Monday 29 August 2005
Definition: Cryptococcus neoformans (formerly known as Torula histolytica) is an encapsulated yeast-like fungus found in dried avian (particularly pigeon) and bat excreta, and in dust contaminated with such droppings.
Cryptococcus neoformans is an encapsulated yeast that can live in both plants and animals. Its teleomorph is Filobasidiella neoformans, a filamentous fungus belonging to the class Tremellomycetes. It is often found in pigeon excrement.
Its usual portal of entry is the respiratory tract, leading to the formation of pulmonary granulomas. Meningoencephalitis is another clinical presentation of cryptococcosis. Hematogenous dissemination leading to cutaneous involvement occurs in about 10–15% of cases of cryptococcosis.
Cryptococcus neoformans is an encapsulated yeast that causes meningoencephalitis in normal individuals but more frequently presents as an opportunistic infection in patients with AIDS, leukemia, lymphoma, systemic lupus erythematosus, Hodgkin lymphoma, or sarcoidosis and in transplant recipients.
Many of these patients receive high-dose corticosteroids, a major risk factor for Cryptococcus infection.
Infection with C. neoformans is termed cryptococcosis. Most infections with C. neoformans consist of a lung infection.
However, fungal meningitis, especially as a secondary infection for AIDS patients, is often caused by C. neoformans making it a particularly dangerous fungus.
Infections with this fungus are rare in those with fully functioning immune systems.
For this reason, C. neoformans is sometimes referred to as an opportunistic fungus. It is a facultative intracellular pathogen
- localized cryptococcosis
- cutaneous cryptococcosis
- pulmonary cryptococcosis
- systemic cryptococcosis
C. neoformans is present in the soil and in bird (particularly pigeon) droppings and infects patients when it is inhaled.
C. neoformans can undergo phenotypic switching, which leads to changes in the structure and size of the cap-sule polysaccharide, providing a means to evade immune responses.
C. neoformans makes laccase, which catalyzes the formation of a melaninlike pigment. Laccase mutants of C. neoformans have reduced virulence in animal models.
The role of melanin in cryptococcal pathogenesis may be related to the antioxidant properties of melanin. The melanin synthetic pathway consumes host epinephrine in the synthesis of fungal melanin, protecting the fungi from the epinephrine oxidative system present in the host nervous system.
This suggests a potential mechanism for the neurotropism of C. neoformans.
These fungi make a number of other enzymes, including a serine proteinase that cleaves fibronectin and other basement membrane proteins, which may aid tissue invasion.
Cryptococcus neoformans grows as a yeast (unicellular) and replicates by budding.
C. neoformans makes hyphae during mating, and eventually creates basidiospores at the end of the hyphae before producing spores.
Under host-relevant conditions, including low glucose, serum, 5% carbon dioxide, and low iron, among others, the cells produce a characteristic polysaccharide capsule.
When grown as a yeast, C. neoformans has a prominent capsule composed mostly of polysaccharides.
Microscopically, the India ink stain is used for easy visualization of the capsule.
The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or "halo" around the cells. This allows for quick and easy identification of C. neoformans.
C. neoformans grows rapidly on exposure to radiation such as gamma-radiation. Radiation seems to increase the electron-transfer capability of melanin in the fungus, increasing its total metabolic activity
Several virulence factors enable it to evade host defenses. The virulence factors include (1) a polysaccharide capsule, (2) melanin production, and (3) enzymes.
These mechanisms are not very effective when C. neoformans infects hosts with intact immune defenses, but they can lead to disseminated disease in immunosuppressed individuals.
The polysaccharide capsule of C. neoformans is a major virulence factor, preventing phagocytosis of cryptococci by alveolar macrophages.
Capsular polysaccharide inhibits phagocytosis, leukocyte migration, and recruitment of inflammatory cells. Acapsular strains are less virulent in animal models.
C. neoformans can establish latent infections accompanied by granuloma formation but can reactivate in immunosuppressed hosts. Studies in rat models indicate that yeast cells can persist in macrophages within granulomas.
Cryptococcus laurentii is a rare human pathogen.
In contrast to Candida, cryptococcus has yeast but not pseudohyphal or hyphal forms. The 5- to 10-μm cryptococcal yeast has a thick gelatinous capsule that is valuable for diagnosis.
Capsular polysaccharide stains intense red with periodic acid-Schiff and mucicarmine in tissues and can be detected with antibody-coated beads in an agglutination assay. India ink preparations create a negative image, visualizing the thick capsule as a clear halo within a dark background, but do not stain the yeast.
Although the lung is the primary site of localization, pulmonary infection with C. neoformans is usually mild and asymptomatic, even while the fungus is spreading to the central nervous system.
C. neoformans, however, may form a solitary pulmonary granuloma similar to the circumscribed (coin) lesions caused by Histoplasma. The major lesions caused by C. neoformans are in the central nervous system, involving the meninges, cortical gray matter, and basal nuclei. The tissue response to cryptococci is extremely variable.
In immunosuppressed patients, organisms may evoke virtually no inflammatory reaction, so gelatinous masses of fungi grow in the meninges or expand the perivascular Virchow-Robin spaces within the gray matter, producing the so-called soap-bubble lesions.
In nonimmunosuppressed patients or in those with protracted disease, the fungi induce a chronic granulomatous reaction composed of macrophages, lymphocytes, and foreign body type giant cells.
Neutrophils and suppuration also may occur, as well as a rare granulomatous arteritis of the circle of Willis. In severely immunosuppressed persons, C. neoformans may disseminate widely to the skin, liver, spleen, adrenals, and bones.
Casadevall A, Pirofski L. Insights into mechanisms of antibody-mediated immunity from studies with Cryptococcus neoformans. Curr Mol Med. 2005 Jun;5(4):421-33. PMID: #15977998#
Vecchiarelli A. The cellular responses induced by the capsular polysaccharide of Cryptococcus neoformans differ depending on the presence or absence of specific protective antibodies. Curr Mol Med. 2005 Jun;5(4):413-20. PMID: #15977997#