Complete septa are walls that have no pores. These are usually found between the vegetative and reproductive or specialized cells of a fungus (such as gametangia) to ensure that the two regions are kept distinct.

Micropore septa are walls which have very small pores between adjacent cells. This allows cells to communicate with neighboring cells also allows nuclear migration (the movement of a nucleus form one cell to another). Since micropore septa allow the cytoplasm of two cells to mix, there is debate as to whether or not these fungi are continuous.

Aseptate is a term used to describe fungi that lack septa except to wall off their reproductive cells (with complete septa). Since nothing separates one cell from another, these fungi are often called coenocytes, meaning that they are multinucleate. Aseptate fungi include the Oomycota and the Chytridiomycota.

Regularly septate is a term used to describe fungi that have septa at regular intervals. These fungi include the Ascomycota, Basidiomycota and Fungi Imperfecti.

Irregularly septate is a term that is used to describe fungi which have septa at random positions. Irregularly septate fungi include the Zygomycota.

Fungal-like protists and the Chytridiomycota tend be aseptate, except to delimit reproductive or specialized cells (such as sporangia and gametangia). Since they are multinucleate, they are often call coencytes.

The Zygomycota tend to be aseptate or have septa formed at irregular intervals in their hyphae. (Complete septa may also form to wall of specialized regions.)

Ascomycota and Basidiomycota are regularly septate and tend to form complete septa or micropore septa between mother and daughter cells.

Hyphal Oomycota exhibit random dispersion of apical vesicles

Hyphal Zygomycota have a high concentration of apical vesicles at the tip

Hyphal Ascomycota, Basidiomycota, and Fungi Imperfecti develop structures called spitzenkarpers at their growing hyphal tips.

clinical history that suggests fungal infection (usually provided by the patient)

observation of fungus in clinical specimens

the fungus observed must be compatible with the disease reported

adequate evidence must be provided that the causative agent is actually a fungus that was properly identified

There is a general lack of government reporting requirements as far as funagal infection is concerned, though the CDC strongly suggests reporting any incidences of histoplasmosis and coccidiodomycosis.

It is relatively difficult to document cases of fungal infection since symptoms can easily be confused for symptoms of the flu or heart disease.

Fungal diseases are generally not communicable, so they are not a real threat to public health.

The exact mycosis or the relevance of mycosis may be difficult to establish, especially in patients who are immunocompromised due cancer or other degenerative diseases and may have illnesses other than fungal infection.

Some organisms (such as P. carinii, which was once thought to be a protozoan) have only recently been defined as fungi.

There is increased awareness of fungal infection and as a result more professionals get mycological training.

Beginning with the advent of antibiotics, people have been living longer. As a result, more people reach the age at which their immune systems begin to fail and they become compromised and are at risk for fungal infection. The AIDS epidemic has also contributed to the increase in number of immunosuppressed hosts.

· Factors that predispose humans to fungal infections generally compromise the host’s immune system such that the host cannot resist a fungal infection as a healthy person would. Such factors include prolonged antibiotic therapy, underlying disease (such as HIV, cancer, diabetes, etc.), age, immunosuppressive drugs, irradiation therapy, and burns.

· Other factors that predispose us to mycosis allow fungi to bypass the skin and mucous barriers that generally protect us, invade our systemic circulation, and access areas than microbes would otherwise never be able to colonize. These factors include surgical procedures iatrogenic dialysis, drug abuse using needles, burns and transplants.

· People who travel may also be exposed to strains of fungi in doses their bodies may not be able to handle.

In immunocompromised patients, typical signs and symptoms of fungal infection are frequently absent.

Few clinical features are unique to fungal infection so many cases may be misdiagnosed.

Even when assay for the presence of fungi, sputum and blood cultures may give false positive results

Invasive procedures are sometimes necessary to diagnose fungal infection, but these procedures are often contraindicated in immunocompromised hosts.

Primary pathogenic fungi are fungi that are free-living fungi which are commonly pathogenic in normal hosts and severely pathogenic in compromised hosts

Secondary pathogenic fungi differ from primary pathogenic fungi in that they can be either free-ling, exosymbionts, or endosymbionts and are pathogenic only in compromised hosts. For example, dermatophytes (fungi which live on our skin) may enter the body of an immunocompromised host through a cut and cause and systemic fungal infection. Secondary pathogenic fungi do not pose a threat to persons with a healthy immune system ands are opportunistic.

This can be through the lungs or other orifices, through traumatic implantation (in which case fungus gets introduced into tissues and establishes lesions), or by surface colonizers (such as Candida albicans) invading deeper tissues to produce a systemic infections.

multiply and grow within the host until there are sufficient numbers of the fungi to threaten the host and illicit symptoms of infection

This can result in necrosis (tissue death) and/or tissue irritation (rashes, granulomas, etc.) Granulomas (structures that arise when the host tries to "wall off" the pathogen) are significant in that they are signs that the host has recognized and is trying the limit the infection.

Pathogenic fungi must be able to grow at elevated temperatures, (usually between 35 – 40*C). Any fungus that can grow near this range is a potential pathogen. Dermatophytes (which live on the skin where it is slightly cooler) must be able to live near 33*C

They must be able to grow at the reduced redox potentials characteristic of human hosts

As already discussed, they must be able to avoid cell-mediated and innate immunity of hosts. Our immune systems have evolved to withstand the vast majority of fungal infections, so most fungi do not pose a threat.

Capsules (See C. neoformans above)

Fungal cell walls are composed of beta-glucans, chitin, chitosan, melanin, and mannoprotein which may act as virulence factors. (The chitin and beta-glucan aggregate to form microfibrils.) Certain surface antigens and surface hydrophobicity may also play a role in the virulence of certain fungal species, such as Candida albicans.

These are organic Fe3+ chelating substances used to collect iron in the host.

Fungal plasma membranes contain ergosterol rather than cholesterol.

physical barriers, such as skin and mucous membranes

chemical barriers, such as secretions and serum factors

the body’s natural effector cells, which may or may not be phagocytic

Those that allow the fungus to enter the host and cause disease

Those of the host that either limit the growth or the survival of the fungus within host tissues

The size of the inoculum. Infection often only depends upon exposure to a sufficient inoculum size (particularly for pulmonary inocula and for traumatic implantation of the inoculum into tissue) for primary infections. Endemic areas are regions where spores can be found in large numbers and have a high incidence of fungal infection.

The general resistance of the host. The lower host defenses are, the more likely it is that the host will be susceptible to fungal attack and the more severe the outcome. Lower resistance implies that a smaller inoculum is required to develop an infection.

The inherent virulence of the fungus. Obviously, the more virulent the fungus, the harder it is for the host to fight infection and the more severe the illness.

Fungi have enhanced pathogenicity in immunosuppresed humans (i.e. those afflicted with HIV) or in T-cell-deficient experimental animals.

Specific fungal antigens have been demonstrated to induce blastogenic transformations and release of lymphokines (CKs produced by lymphocytes) among sensitized lymphocytes. These lymphokines are presumed to function by interacting with portions of the CMI system. (Monokines are CKs produced by monocytes and macrophages.)

Lymphokine interactions function to

Contact allergy (dermatitis, etc.)

Activation of macrophages and TC cells This is important because activated cells are more likely to kill fungus.

Chronic granulomatous reactions. These are the predominant tissue reaction to fungi in CMI-competent patients (that is, patients who are not immunocompromised). It is a type of DTH response the body mounts against a pathogen that it cannot kill in which large numbers of macrophages (which may fuse to become multinucleated cells which are more efficient phagocytes) congregate with lymphocytes and fibroblasts around large or numerous target fungi to wall off the pathogen and control the infection. There is generally no tissue death associated with granuloma formation.

Traditionally, skin tests assay are used to test for DTH. If the skin test is positive, then one can safely assume that the patient has a competent immune system.

There are three responses:

Lymphocyte Transformation assays (LT assays)

These tests involve sensitized T lymphocyte responses to specific fungal antigens as measured by (1) increased synthesis of DNA, RNA, or protein or (2) a greater number of cells of the blast type resulting form blast cell transformation. One can use peripheral blood, spleen tissue, lymph nose tissue, or other tissue which contains a sufficient number of lymphocytes.

Macrophage migration inhibition factor assays (MIF assays)

This involves sensitized lymphocytes that respond to specific antigens in vitro by production of MIF. MIF lymphokines acts to retard or inhibit migration of macrophage.

Cytotoxicity assays

This involves activated lymphocytes that release cytotoxins, which bring about lysis of target cells

The fungus involved (e.g. low/high virulence)

The exact immunological state of the host

The number of infecting units involved

The route of infection

The site of the lesions involved

The duration of infection

Phagocytosis by macrophage resulting in a pyogenic (or cystic) type of reaction

Followed by another CMI step that promotes granuloma formation and possibly more killing

Ø WT mice infected with C. neoformans formed granuloma on liver (no cyst).

Ø Athymic mice infected with C. neoformans developed cystic lesions and necrosis.

Ø When lymph noses were transferred to athymic mice, granuloma formed.

Ø When carrageen (a macrophage blocking agent) to WT mouse cyst formed.

pyogenic ("pus-like") reactions

followed by granulomatous reactions. Granulomatous reactions are generally associated with a functional immune system; that is, granuloma formation is often indicative of an intact (CMI) immune system. Granulomas generally form in the lungs when professional phagocytes cannot clear the pathogen form the lungs and are not associated with tissue death. These can lead to scarring or result in calcified lesions, which may reduce the respiratory capacity of the host.

necrotic (extensive tissue death)

suppurative (lesions may be fluid filled)

cysts – nonfibrous or fibrous walls filled with fluid. These can be contrasted to granulomas. The inability of a patient to form a granuloma may indicate the the host has an abrogated immune system and cannot mount an adequate attack on the pathogen.

Grouping within this phylum does not necessarily reflect phylogeny – species in the same genus may be less related than species in a different genus.

Most species are, in reality, members of other phyla, particularly Ascomycota & Basidiomycota, but cannot be classified morphologically since they do not exhibit a sexual state. Most Fungi Imperfecti are probably Ascomycota based on studies of septa, etc.

Members of the Deuteromycota often have two or more acceptable scientific names.

If a fungus grows, it usually exhibits its asexual (anamorphic) phase first.

With medically important fungi, one can identify and treat a mycosis without knowing anything about its sexual stage or how it is classified, so there is little initiative to take the time to re-categorize.

Induction of the sexual state form the asexual state is often dependent upon inducing sex in mated self-sterile strains (heterothallic strains), which can be difficult.

Induction of sexual states often requires special environmental or physiological conditions which may not be known.

The anamorphic phase (or anamorph) is the asexual phase of the fungus. During this stage, no meiosis occurs, only mitosis.

The teleomorphic phase (or teleomorph) is the phase during which kayogamy and meiosis occur.

The holomorph is the term used to speak of both the asexual (anamorph) and sexual (teleomorph) phases.

Synanomorphy (or synanomorph) is a term used to refer to the different asexual morphological phases of the same fungus. These fungi have different names because they are dimorphic in their asexual phase. For example, using molecular techniques, it has been discovered that many fungi are the same genetically. These fungi are called synanomorphs.

The Fungi Imperfecti are subdivided into nonphylogenetic form-classes.

Blastomycetes: asexual yeasts or the nonsexual yeast phases (anamorphs) of ascomycetous, basidiomycetous, or dimorphic fungi.

Hyphomycetes: asexual conidial fungi or nonsexual phases (anamorphs) of ascomycetous, basidiomycetous, or dimorphic fungi.

Coelomycetes: asexual fungi or nonsexual phases (anamorphs) of ascomycetous or basidiomycetous hyphal fungi that produce conidia in multihyphal aggregates called conidiomata (pl. conidioma). These are conidial fungi.

Mycelia Sterilia: nonconidiogenous hyphal fungi that reproduce only by fragmentation. These grow vegetatively only, they never make spores.

Identification, based on recognition

Classification, determines relationships between specimens and reflect phylogeny/evolutionary history

Nomenclature, the naming of specimens

A spore is a microscopic propagating unit without an embryo. One way to classify spores is based on the way they are derived, either through mitosis or meiosis. Mitospores are spores which result from mitosis. Meiospores are spores which result from meiosis.

Zoospores are non-walled, flagellated cells derived by mitosis (mitospores). Note that they have flagella, which means that they are motile. (Recall, also that eukaryotic flagella have a "9+2 microtubule" structure.) They must encyst and acquire dormancy qualities before they become true spores.

Sporangiospores are nonmotile spores which (like zoospores) are derived by mitosis (mitospores).

A sporangium (or mitosporangium)is a cell in which mitotically derived reproductive cells are produced by cytoplasmic, vesicle-mediated cleavage to produce mitospores (zoospores or sporangiospores). A meiosporangium produces meiospores.

Zygospores are diploid spores which undergo meiosis upon germination.

Teliospores are spores which contain two nuclei of the opposite mating type (dikaryotic spores). Germination of the spores results in karyogamy followed by meiosis.

The kingdom Protoctista contains some organisms that resemble fungi.

These fungal-like protists are classified in the phylum Plasmodiophoromycota. Plasmodiophoromycota produce zoospores which each have one whip-lash flagellum and one stub.

The kingdom Chromista also contains some organisms that resemble fungi.

These fungal-like protists are classified in the phyla Hyphochytridiomycota and Oomycota. The Hyphochytridiomycota produce zoospores which each have one anterior tinsel flagellum while the Oomycota produce zoospores which each have one whip-lash and one tinsel flagellum.

The kingdom Fungi contains three subkingdoms:

The subkingdom Mastigomycotera contains fungi which are zoosporic (that is, produce flagellated spores). This subkingdom contains the phylum Chytridiomycota, which are fungi that produce zoospores (each with a posterior whip-lash flagellum).

The subkingdom Amastigomycotera contain fungi which are non-zoosporic (that is, produce spores that lack flagella). This subkingdom contains the phylum Zygomycota, which are fungi that produce nonmotile sporangiospores and/or zygospores.

The subkingdom Eumycotera contains non-sporangial fungi. They are found as yeast or filamentous fungi and are classified based the presence or absence of structures called asci and basidia.

The phylum Ascomycota contains fungi which produce endogenous meiospores, known as ascospores, in a cell(s) called an ascus (asci). The ascus is called the meiosporangium of Ascomycota because it parallels the role that a sporangium plays in the production of mitospores, but produces meiospores instead. These fungi are regularly septate hyphal (that is, their hyphae are walled off at regular intervals) or yeast fungi.

The phylum Basidomycota contains fungi which produce exogenous meiospores called basidiospores on a structure called a basidium. The basidium is called the meiosporangium of Basidiomycota. These fungi are also regularly septate hyphal or yeast fungi.

The phylum Fungi Imperfecti (Deuteromycota) contains fungi that are regularly septate hyphal fungi or yeast fungi which are not known to produce meiospores (no ascospores or basidiospores)

It should be noted that sexual reproduction in fungi involves three phases

plasmogamy – the fusion of protoplasts

karyogamy – the fusion of two nuclei

The subphylum Hemiascomycotina contains Ascomycota that lack ascocarps (nonascococarpic ascomycetes I).

The subphylum Archiascomycetes also contains Ascomycota which lack ascocarps (nonascocarpic ascomycetes II).

The subphylum Euascomycotina contains Ascomycota that have ascocarps (ascocarpic ascomycetes). Within this subphylum, fungi are further classified into four classes according to the type of ascocarp that develops.

Include several clinical entities (known as tineas) which indicate the anatomical site of infection. Tinea is a clinical term, not a taxonomical name. Therefore, a tinea can be caused by different species of fungi.

Have a pathology with is initially eczemaform (itchy) and followed by DTH allergic inflammatory responses. (The DTH response is usually a reaction against metabolites the fungus has secreted.)

They confirmed a fungus causes favus.

They described beard dermatophytosis (caused by a fungus later named M. mentgrophytes by Robin in 1853.)

They described an epidemic of prepubertal scalp ringworm caused by M. audouinii

They recognized that there were three distinct types of scalp ringworm.

They also described the isolation of the favus fungus on potato slices, it culture, and its subsequent ability to cause infection (via self-inoculation).

All sexual strains are heterothallic and dimictic.

Tester strains would have to be maintained.

The most common pathogens of man are , so far, only known as imperfects.

Treatment is usually possible without knowledge of the absolute identity of the species.

Species identity most important for epidemiology-type studies. DNA identities will help.

· Group of soil saprophytes became adapted to keratin utilization (possibly on skin scales or shed animal hair). This may have conveyed an advantage because it provided these fungi with a source of nutrition not widely utilized in nature.

· Some of these fungi became associated more directly with furred animals and gained the ability to form transient infections.

· A subset of these fungi adapted to growth on the keratinized zones of animals and man.

· Some of these fungi equilibrated with the host so that only slight host reactions occurred.

· Of these, a few developed specialized methods of reproduction different that their geophillic cousins which included the formation of specialized types of arthroconidia in hair and possible the loss of frequent sexuality.

· Finally, some of these became associated more or less specifically with certain hosts, including man. This may be due to the utilization of different keratins by different species, segregations of strains and species over time, and/or the loss of a mating type.

These are exothrix invasions of the hair involving small, holoarthric conidia are generally caused by M. audouinii and M. canus.

Black dot. This is an endothrix invasion of the hair involving large holoarthric conidia and is caused by Trichophyton species.

Favus. This does not involve conidiation of hair and is caused by T. scholenleinii.

Nondescript. This is a rare type of tinea capitis caused by Trichophyton infections and is generally an ectothrix type of invasion.

Lesions can be either scaling or pussy, though they are generally not terribly itchy. Deep granulomas are very rare. Very high inflammatory response may produce vesicular lesions which sometimes (rarely) yield a spontaneous cure.

Aspergillosis is an opportunistic disease involving a member of the form-genus Aspergillosis. Aspergillosis is generally initiated when conidia are inhaled and germinate into hyphae, which invade lung & systemic vessels. If host defenses fail, hyphae break off & disseminate to other organs. The main predisposing factor of Aspergillosis is neutropenia, a reduction in the number of PMNs

Aspergillus is a large form-genus with phialidic anamorphs (conidia produced by enteroblastic phialides). Teleomorphs are known as (psuedoparenchymatous) Plectomycetes, Eurotiales, and Eurotiaceae.

Main agents of Aspergillosis are:

1) Aspergillus funigatus (which is responsible for 80% of cases. The fungus is uniserate and its thermophilic qualities may be considered virulence factors.)

2) A. flavus(biserate)

3) A. niger (biserate)

4) A. terreus (biserate)

5) A. ochraceus

6) A. niulans (This is a homothallic plectomycete of the Urotiales order)

7) A. clavatus

Toxicity due to ingestion of moldy food

Allergy and sequelae to conidia or transient hyphal growth in body orifices

Colonization without invasion into preformed cavities or debilitated tissue

Disease of lungs and other tissue

Systemic and fatal dissemination disease

colony morphology / color

conidiophore & phialide morphology (whether the fungus is uniserte or biserate)

conidium morphology (A. fumigatus is thermotolerant up to 45*, while other speciescan wthsatand temperatures only within the 37-40* range.)

Allergic. This is usually a response to conidia which are controlled by macrophages and don’t germinate The response is IgE-mediated and treatment usually revolves around anti-allergy treatments.

Colonizing (Aspegilloma). This form is usually found in individuals with repeated exposure to the fungus. (i.e. Farmer’s Lung) Treatment usually involves intensive anti-fungal therapy

Invasive. This form is usually due to lowered resistance of the host caused by disease or drugs. Amphotericin B is generally used.

These fungi generally do not elicit a host cellular response in normal hosts, but may do so in compromised patients.

Their infections do not exhibit a pathology (no granulomatous cysts or other lesions)

The patient usually only becomes concerned for cosmetic reasons, not due to any discomfort.

They generally affect the stratum corneum layer of the skin and/or the hair

Taxonomy: Malassezia furfur is classified under the nonphlogenetic taxon Fungi Imperfecti and is of the form-species blastomycetes with suspected (hetero)basidiomycota affinity based on rDNA analysis. The most common synonym is Pitryospornum obiculare. It may represent up to 6 lip-dependent species in 4 sirovors. M. pachydermatitis is a non-lipodependent species. Within the host it can be found as enteroblastic budding yeast and as hyphae.

Pathology: Malassezia furfur is the causative agent of the skin condition pityriasis versicolor (Pityriasis is commonly, erroneously called tinea versicolor. This is improper because "tinea" is used to refer to dermatophytoses.) It may also cause seborrheic dermatitis, a disease of the skin and scalp due to entrance of the fungus into the sebacaus glands. In AIDS and other compromised patients, this may be difficult to cure.

History: in 1846, Eicksteadt described the disease and in 1847 Sluyter named the disease pityriasis versicolor. Neither of the two scientists tried to isolate the disease. In 1853, Robin renamed the disease tinea versicolor, believing it to have been caused by the fungus Microsporum furfur. In 1889, Bailon renamed the fungus Malassezia furfur since it could be proven that Microsporum was not the correct genus.

Diagnosis of Pityriasis versicolor:

Treatment: Generally Nizerol cream or Nizoral pills (both of which contain ketoconazole) are used in addition to other azoles.

Taxonomy: This is a member of the Fungi Imperfecti of the form-class hyphomycetes with suspected Ascomycota (specifically Euascomycotina) affinity based on studies of septal structure. It is a melanized (meaning melanin can be found in its cell wall), which may contribute to pathology as a virulence factor. Within the host, it is commonly found as enteroblastic annellate yeast and hypha on the stratum corneum.

Pathology: Exophala werneckii is the causative agent of Tinea nigra (a.k.a. Tinea nigra palmaris, since it is commonly found on the palms of the hands). Disease is characterized by black to brown nonscaly lesions.

Diagnosis of Tinea nigra:

 Treatment: Miconazole or ketoconazole cream.

Taxonomy: The teleomorph of this species is Piedraia hortae, the anamorph is Trichosporon hortae. (The teleomorph was the first phase observed.) This fungus has a melanized cell wall. It is classified as a loculoascomycete of the Ascomycota.

Pathology: When it causes infection, Piedraia hortae forms hard, black nodules (which are actually loculoascostroma containing asci) on scalp hair.

Treatment: oral and topical azoles and cutting of hair.

Taxonomy: Trichsporon beigelii is classified under Fungi Imperfecti, so Trichsporon beigelii is its anamorphic name. It is included in the blastomycete form-class, though (based on studies of septal structure and rDNA) it has suspected Basidiomycota affinity. Like Cryptococcus, it has a capsule.

Pathology: When it causes infection, Trichsporon beigelii form soft, white nodules (which are arthroconidiogenous) on the beard, axilla, or pubic hair. Hypha break holoarthric thalloconidia to disseminate. Recently, Trichsporonosis has been noted as an emerging disease of compromised hosts and can be manifested as systemic trichsporonosis and genital white piedra. One strain notable for developing resistance is Trichosporon asahii.

Treatment: oral and topical azoles and cutting of hair.

Polyene macrolide antibiotics

Ergosterol Biosynthesis-Inhibiting Antifungals

Ketoconazole, Fluconazole, & Itraconazole are oral drugs which are replacing Ampho B therapy in some cases.

Griseofulvin – used in human and veterinary medicine

5-Fluorocytosine – used often in combination with other antifungal drugs, especially Amphotericin B

KI – used for sporotrichosis

Glucan Sythase Inhibitors