The Pathogenicity of Fungi - Cryptococcus neoformans Flashcards
Is cryptococcus neoformans part of the commensal human flora?
no
What disease is caused by cryptococcus neoformans?
Meningoencephalitis
Who is susceptible to getting cryptococcus neoformans?
Immunocompromised individuals
How does c. neoformans enter the body?
Via the respiratory tract.
In what form does c neoformans enter the body?
In the form of dehydrated yeast cells or basidiospores
List the virulence factors associated with c. neoformans.
- Capsule
- Cryptococcal products
- melanin production
- Mannitol production
- Superoxide Dismutase
- Proteases
- Phospholipase B
- Lysophospholipase
Describe the structure of the C. neoformans capsule.
Ciomposed of the polysaccharide GLUCURONXYLOMANNAN:
Backbond of 1,3-D-mannopyranose units with single residues of Beta-D-xylopyranosyl and Beta-D-glucuronopyranosyl attached.
How does the capsule contribute to virulence?
Protection from host defences by interference with important binding required for oposonisation and phagocytosis by macrophages, neutrophils or monocytes:
- Masking of C3b and C3bi deposits on the surface of c. neoformans preventing their binding to CR3 of leucocytes
- Capsule is capable of blocking the Fc portion of antibodies and therefore it may also interfere with its binding to phagocytic host cells
- Strong negative charge of capsule causes electrostatic repulsion between c. neoformans and host immune cells preventing their clearance.
What is the consequence of the capsule mediated inhibition of phagocytosis?
- Ultimately the inability of these cells to phagocytose the organism results in reduced antigen presentation and an inability to activate the adaptive immune response.
- Cytokine production such as that of TNF-alpha, IL-1beta and IL-6 is also consequentially inhibited by the difficulty in macrophage and monocyte binding.
Name 3 intrvascular c. neoforman antigens.
- GXM
- GalXM
- MP
What is the consequence of the release of these three antigens into the vascular tissue?
They inhibit migration of leucocytes to a site of inflammation
as seen in murine experiments
It is not known exactly how GXM, GalXM and MP inhibit migration of leucocytes. What theories have been proposed to explain this observation?
GXM can stimulate neutrophils to shed L-selectin which is required for neutrophils to slow down at inflamed tissue in preparation for attachment
GXM and GalXM also bind to LFA-1 of neutrophils and block its binding to its CAM-1 receptor on inflamed endothelial cells.
What is the purpose of the production of Melanin?
Experiments have shown that C. neoformans can produce melanin which protects itself from oxidative stress induced by macrophages.
Inhibits opsonisation by specific antibodies.
How is melanin produced by C. neoformans?
C. neoformans catalyses the conversion of dihydroxyphenols such as DOPA (3,4-dihydroxyphenylalanine) to dopaquinone using the enzyme phenoloxidase.
Dopaquinone is rearranged to form dopachrome.
Dopachrome is autoxidated to melanin
What role does mannitol play in C. neoforman virulence?
Production of D-mannitol has shown to aid in survival within a host:
- High D-mannitol in the CNS may contribute to brain edema
- Mannitol is a potent scavenger hydroxyl radicals protecting the organism from oxidative stress
