Cryptococcus Gattii Is Emerging Biology Essay

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Fungi belong to a collection of eukaryotic plant like organisms which lack chlorophyll. There are over 100,000 species and more are being discovered regularly. Scientists believe there could be up to 1 million undiscovered species. The fungi kingdom which is one of five kingdoms of life that include monera, protists, plants and animals, includes moulds, yeasts, mildews and mushrooms. Fungi can be either unicellular or multi-cellular and are separated into groups based on their life cycles and the type of spores they produce (distributional cells or reproductive cells). Because of their lack of chlorophyll, fungi absorb food from their environment and do not rely on the conversion of light, because of this, they can usually be found in dark and moist places, usually on land in soil or plant matter. Fungi have many important functions in the environment. They are decomposers of rubbish and debris, they break down elements imperative for plants and animals to live such as carbon and nitrogen and reintroduce them into the atmosphere they also form mycorrhizal associations with plants. Some fungi, such as mushrooms, are used as food for humans and animals. Saccharomyces Cerevisiae is the fungus responsible for the alcohol in beer and the reason bread rises. Some other fungi are crucially used as medicine, for instance Penicillium which is used as Penicillin. Some fungi are used for bio-control to help maintain crops.

There are three main types of fungi. Multi-cellular filamentous moulds emit digestive enzymes from the hyphal tip which allows the fungi to breakdown organic compounds in soil to feed on. The hyphal tip is formed by fine hyphae which expand and divide at the tip and interweave along their length to form branching threads called mycelium. Unicellular microscopic yeasts reproduce by growing a daughter cell from a parent cell. It is yeasts that are most widely used in the study of genetics. Marcroscopic filamentous fungi are similar to multi-cellular filamentous moulds but they form large fruiting bodies that hold spores. The body consists of closely packed hypae which separate to form the structure of the fungus.

There are four main fungi phyla, Zygomycota, Ascomycota, Basidiomycota and Fungi imperfecti. There are 900 species of Zygomycota (also known as pin moulds because of their appearance or sugar moulds because this species infects fruit rich in sugar) which make up about 1% of all fungi. They reproduce sexually and the phyla includes seven orders, Endogonales, Mucorales, Mortierellales, Asellariales, Kickxellales, Dimargaritales and Harpellales. They are the oldest terrestrial fungi and emerged at least 600 years ago. (, 2010)

Fungi imperfecti, also known as Deuteromycota consist of fungi that do not fit into the common taxonomic groups. Their sexual form of reproduction is not known as it has never been studied but a little is known about their asexual activity. The term Deuteromycota is only usually used to describe fungi classified as Ascomycota or Basidiomycota that reproduce asexually. 25,000 species have been classified as Fungi imperfecti to date.

Ascomycota is also known as sac fungi makes up about 75% of all fungi. They can reproduce either sexually or asexually. There are three subdivisions, the Pezizomycotina, the Saccharomycotina and the Taphrinomycotina. It is quite recently discovered (around 300 million years ago) having previously been classified within the Deuromycota group. Ascomycota describes many fungi and includes yeasts such as Saccharomyces Cerevisiae, Penicillium chrysogenum, Morchella esculentum, Aspergillus flavus, and Candid albicans. (, 2010)

Ascomycota are considered to be the sister phylum of Basidiomycota of which there are 30,000 species , a number that is growing constantly. Bastidiomycota account for roughly 37% of fungi and they are the most evolutionarily evolved group. They can produce either sexual or asexual spores There are four main classes of Bastidiomycota including Agaricomycotina, Pucciniomycotina, Ustilaginomycotina and Wallemiomycetes. Bastidiomycota can be unicellular or multi-cellular as some yeasts have been classed in this phylum. A unique characteristic of Bastidiomycota is that they can ballistospore which means that they launch sexual or asexual spores into the air for reproduction purposes. Cryptococcus is classified in the Basidiomycota phylum. (, 2010)

Fungi imperfecti, also known as Deuteromycota consist of fungi that do not fit into the common taxonomic groups. Their sexual form of reproduction is not known as it has never been studied but a little is known about their asexual activity. The term Deuteromycota is only usually used to describe fungi classified as Ascomycota or Basidiomycota that reproduce asexually. 25,000 species have been classified as Fungi imperfecti to date.

Most fungi are not pathogenic to humans, animals and plants. However, there are approximately 400 species that are known to cause disease. These include Candida which causes thrush in healthy individuals, Aspergillus, especially Aspergillus flavus which generates aflatoxin (a toxin and carcinogen). Pneumocystis causes pneumonia and only infects humans, no animals have found to be diseased. Pneumocystis is usually found in healthy individuals but can be found in the lungs of immunocompromised people. Histoplasma is found in bird and bat faeces and causes histoplasmosis mainly in immunosupressed people. It's is found in the lungs and is potentially fatal.

Cryptococcus is a yeast belonging to the Basidiomycota phylum, class tremellomycetes, order tremellales and family tremellaceae. There are 37 species of Cryptococcus mostly found in soil, most of which are harmless to humans, plants and animals (Dixit, Carroll and Qureshi 2009). The most common species are Cryptococcus laurentii, Cryptococcus albidus and Cryptococcus neoformans. Cryptococcus laurentii and Cryptococcus albidus do cause illness such as meningitis in immune compromised individuals, but Cryptococcus neoformans is the most common and harmful pathogen and causes acute meningitis and pulmonary disease in animals and humans. There are two varieties of Cryptococcus neoformans, C. neoformans var. grubii [serotype A] and C. neoformans var. neoformans [serotype D]. Cryptococcus is found in decaying wood, bird droppings and trees. It is a yeast with a polysaccharide cap, oval in shape and reproduces both sexually and asexually. Asexual reproduction occurs via budding while sexual reproduction takes place when two haploid cells combine and produce hyphae with a basidium on the end. The basidium produces spores via mitosis and meiosis and these enter the host via the respiratory system. Once inhaled, the immune system will stop infection taking hold but if the individual has a compromised immune system, the spores will duplicate and cause symptoms of cryptococcosis.

Infection is not known to be caused by animal-to-human transmission or human-to-human transmission, with the exception of individuals who have had organ transplants in which case the organ recipient may become infected.

There is another type of Cryptococcus, Cryptococcus gattii which is considered pathogenic to healthy individuals. It was known, until recently, known as Cryptococcus neoformans var gattii. Cryptococcus gattii causes lung infection, cerebral cryptococcomas and basal meningitis. It has also been known to cause infection in soft tissues such as lymph nodes and skin as well as bone and joints. There are four C. gattii genotypes (VGI-VGIV) and four C. neoformans genotpes (VNI, VNB, VNII and VNIV). (Chaturvedi and Chaturvedi, 2011).

Symptoms of cryptococcosis vary and can depend on the immune system of the infected individual. Individuals with healthy immune systems who are infected with the pulmonary form of the disease might not show symptoms at all. Indications of infection include distorted vision, sternum tenderness, confusion, pain in the chest, exhaustion, a dry cough, headaches, fever and sweating, nausea, weight loss, swollen glands and a skin rash. The listed symptoms may cause meningitis or permanent brain or nerve damage. It is estimated that 20% of patients will die within 3 months of contracting cryptococcosis and this figure is even higher in immunocompromised individuals (Dromer ref). There are a limited number of treatments for cryptococcosis but most are antifungal therapies including Amphotericin B, Flucytosine and Fluconazole. Amphotericin B is an antifungal polyene antibiotic medicine derived from Streptomyces nodosus. In the case of cryptococcosis it is administered intravenously but can be given orally for other, less fatal fungal infections. Amphotericin B works by binding to Ergosterol (a sterol found in the membrane of fungi) and forming a channel across the membrane that leads to monovalent ion (K+, Na+, H+ and Cl−) seepage and causes the fungal cell to die. Current research suggests that pore configuration may not be related to cell death. Recently, however, researchers found evidence that pore formation is not necessarily linked to cell death (Baginski, M.; Czub, J. (2009). Flucytosine is an antimetabolite that works by changing the chemistry of the cell and therefore prohibiting fungal cell growth. There are two known modes of action. The first occurs when Flucytosine is converted into 5-fluorouracil and interacts as 5-fluorouridinetriphosphate with the biosynthesis of RNA, this interrupts the structure of some vital proteins and causes the cells to die. The second mode of action takes place when Flucytosine becomes 5-fluorodeoxyuridinemonophosphate, this prevents fungal DNA synthesis. Flucytosine is available as an oral medication and as an injectable and patients receiving treatment must be under close medical supervision as it is known to cause renal and liver problems and research is on going to determine whether it is carcinogenic. Research carried out in 2008 by Dromer et al. Confirmed that the combined administration of intravenous Amphotericin B and oral Flucytosine for at least a 14 day period is more effective than administering either Amphotericin B or Flucytosine alone (Dromer ref). Fluconazole is the third type of antifungal medication, it works by hindering the actions of the cytochrome P450 enzyme in the sterol biosynthesis pathway,14α-demethylase therefore stopping the conversion of lanosterol to ergosterol. Ergosterol needs to be in the membrane of the cell to enable it to function properly (Lyman, C. A., and T. J. Walsh. 1992). Fluconazole can be used orally with intravenous Amphotericin B in the absence of Flucytosine.

Baginski, M.; Czub, J. (2009). "Amphotericin B and Its New Derivatives-Mode of Action". Current Drug Metabolism 10 (5): 459-69. PMID 19689243.

Dromer reference - Major Role for Amphotericin B-Flucytosine Combination in Severe Cryptococcosis - endnote

Lyman, C. A., and T. J. Walsh. 1992. Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs. 44:9-35. (not in endnote yet)

In 1999 an outbreak of Cryptococcus gattii became evident on Vancouver Island, British Columbia, Canada. It was the highest incidence of the infection globally and the mortality rate for those infected between 1999 and 2007 was 8.7%. A number of risk factors (behavioural, medical and demographic) associated with infection of Cryptococcus gattii in British Columbia have been identified as a result of a study by MacDougall et al. in 2011. The research found that the mean age of infected individuals in British Columbia was 58.7. Less than four cases in nine years since the outbreak were in children. This suggests that infection is more likely to occur in those over 50 years old although this could be because those over 50 years old have more medical risk factors for infection of C. gattii. A history of lung conditions such as pneumonia and chronic bronchitis were associated with contraction of C. gattii as was the presence of an invasion cancer (commonly lung cancer). It was also found that current smokers were more likely to become infected than non-smokers. It was suggested that the reason for this is that infectious spores are inhaled along with the smoke. The study identifies that individuals undergoing corticosteroid treatment, a widely used treatment, used to remedy a number of complaints ranging from skin disease to brain tumours, are more susceptible to C. gattii infection. This is supported by a study undertaken in the 1950s by Levine et al. which demonstrated that mice, usually resilient to Cryptococcus infection became easily infected after receiving a small dose of corticosteroid. This may be a major problem as steroids are sometimes used in the treatment of cryptococcosis. The study found that although infection of HIV positive patients is rare, it is still more frequent than in the general population. The research suggests that 40% of C. gattii infected patients tested were immune-compromised which contradicts the previous view that C. gattii infected healthy individuals while C. neoformans infected immuno-suppressed persons (MacDougall 2011). Previous research in Vietman by Chau et al. on cryptococcal meningitis in HIV negative individuals showed that it usually occurs in persons who have no underlying medical conditions and the majority of cases were due to C. neoformans var grubii (70%) the other cases were caused by C. gattii (30%) (Chau et al. 2010). Prior to these studies, in 2008, research was conducted in China where there had been 7,372 cases of cryptococcosis reported between 1985 and 2007. The aim of the study was to understand the population structure of cryptococcosis agents across the country. It examined the genotype of nine C. gattii and 120 C.neoformans strains isolated from 129 infected patients between 1980 and 2006 and found that 71% (91/129) came from participants that had no underlying medical condition, only 8.5% (11/129) came from AIDS or HIV patients and the other 20.5% (27/129) came from individuals who were immmuno-compromised due to diseases other than HIV or AIDS. Of the 129 isolates, 120 were C. neoformans Serotype A, MATa (molecular type VNI), the other nine were C. gattii serotype B, MATa (molecular type VGI). (Chen et al. 2008). These findings contract the findings of the MacDougall et al. study.

In the nine years following the initial outbreak, C. gattii and C. neoformans var grubii have spread to various non-tropical climates. The disease has been identified in the northwest pacific, in Washington and Oregon.

Now evidence suggests that both varieties of Cryptococcus are infecting otherwise healthy individuals. (Lindberg et al. 2007)

A lot is understood about the virulence factors of C. neoformans var grubii and C. Gattii. They share many qualities that make them able to enter and survive in a host and cause infection. Features include mannitol, melanin pigment and a tolerance to high temperatures, low pH and high salt levels. Both C. neoformans var grubii and C. Gattii share similar cellular signalling pathways, extracellular proteinase and means to penetrate the blood-brain barrier. Both species also have an outer polysaccharide capsule that is rich in the carbohydrates glucuronoxylomannan (GXM), galactoxylomannan (GalXM) and manno-proteins. This attribute allows the outer capsule to change in structure, a procedure known as phenotypic switching. The ability to do this suppresses the host organisms immune reaction by down regulating chemokine and cytokine expression (Dixit, 2008). However, it has been suggested that there must be differences between the two species which would explain why C. Gattii is more infectious than C. neoformans var grubii. One theory is that complement component 3 is not as effective at binding to C. gattii as it is at binding to C. neoformans meaning that C. gattii has a better ability to evade recognition by the immune response. (Chaturvedi and Chaturvedi 2011)

Hybrid strains of Cryptococcus have become a worry in recent years. A different strain of the pathogen (genotype VGIIc) was then seen to be spreading in 2010 when it appeared in Oregon and nowhere else. This strain is highly infectious and the most harmful variety to be found so far. (Byrnes Iii et al. 2010)

Some evidence suggests that C. neoformans var grubii originates from ancestral Africa (Litvintseva et al. 2007). The work of Simwami et al. (2011) showed that isolates from 11 different providences in Thailand were very similar and had the same genetic background (known internationally as VNI). The samples only revealed ten almost identical sequence types. This suggests that Cng VNI has grown out of Africa and resulted in a restricted number of genotypes found in Asian populations. (Simwami et al. 2011)

There are several possible reasons for the spread of C. neoformans var grubii and C. Gattii to non tropical environments and to a diverse number of hosts, to persons who are both immuno-compromised and persons who are not.. Climate change has been mentioned as a possible cause. The production of greenhouse gases namely methane and carbon dioxide has caused the earth's temperature to increase. Heavy winter precipitation and dry, warm summers have granted the best possible conditions for infectious fungal spores to grow and infect in regions that they would not be present in previously. (Greer, 2008). (Datta et al. 2009) and newly discovered hybrid strains of C. Gattii (Litvintseva et al. 2007).

Need to look at and C. Gattii and Grubii