Mycologist, Volume 16, Part 3 August 2002. ©Cambridge University Press Printed in the United Kingdom.DOI: 10.1017/S0269915X02003038

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I’VE GOT YOU UNDER MY SKIN – THE MOULDS OF MAN

There are thought to be over 1.5 million species of fungi. Of these, most live on decaying vegetation, in partner-ship with algae (lichens) or tree roots (mycorrhizas) or are parasites of plants or insects. Only a few tens of speciescause us any direct harm but Mycologist is featuring a series of articles about the main species that do causeirritating, and in some cases life-threatening human infections. In this issue Cryptococcus neoformans, the ‘awak-ening giant’ among fungal infections, is discussed.

Cryptococcus neoformans – the encapsulated menace

ANDY HAMILTON

St Johns Institute of Dermatology, Guys Hospital; Guys, Kings and St Thomas’s Medical Schools,Kings College, London SE1 9RT.

Opportunistic fungal infections have emerged in thepast ten to twenty years as some of the most significantand potentially lethal infectious diseases to confrontcontemporary medicine. Fungi such as Candida albicans,Aspergillus fumigatus and Cryptococcus neoformans haveemerged from obscurity to threaten many patientgroups. Although the latter of these, the yeast C.neoformans, was identified as a potential pathogen asearly as 1894, it was not until the 1950s that asystematic appreciation of its potential as anopportunistic pathogen began. During this decade theassociation between the heightened risk of C.neoformans infection (cryptococcosis) and variouscancers of the blood became obvious. Fortunately, justas the risk posed by this yeast to human health wasbeing clearly defined (in the late 1950s), the firsteffective therapy to treat cryptococcosis appeared – thedrug amphotericin B. This was particularly timely sinceit had been recognised that C. neoformans infectionoften led to a rapidly fatal form of meningitis ifuntreated.

Throughout the 1960s the infection remainedrelatively rare, being largely confined to the patientgroup described above. However, by the late 1970s theincidence of C. neoformans infection began to riserapidly. Cases were now being seen in patientsundergoing organ transplantation, in those withautoimmune diseases and in others who were receivingimmunosuppressive drugs to treat various cancers.Cryptococcosis had suddenly become ‘the awakeninggiant’ amongst fungal infections (Kaufman &Blumer,1977); but quite how much of a ‘giant’ would

only become clear in the next two decades with thedevelopment of the human immunodeficiency virus(HIV) epidemic.

Indeed, by the late 1980s and into the 1990scryptococcosis was being seen in 20% or more of AIDSpatients from some regions of Central Africa. Again, innorthern Thailand by the end of the 1990s close to30% of AIDS patients were developing cryptococcosis.In the developed world its rise was almost as dramatic –in New York city alone in 1991 there were over 1,200cases of cryptococcal meningitis in AIDS patients(Casadevall & Perfect, 1998). To put this figure intocontext, this was more than double the total ofmeningitis cases arising from bacterial or viral infectionin the city in the same year. Thus, in the space of littlemore than 20 years, cryptococcosis had become acommon affliction in many parts of the world.

Such an explosive growth in infection ratespredictably stimulated enormous interest in this buddingyeast; by the mid-1980s crucial work was beingperformed on various aspects of the immunology, cellbiology and pathogenicity of C. neoformans. The mostdistinctive structural element of C. neoformans, itscarbohydrate capsule, which surrounds this yeast, anddwarfs (in size and thickness) its cell wall, was quicklyestablished as playing a key role in enabling the organismto cause disease. Whilst being detrimental to the host inmany respects (capsule material causes a range ofdamage to the immune system), the carbohydrate whichmakes up the majority of the capsule does have its uses.Detection of this material in patient tissues is the keymeans of diagnosing cryptococcosis.

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For a time the capsule was defined as the prime moverbehind the ability of C. neoformans to cause disease, but aseries of studies have now shown that several factors areimplicated in its pathogenicity. Perhaps most intriguinglyC. neoformans has been shown to produce the pigmentmelanin – this appears to act as a type of ‘body armour’protecting the yeast against a wide variety ofenvironmental and immunological hazards.Significantly it has recently been demonstrated thatchemical inhibition of the production of melanin(Nosanchuk et al., 2001) by C. neoformans in infectedanimals can have a deleterious effect on the ability of theyeast to cause disease. This opens up new and excitingavenues for potential treatment of the disease. Perhapsthis is as well, given that we still have only a handful ofavailable drugs with which to treat infection. Some ofthese drugs have unpleasant side effects, so thedevelopment of new therapies remains a key goal incryptococcosis research. The search for new drug targetsshould be significantly enhanced by the availability of C.neoformans genome data, which has recently becomeavailable (http://www.genome.ou.edu/cneo.html).

Parallel developments in molecular and genomicstudies in the yeast Saccharomyces cerevisiae are alsocontributing significantly to our knowledge of themechanisms by which C. neoformans detects andresponds to changes in its environment (D’Souza &Heitman, 2001). Indeed, environmental change issomething C. neoformans must rapidly respond to – afterall this yeast is first inhaled into the lungs prior todisease causation and dissemination. This eventtriggers major changes, including massive synthesis ofcapsular material. It now seems that in urbanenvironments (and presumably elsewhere), such asNew York city, children over the age of two routinelyinhale C. neoformans, which must presumably lead tosome sort of asymptomatic infection: as a consequencemany children show antibody responses to the yeastwhen tested. Such children would not be expected todevelop any apparent disease unless they wereimmunosuppressed or subsequently became so.

Cryptococcus neoformans can be easily isolated frombird excreta such as pigeon droppings and this mostlikely represents the reservoir from which children (andpresumably also adults) acquire infection in suchsituations.

It is worth briefly noting that there is a second,more rarely occurring form of the disease, caused by aform of C. neoformans different from that whichpredominates, for example, in Europe and NorthAmerica. This form of C. neoformans is particularlyprevalent in parts of Papua New Guinea andNorthern Australia, and unusually it has anenvironmental association with trees (types ofeucalyptus), rather than birds. This form of thedisease also seems to occur with regularity in healthyyoung men who do not appear to have any underlyingimmunosuppression – however, perhaps thankfully, itdoes not appear to be becoming any commoner in thepopulation at large.

As to the future; although new anti-HIV therapieshave had beneficial effects in lowering the incidences ofopportunistic fungal infections in AIDS patients in thedeveloped world (incidences of cryptococcosis in thesepatients have dropped off rapidly in the US and Europe),in patients not receiving these costly drugs the outlookis still bleak. Thus, cryptococcosis is still a major threatin African and Asian AIDS patients. Consequently thesearch will go on for new and improved methods totreat this infection.

ReferencesCasadevall, A. & Perfect, J. R.(1998) Cryptococcus neoformans.

ASM Press. ISBN 1- 5581-107-8.D’Souza, C. A. & Heitman, J. (2001) FEMS Microbiology

Reviews. 25: 349-64.Kaufman, L. & Blumer, S. (1977). Cryptococcosis: the awak-

ening giant. Proceedings of the Fourth InternationalConference on the Mycoses. PAHO Scientific Publication No356.

Nosanchuk, J. D, Ovalle, R. & Casadevall, A. (2001) J.Infectious Diseases. 183: 1093- 1099.