untitled

var. gattiiseems to be eucalypt trees and hollows in

decaying wood.

The pathogenicity and virulence

determinants of C. neoformans

As noted earlier in this chapter, pathogenicity deter-

minants include all those factors that enable an

invasive organism to live in a host environment.

Virulence determinants include the factors that deter-

mine the severity of disease. For C. neoformansthe major

pathogenicity determinantsare the ability to grow

at 37°C in an atmosphere of about 5% CO 2 and at a

pH of about 7.3. The key to this seems to be a gene

that codes for calcineurin A, a specific type of protein

phosphatase that is activated by Ca^2 +-calmodulin and

that is involved in stress responses in yeasts. Mutants

that are defective in calcineurin A can grow at 24°C

but not at 37°C, and they cannot survive in 5% CO 2

or alkaline pH.

There are several virulence determinants of C.

neoformans. The most conspicuous of these – both

in laboratory culture and in clinical specimens – is

the presence of a thick, rigid polysaccharide capsule

around the yeast cells, similar to the capsules seen

in Fig. 16.9. The capsule consists of a high molecular

weight polysaccharide, with a backbone of α-1,3-

linked d-mannose units and single units of d-xylose and

d-glucuronic acid. It seems to be a key virulence deter-

minant of C. neoformans, because naturally noncapsu-

late strains, or mutants that lack the capsule, are

nonvirulent. The encapsulated cells are not as easily

phagocytized or killed by neutrophils, monocytes or

macrophages, compared with noncapsular cells, and

their high net negative charge can reduce cell–cell

interactions required for clearance of the cryptococci.

Pathogenic strains of C. neoformansalso produce

brown or black pigments containing diphenolic com-

pounds. Through the action of phenoloxidase, these

compounds are oxidized and polymerized to produce

melanin, which is deposited in the yeast walls, perhaps

helping to protect against reactive oxidants in the

host tissues. A similar protective role has been proposed

for d-mannitol, which is produced by Cryptococcusand

is especially effective as a scavenger of hydroxyl rad-

icals. Thus, overall there seem to be several potential

virulence determinants in C. neoformans, even if the

precise roles of some of these are not fully understood

at present. The virulence determinants of Cryptococcus

are reviewed by Perfect (2004).

Pneumocystisspecies

So far in this chapter, we have seen some quite

astonishing examples of fungi that cause serious dis-

eases of humans, often as opportunistic or incidental

pathogens. They include fungi whose natural habitat

is eucalypt trees, or pigeon excreta, or the excreta of

cave-dwelling bats, and soil fungi that are endemic to

specific regions of the globe. We have also seen fungi

that disseminate “silently” in the tissues of humans and

that show predilections for certain organs of the body.

And yet many of these aggressive fungi have no obvi-

ous natural means of transmission from one host to

another. For many of them, the infection of a human

host seems to be purely incidental.

Now we turn to perhaps the most astonishing fungi

of all – the many Pneumocystisspecies that cause viru-

lent pneumonia-like symptoms associated with AIDS

and immunosuppressive therapies. These organisms

were first described as protozoa (protists), under the

name Pneumocystis carinii, over 100 years ago, and have

a life cycle that more closely resembles that of a pro-

tist than a typical fungus. Phylogenetic analysis (based

on 18S ribosomal DNA sequence) places them closest

to the early ascomycota, along with the fission yeast

Schizosaccharomyces pombe. But they have one unique

feature: they are the only fungi that have cholesterol

in the cell membrane, whereas most other fungi (with

the exception of some zygomycota) have ergosterol as

their characteristic membrane sterol. One consequence

of this is that Pneumocystisis not susceptible to the com-

mon antifungal agents that target ergosterol; instead

Pneumocystisis controlled by some of the antiprotozoal

agents.

The natural occurrence of Pneumocystis

species

Pneumocystisspecies are found worldwide in human

hosts and in the lungs of a wide range of wild mam-

mals. However, before the widespread development

THE MOULDS OF MAN 335

Fig. 16.9Cells of a Cryptococcusspecies (C. albidus) viewed

by phase-contrast microscopy in the presence of India ink,

which clearly shows the rigid polysaccharide capsules.

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