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Receptor-mediated recognition of Cryptococcus neoformans
1The Evans Memorial Department of Clinical Research and the Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Abstract:
Cryptococcus neoformans, a facultative intracellular pathogen of macrophages, is unique among medically important fungi in its possession of a polysaccharide capsule. Capsule represents the organism's major virulence factor. In the absence of opsonins, binding of encapsulated C. neoformans to macrophages is minimal. Following incubation in serum, C. neoformans potently activates complement, resulting in surface deposition of the third component of complement. Macrophages bind and phagocytose opsonized C. neoformans via three major complement receptors (CR) for C3 fragments, designated CD35 (CR1), CD11b/CD18 (CR3), and CD11c/CD18 (CR4). Antibody in normal human serum generally lacks opsonic activity, although vaccination can elicit anticapsular antibodies that are opsonic. The major component of cryptococcal capsule, glucuronoxylomannan (GXM), is shed from the fungus and circulates in the blood and cerebrospinal fluid of patients with cryptococcosis. Cellular receptors defined for GXM include CD14, toll-like receptor-2, toll-like receptor-4, and CD18. GXM binding to macrophage receptors triggers activation of nuclear factor-kB, but not mitogen-activated protein kinases. This results in no proinflammatory gene expression or release. C. neoformans also secretes mannoproteins, which are recognized by mannose receptors as well as by mannose-binding lectin, perhaps in conjunction with CD14. Strategies directed at modulating how intact C. neoformans and its released components are recognized by phagocytes could lead to novel approaches to treating cryptococcosis
Insights
Cryptococcus neoformans uses its capsule to evade immune cells. Targeting how macrophages recognize this fungus and its components offers new treatment strategies for cryptococcosis.
Area of Science:
- Mycology
- Immunology
- Pathogen Recognition
Background:
- Cryptococcus neoformans is a fungal pathogen with a polysaccharide capsule, its main virulence factor.
- Encapsulated C. neoformans has minimal interaction with macrophages without opsonins.
- Complement activation leads to C3 fragment deposition, enabling macrophage binding via complement receptors (CR1, CR3, CR4).
Purpose of the Study:
- To investigate the mechanisms of C. neoformans recognition by macrophages.
- To understand the role of fungal components like glucuronoxylomannan (GXM) and mannoproteins in host-pathogen interactions.
- To identify potential therapeutic targets for cryptococcosis.
Main Methods:
- Analysis of C. neoformans-macrophage interactions.
- Investigation of complement activation and opsonization.
- Identification of cellular receptors for GXM and mannoproteins.
- Assessment of signaling pathways triggered by GXM binding.
Main Results:
- Macrophages phagocytose opsonized C. neoformans via complement receptors.
- Glucuronoxylomannan (GXM) binds to macrophage receptors (CD14, TLR2, TLR4, CD18), activating NF-kB but not MAPK, thus inhibiting pro-inflammatory responses.
- Mannoproteins are recognized by mannose receptors and mannose-binding lectin.
Conclusions:
- C. neoformans employs its capsule and secreted components to modulate macrophage responses.
- Targeting the recognition pathways between phagocytes and C. neoformans or its components could be a novel therapeutic strategy for cryptococcosis.