other receptors such as Fc␥RIII and Fc␥RI are engaged by the GXM-mAb complex and cooperate to trigger activation signals.…”

Of Mice and Men, Revisited: New Insights into an Ancient Molecule from Studies of Complement Activation byCryptococcus neoformans

“…GXM exerts a variety of deleterious effects on host immunity, including inhibition of leukocyte migration, reduced costimulatory molecule expression, altered cytokine expression, and reduced antibody responsiveness (17,46,66). Perhaps of the greatest relevance to virulence, the cryptococcal capsule inhibits phagocytosis (32,72).…”

The Presence of Capsule inCryptococcus neoformansInfluences the Gene Expression Profile in Dendritic Cells during Interaction with the Fungus

“…These acapsular strains were avirulent in mice, and they were readily ingested by phagocytes, but their ingestion could be inhibited by the addition of purified polysaccharide (3). The effect of the C. neoformans polysaccharide capsule on the host cells can be summarized as follows: it interferes with phagocytosis, blocks the recruitment of inflammatory cells, increases costimulatory molecules, suppresses the delayed-type-hypersensitivity response, and reduces the antibody production in response to fungal infection (11,43).Dendritic cells (DC) are professional antigen-presenting cells that can initiate the innate and adaptive immune response against invading pathogens, thus enabling the decoding of microbe-associated information which then results in qualitatively different adaptive T-helper responses in vitro and in vivo (2, 8).Mouse DC internalize C. neoformans cells via the mannose receptor and the Fc receptor for immunoglobulin G (Fc␥R). The cryptococcal antigens are then presented to T cells, which undergo proliferation and activation (40).…”

“…These acapsular strains were avirulent in mice, and they were readily ingested by phagocytes, but their ingestion could be inhibited by the addition of purified polysaccharide (3). The effect of the C. neoformans polysaccharide capsule on the host cells can be summarized as follows: it interferes with phagocytosis, blocks the recruitment of inflammatory cells, increases costimulatory molecules, suppresses the delayed-type-hypersensitivity response, and reduces the antibody production in response to fungal infection (11,43).…”