Definition
Fungi share certain characteristics: eukaryotic cells with membrane-bound nuclei and cellular
organelles; a filamentous growth form (unicellular in some species) with limited
vegetative differentiation; a protoplast surrounded by a rigid cell wall;
characteristic storage products including trehalose, glycogen, sugar alcohols, and
lipids; sexual and asexual reproduction by means of microscopic spores; and lack
of chlorophyll. All are chemoheterotrophic, using preexisting sources of organic
carbon and the energy from chemical reactions for growth and energy. Most are
haploid in the vegetative state.
General Characteristics
Fungi organisms belong to two distinct evolutionary lines, the Kingdom Straminopiles, which includes water molds of the phylum Oomycota, and the Eumycota, including most terrestrial fungi. This discussion pertains principally to those Eumycota that lack flagellated zoospores—the Mucormycota or Zygomycetes, Ascomycota, and Basidiomycota. With the exception of a few rare opportunistic infections, this encompasses all medically important fungi.
Structure: Cellular Ultrastructure
Fungal cells are eukaryotic, with one or more membrane-bound nuclei containing chromosomes. Instead of centrioles, the cells possess a simpler structure, the spindle pole body, which serves to divide replicated chromosomes during cell division. The nuclear envelope remains intact during mitosis and meiosis. Fungal chromosomes are small and few. The small genome and predominantly haploid life cycle are correlated with the absence of centrioles; Oomycota and Chytridiomycota, which possess them, have diploid vegetative states and genomes comparable in size to eukaryotic algae.
Fungal mitochondria are typically elongate and have distinctive flattened cristae. Other cellular components include endoplasmic reticulum, ribosomes, Golgi bodies, and vacuoles that serve as storage area for cellular byproducts. The cell is bound by a proteinaceous plasma membrane, outside of which is a rigid cell wall. The cell wall itself consists of a network of fibrils composed of chitin, an insoluble nitrogen-containing polysaccharide, within a matrix of soluble polysaccharides.
Structure: Hyphae and Vegetative Structures
The basic building block of a fungus is the hypha, a slender tube divided by septa. In aggregate, a mass of hyphae is called a mycelium. In Zygomycota, septa are infrequent except in fruiting structures; the mycelium is coenocytic and cells have numerous nuclei. In Ascomycota and Basidiomycota, septa occur at regular intervals. Ascomycete septa have simple pores large enough for nuclei and other organelles to pass through, allowing for limited internal transport within a thallus. Many Basidiomycetes have a specialized dolipore septum surrounded by parenthosomes(membranous caps). During cell division in the dikaryophase, Basidiomycetes produce a septal structure called a clamp connection that allows the two parent nuclei to divide in tandem. Clamp connections and dolipore septa are evident even in fragmentary material and can be useful in clinical diagnosis or evaluation of microfossils.
Hyphal branching is usually sympodial, initiated at some distance behind the growing tip. The assimilative phase of a fungus consists of undifferentiated branched hyphae growing in a loose network on or within the substrate.
Some fungi, including many human pathogens, have a yeast growth form,
with isolated single cells that reproduce by budding. The mechanisms for bud
formation mirror those for formation of asexual conidia in filamentous forms. They
vary among yeasts, reflecting their diverse taxonomic affiliations. A number of
human pathogens are thermally dimorphic, producing true hyphae at lower
temperatures and yeast cells at body temperature.
Vegetative structures exhibiting cellular differentiation include rhizomorphs, stromata, and sclerotia. Rhizomorphs, produced by wood-decaying Basidiomycetes, are long bundles of hyphae with an outer cortex of thick-walled, melanized cells. Stromata are cushionlike plates of solid mycelium. Sclerotia are multicellular resting bodies, also with a rind of thick-walled cells. The tissue, in common with sterile portions of many fruit bodies, may be composed of pseudoparenchyma (of tightly packed isodiametric cells). Ontogenetically, fungal pseudoparenchyma originates from closely septate tubular hyphae rather than from a meristematic cell that divides in three planes.
Many biotrophic plant parasites produce specialized appresoria for attaching to plant surfaces and penetrating host cuticle. Among the Ascomycota, two exceptions to the general rule of undifferentiated vegetative structures may be noted. The thalli of lichens, whose form is determined by the mycobiont, are often quite complex, and hyphal types and specialized structures among tropical leaf-inhabiting Loculoascomycetes are very diverse.
Cellular differentiation in fungi is generally reversible, with any viable cell being capable, given the right growing conditions, of reconstituting the entire organism.
Structure: Sporocarps and Spores
Most diversity in fungal morphology is associated with the production of spores, both sexual and asexual. Asexual spores, the product of mitotic division of haploid nuclei, may be produced by internal cleavage within a sporangium (sporangiospores, characteristic of Zygomycota, and zoospores, characteristic of Chytridiomycota and Oomycota) or by extrusion from a more or less modified hyphal cell (conidia, characteristic of Ascomycota, and uredospores and teliospores in the Basidiomycota). Sexual spores are the immediate product of either fusion of nuclei called karyogamy (Oomycota, Zygomycota) or karyogamy followed by meiosis (Asomycota, Basidiomycota). In the latter two, sometimes grouped in the Subkingdom Dikarya, they are often produced on highly differentiated sporocarps, of which mushrooms are a conspicuous example.
Among the Zygomycetes, human pathogens are found in the Mucorales and Entomophthorales. Both groups have isolated zygospores, often thick-walled and ornamented. Meiosis occurs upon zygospore germination, and the immediate product is either a germ sporangium or haploid mycelium. Typical Mucorales produce stalked sporangia containing numerous unicellular asexual spores. In the Entomophthorales, spores are solitary and are actively discharged. The Glomales, mycorrizal zygospore-forming fungi whose evolutionary affinities may be closer to the Dikarya, produce zygospores in hypogeous gastroid sporocarps.
The asexual stages of Ascomycota are classified according to means of spore production, type of sporocarp (if any), and morphology of the spores themselves. Spore production may be through hyphal fragmentation at the septa or, more commonly, through extrusion from specialized conidiogenous cells borne on conidiophores. A common type of conidiogenesis, found in Aspergillus and Penicillium, involves flask-shaped cells called phialides that produce long chains of spores. In Aspergillus, the phialidesare clustered on a swollen cell at the apex of a long multicellular conidiophore.
In addition to condiophores on undifferentiated mycelium, asexual sporulation may also involve fruit bodies consisting of hyphae aggregated to form a stalk with a spore-bearing head (synnemata), flattened structures with an exposed sporulating surface (sporodochia), and flask-shaped structures with pores (pycnidia). Pycnidia may bear appendages or be embedded in stromatic tissue.
Conidia may be unicellular or multicellular, smooth or ornamented, and
pigmented or unpigmented. Aquatic freshwater forms are often branched or coiled to
aid flotation.
The diagnostic feature of an Ascomycete is the ascus, a saclike structure in which karyogamy and meiosis take place. Following meiosis, and usually one or more mitotic divisions, membranes delimit ascospores. When fully mature, turgor pressure builds up and ascospores are actively discharged through an apical pore. Some groups have rings or other structures associated with the pore, and one large class, the Loculoascomycetes, has bitunicate asci with an inner separable wall that extrudes during discharge.
The Saccharomycetales (yeasts) and Taphrinales lack fruit
bodies. Remaining orders of Ascomycota may have cleistothecia (enclosed bodies
with no defined opening), apothecia (cup-shaped structures with an exposed
hymenium), or perithecia (flask-shaped bodies with a preformed pore). Perithecia
may be imbedded in a stroma. The majority of true human pathogens belong to the
cleistothecial orders Eurotiales and Onygenales. Sexual states of these species,
if known, are only produced in culture. In contrast, plant-pathogenic species
often fruit abundantly on the host. One apothecial group, the Pezizales, has given
rise through increasing convolutions of the hymenium to both the morels and to
true truffles, in which the hymenium is entirely enclosed and spores are passively
dispersed by animals. The human pathogens Sporothrix and
Fusarium are asexual states of perithecial fungi.
Ascospores may be unicellular or septate, hyaline or pigmented, with ornaments, mucilaginous sheaths, and appendages. The diagnostic feature of a Basidiomycete is a basidium, a club-shaped or filamentous structure within which karyogamy and meiosis take place. Basidiospores are produced externally and are actively discharged. The Agaricomycotina, the largest subphylum, have club-shaped basidia bearing basidiospores, usually four, on peglike sterigmata. A tremendous variety or sporocarps are produced, with a common design feature of presenting the largest possible surface area of hymenium to the air while protecting it from the elements. In gill fungi (Agaricales) and pore fungi (Polyporales), the basidia are arranged on the surface of closely packed cavities spaced so that the actively discharged basidiospore just clears the hymenium and falls vertically to the air space below the stalked or laterally attached fruit body. In gastroid forms, the hymenium is permanently enclosed. Sporocarps in some species may weigh several kilograms and produce millions of spores. Some soil-inhabiting and root-parasitic agarics form so-called fairy rings—the visible manifestation, in fruiting season, of an underground mycelium that can extend for hundreds of feet.
The core of the subphylum Pucciniomycotina consists of plant rusts, specialized
parasites of higher plants that alternate between hosts, producing different spore
types on each. Of more interest to medicine are the Sporidiobolales, the
Basidiomycetous yeasts, whose deoxyribonucleic acid (DNA) places them close to
Puccinia and other plant rusts. The one important human pathogen,
Cryptococcus (Filobasidiella) neoformans, produces unique
basidia within which multiple mitotic divisions following meiosis support
production of chains of basidiospores on the sterigmata.
Growth: Hyphal Elongation and Differentiation
Fungal hyphal growth takes place at the apex, with little or no elongation as a result of the addition of wall material to older cells and no secondary thickening as a result of lateral division. When fungal structures expand from the addition of tissue, this expansion comes from the initiation of lateral branches along existing hyphae.
Close to the tip of a growing hypha is a region of dense vesicles containing the precursors for cell wall formation, synthase enzymes to catalyze polymerization, and lytic enzymes to break down existing cell wall to allow for insertion of additional material. The apex of a hypha is in a state of dynamic equilibrium that maintains rigidity and structural integrity while allowing for expansion.
Nutrient depletion and release of inhibitory compounds suppress branching, controlling the density of vegetative mycelium. Hyphal tips may be geotropic, chemotropic, or, rarely, phototropic. Germination and growth of parasitic species may be stimulated by specific compounds produced by the host. Hyphae will grow along a nutrient gradient and also toward mycelia of a compatible mating type.
Growth rates vary widely. Under optimal conditions in the laboratory, Neurospora crassa and a few saprophytic Mucorales can increase biomass by 60 percent in an hour. In nature, such species rapidly deplete substrates of nutrients and survive by producing durable resting stages. At the other extreme, some lichenized fungi in harsh environments grow less than a millimeter a year.
Dikaryotic mycelia of Agaricales, apparently originating from a single hyphal fusion, can be impressively large and long-lived. The current record appears to be an individual colony of Armillaria ostryae, a wood-destroying mushroom, in Malheur County, Oregon. The colony is 3.5 miles in diameter, at least 2,400 years old, and genetically uniform.
Growth: Assimilation and Nutrition
Fungi obtain nutrients by secreting enzymes that break down complex organic molecules into simple soluble fragments that are absorbed through the cell wall. Parasitic forms may also excrete compounds that alter host metabolism to produce simpler compounds. Eumycota are among the few eukaryotes that can degrade cellulose. The ability to degrade lignin, the main structural component of woody plants, is restricted to Basidiomycota.
Most fungi are aerobic. A few, including the familiar brewer’s yeast, are facultative anaerobes. The facultative anaerobes are most likely to be implicated in life-threatening human infections, because in all of these the fungus invades only dead tissue, which is no longer oxygenated. Most fungi require a moist environment for active growth, but many can persist for long periods under very dry conditions. Some are resistant to high osmotic tension and can live in saline environments.
As a group, fungi have enormous biosynthetic capabilities that are extensively exploited for industrial purposes. Some can synthesize the complete range of essential amino acids from inorganic sources of nitrogen, sulfur, and phosphorus. Fungal protein is better balanced for human nutrition than is protein from green plants, one of the reasons that fermentation of grain for human consumption has been a human practice since the Stone Age.
There is an extensive literature on the specific nutrient requirements of fungal species of interest to humans. In general, obligate parasites, whether of humans or of their crop plants, have very specific requirements, while opportunistic invaders do not.
Impact
Probably the greatest impact that fungi have on human infectious diseases is
not in their role as agents of mycoses but as allies is the fight against infections caused by other organisms.
Since the discovery, in 1928, of the first form of penicillin, a
secondary metabolite of Penicillium notatum (now called
P. chrysogenum) and other species, scientists have identified
a host of clinically useful antimicrobial compounds produced by fungi in nature,
as well as enzymes, vitamins, and other organic compounds useful in therapy. With
the advent of genetic engineering, it has become possible to insert genes
from diverse parts of the plant and animal world into a fungal genome, using the genetically engineered fungus as a factory to manufacture complex
biologically active compounds. Fungi are ideal for this purpose because the
technology for growing them in bioreactors on an industrial scale is well
established.
As laboratory organisms, fungi have contributed a great deal to the basic understanding of eukaryotic biochemistry and genetics. The simplicity, short generation time, and ease of manipulation of fungi make them ideal subjects for basic research. Such research rarely translates directly into clinical practice but is vital to the development of modern highly targeted disease therapies that depend on understanding host-parasite interactions at the molecular level.
Human pathogenic fungi have always presented a challenge to medicine, because
fungi are more closely related to humans than are bacteria and most protozoa.
Until recently, however, most common fungal infections seen in clinical
practice in the developed world were superficial or localized and thus could be
treated topically. However, growing populations of immunocompromised persons,
including those infected with the human immunodeficiency virus (HIV), transplant
patients, and persons undergoing chemotherapy, have led to the emergence of a
number of systemic, life-threatening mycoses as growing threats to human health.
Responding to this challenge will require understanding fungal growth and
metabolism at the molecular level.
Bibliography
Alexopoulos, Constantine J., C. W. Mims, and M. Blackwell. Introductory Mycology. New York: John Wiley & Sons, 1996. A standard textbook for college biology majors, covering general ultrastructure and metabolism and the morphology of various taxa.
Kendrick, Bryce. The Fifth Kingdom. 3d ed. Newburyport, Mass.: Focus, 2000. A strength of this book on fungi are the numerous line drawings illustrating the structure and development of all major fungal groups.
Larone, Davise H. Medically Important Fungi: A Guide to Identification. 4th ed. Washington, D.C.: ASM Press, 2003. Includes an outline classification, descriptions and illustrations of human pathogenic species in tissue samples and culture, and a guide to common cultural contaminants.
Webster, John, and Roland Weber. Introduction to Fungi. New York: Cambridge University Press, 2007. A textbook for college biology majors that clearly classifies and illustrates fungi. Also incorporates gene sequencing and cladistics.
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