MYCOLOGY
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Yeasts and Molds
These fungi grow as saprophytes, parasites, or both by using specific proteolytic, glycolytic, or lipolytic enzymes to extracellularly break down substrates and to absorb the products of digestion through the fungal cell envelope.
Cell Wall
The fungal cell wall gives shape and form, protects against mechanical injury, prevents osmotic lysis, and provides passive protection against the ingress of potentially harmful macromolecules.
Filamentous Fungi and Filamentous Bacteria
Fungi are different from the Actinomycetes, a group of prokaryotic filamentous bacteria having peptidoglycans in their cell walls and an absence of nuclear membranes and organelles, but the two groups of microorganisms are usually considered together in texts.
Hyphal and Yeast Morphogenesis
Hyphal extension growth occurs apically by a sophisticated organization of tip-growth-related organelles and cytoskeletal elements. Hyphal wall and yeast cell wall polysaccharide synthetases are active at sites where growth is occurring and inactive when no growth is occurring. Morphogenesis is a balance between wall synthesis and wall lysis.
Sexual Reproduction
Sexual reproduction occurs by the fusion of two haploid nuclei (karyogamy), followed by meiotic division of the diploid nucleus. The union of two hyphal protoplasts (plasmogamy) may be followed immediately by karyogamy, or it may be separated in time.
Asexual Reproduction
Asexual reproduction occurs via division of nuclei by mitosis. With the absence of meiosis, other mechanisms associated with the nuclear cycle result in recombination of hereditary properties and genetic variation.
Introduction
Macroscopic fungi such as morels, mushrooms, puffballs, and the cultivated agarics available in grocery stores represent only a small fraction of the diversity in the kingdom Fungi. The molds, for example, are a large group of microscopic fungi that include many of the economically important plant parasites, allergenic species, and opportunistic pathogens of humans and other animals. They are characterized by filamentous, vegetative cells called hyphae. A mass of hyphae forms the thallus (vegetative body) of the fungus, composed of mycelium. The more phylogenetically primitive molds (e.g., water molds, bread molds, and other sporangial—saclike—forms) produce cenocytic filaments (multinucleate cells without cross-walls), while the more advanced forms produce hyphae with cross-walls (septa) that subdivide the filament into uninucleate and multinucleate compartments. The septum, however, still provides for cytoplasmic communication, including intercellular migration of nuclei. Many fungi occur not as hyphae but as unicellular forms called yeasts, which reproduce vegetatively by budding. Some of the opportunistic fungal pathogens of humans are dimorphic, growing as a mycelium in nature and as a vegetatively reproducing yeast in the body. Candida is an example of such a dimorphic fungus (Fig. 73-1). It can undergo rapid transformation from the yeast to the hyphal phase in vivo, which partly contributes to its success in invading host tissue.
Dimorphism in C albicans. DYC, Daughter yeast cell; GT, germ tube; H, hypha; Ph, pseudohypha; YMC, yeast mother cell. (X8,980) (From Cole, GT, Kendrick B: Biology of Conidial Fungi. Vol. 1. Academic Press, San Diego, 1981, with permission.)
The true fungi obtain their carbon compounds from nonliving organic substrates (saprophytes) or living organic material (parasites) by absorption of nutrients through their cell wall. Small molecules (e.g., simple sugars and amino acids) accumulate in a watery film surrounding the hyphae or yeast and simply diffuse through the cell wall. Macromolecules and insoluble polymers (e.g., proteins, glycogen, starch, and cellulose), on the other hand, must undergo preliminary digestion before they can be absorbed by the fungal cell. This process involves release of specific proteolytic, glycolytic, or lipolytic enzymes from the hypha or yeast, extracellular breakdown of the substrate(s), and diffusion of the products of digestion through the fungal cell envelope (Fig. 73-2). Fungal pathogens rely on these digestive enzymes to penetrate natural host barriers.
(A) Extracellular digestion and absorptive nutrition in fungi. (B) Invasive hyphae of C albicans in stratified epithelial tissue of mouse stomach. (X4,250).
Cell Walls
Not all species of fungi have cell walls, but in those that do, cell wall synthesis is an important factor in determining the final morphology of fungal elements. Thus, our knowledge of fungal morphogenesis has evolved in parallel with our understanding of fungal cell wall biosynthesis. The fungal wall also protects cells against mechanical injury and blocks the ingress of toxic macromolecules. This filtering effect may be especially important in protecting fungal pathogens against certain fungicidal products of the host. The fungal cell wall is also essential to prevent osmotic lysis. Even a small lesion in the cell wall can result in extrusion of cytoplasm as a result of the internal (turgor) pressure of the protoplast. The composition of fungal cell walls is relatively simple and includes substances not typically found in animal and plant hosts (e.g., chitin). On this basis, it may be possible to identify pathogen-specific molecular targets from investigations of the biosynthesis of fungal wall components. Such targets may prove pivotal for the successful development of antifungal drugs that are not toxic to mammalian cells. :
Filamentous Fungi and Filamentous Bacteria
Fungi, like bacteria, are ecologically important as decomposers as well as parasites of plants and animals. Both groups of microbes often inhabit the same ecosystem and thus compete for the same food supply. Associated with this competition is the production by both the fungi and bacteria of secondary products that function as microbial growth inhibitors or toxins. These compounds constitute a rich library of antimicrobial agents, many of which have been developed as pharmacologic antibiotics (e.g., penicillin from Penicillium chrysogenum, nystatin from Streptomyces noursei, amphotericin B from S niveus).
The superficial morphologic similarities between actinomycetes (filamentous bacteria) and molds suggest that the two groups have undergone parallel evolution. Despite the production of branching filaments and mold-like spores, the actinomycetes are clearly prokaryotes, whereas fungi are eukaryotes. Moreover, the sexual reproduction of bacteria, which typically occurs by transverse binary fission, should not be confused with asexual processes of budding and fragmentation associated with mitotic nuclear division in fungi. Most of the molds that produce septate vegetative hyphae reproduce exclusively by asexual means, giving rise to airborne propagules called conidia. On the other hand, elaborate mechanisms of sexual reproduction are also demonstrated by members of the Eumycota. Four distinct kinds of meiospores (products of karyogamy-meiosis-cytokinesis) are recognized: oospores (Oomycetes), zygospores (Zygomycetes), ascospores (Ascomycetes), and basidiospores (Basidiomycetes).
A summary of these and other diagnostic features of the fungi is presented in
TABLE 73-1:SUMMARY OF DIAGNOSTIC FEASTURES OF FUNGI |
1 | Heterotrophic(no photosynthetic nutrition) |
2 | Thallus(vegetative body of fungus) on or in the substratum: may be plasmodial, ameboid, pseudoplasmodial, unicellular (yeast), or filamentous (myecelial) |
3 | Absorptive nutrition , typically by extracellular, enzymatic digestion (ingestion rare) |
4 | Occurrence ubiquitous as saprobes, parasites, symbionts, or hyperparasites(fungi parasitic on another fungi) |
5 | Cell wall present in non-plasmodial forms; well defined and typically contains chitin β-13 and β-16-glucans: cellulose and β-14 glucans present in Oomycetes (water molds) |
6 | Eukaryotic; uninucleate or multinucleate, haploid or diploid; myecelium may be homokaryotic (all nuclei are genetically alike) heterokaryotic (genetically different nuclei in the same myecelium), dikaryotic (pair of closely associated nuclei usually derived from different parent cells). |
7 | Asexual or sexual reproduction; spore producing bodies (sporocarps) microscopic or macroscopic, showing limited tissue differentiation. |
Hyphal and Yeast Morphogenesis
Hyphal growth occurs by extension at the tips. This polarization is at least partially determined by directional movement and accumulation of vesicles that carry wall precursors and wall synthetases to the site of exocytosis at the apical dome of the hypha (Fig. 73-3). Despite the apparent simplicity of hyphal morphogenesis, ultrastructural investigations have shown a sophisticated organization of tip-growth-related organelles and cytoskeletal elements. There is evidence that intussusception and polymerization of chitin microfibrils occur at the apical dome of the hypha and that the biosynthesis of this major cell wall product is controlled by the activity of membrane-bound chitin synthetase. The zymogen form of chitin synthetase has been detected in microvesicles called chitosomes, which appear to transport this enzyme to the hyphal tip. The chitosomes may arise from Golgi-like bodies or by a process of self-assembly of subunits freely within the cytoplasm or within larger vesicular bodies. Activation of chitin synthetase occurs upon fusion of the chitosome with the plasmalemma and may be due to the interaction of a membrane-bound protease and the zymogen. Chitin microfibrillogenesis is initiated at these sites of fusion.
Polarized growth of hypha.
Evidence has also been presented, primarily from studies of the yeast Saccharomyces cerevisiae, that biosynthesis of skeletal polysaccharides is catalyzed by polysaccharide synthetases (e.g., chitin synthetase and β1-3-glucan synthetase), which are uniformly distributed within the plasmalemma. These wall-synthesizing, cell - membrane-bound enzymes occur in either zymogen or active forms. The model of yeast morphogenesis (Fig. 73-4) suggests that the synthetase is active at sites where the wall is growing and inactive where it is quiescent. One possibility is that microvesicles transport activating factors (e.g., proteases, ATP, and GTP) to the plasmalemma at specific sites of wall biosynthesis (zones of bud emergence and of septal formation). These two concepts of regulation of wall biosynthesis in fungal hyphae and yeasts have been supported by considerable bodies of evidence, and it is likely that both are correct.
Stages (A to F) of bud emergence and yeast cell cycle.
Extension growth of hyphal tips and yeast buds logically requires a balance between processes of insertion of newly synthesized polymeric material and modification of the existing microfibrillar matrix to accommodate expansion and further intussusception of wall polymers. In other words, a balance between wall synthesis and wall lysis, or plasticization, is essential for maintaining the orderly processes of hyphal tip elongation and bud emergence. The presence of lytic enzymes in the fungal wall has been reported, including, β1-3-glucanase, N-acetyl-β-D-glucosaminadase, and chitinase. Localization of such activity may be mediated by macrovesicles. These organelles, like microvesicles, are probably derived from Golg-like bodies and are directed to the hyphal tip or yeast bud and fuse with the plasmalemma, thereby delivering their contents to the site of wall synthesis.
Reproduction
Sexual reproduction in the fungi typically involves fusion of two haploid nuclei (karyogamy), followed by meiotic division of the resulting diploid nucleus (Fig. 73-5A). In some cases, sexual spores are produced only by fusion of two nuclei of different mating types, which necessitates prior conjugation of different thalli. This condition of sexual reproduction is known as heterothallism, and the nuclear fusion is referred to as heterokaryosis. Normally plasmogamy (union of two hyphal protoplasts which brings the nuclei close together in the same cell) is followed almost immediately by karyogamy. In certain members of the Basidiomycotina, however, these two processes are separated in time and space, with plasmogamy resulting in a pair of nuclei (dikaryon) contained within a single cell. Karyogamy may be delayed until considerably later in the life history of the fungus. Meanwhile, growth and cell division of the binucleate cell occur. The development of a dikaryotic mycelium results from simultaneous division of the two closely associated nuclei and separation of the sister nuclei into two daughter cells (Fig. 73-5B). An alternative mechanism of sexual reproduction in the fungi is homothallism, in which a nucleus within the same thallus can fuse with another nucleus of that thallus (i.e., homokaryosis). An understanding of these nuclear cycles is fundamental to investigations of fungal genetics.
(A) Life cycle of S cerevisiae. (B) Basidiospore formation by Filobasidiella neoformans, sexual state of Cryptococcus neoformans. (1 and 2) Dikaryon formation. (3) Nuclear fusion (Karyogamy). (4 and 5) Meiosis. (6) Basidiospore formation. (7) Mitosis (more...)
As mentioned above some fungi are classified as strictly asexually reproducing forms. These include the large group of asexual (imperfect) yeasts (e.g., Candida species) and conidial fungi (e.g., Coccidioides immitis). Most members of this group have permanently lost their ability to produce meiospores. A few undergo rare sexual reproduction, and perhaps for some species we have yet to discover their sexual (perfect) stage. The most common methods of asexual reproduction, in addition to simple budding in yeasts, are blastic development of conidia from specialized hyphae (conidiogenous cells), fragmentation of hyphae into conidia, and conversion of hyphal elements into conidia or chlamydospores (thick-walled resting spores) (Fig. 73-6).
Methods of asexual reproduction in the conidial fungi. (A) Terminal blastic conidium. (B) Repetitive blastic conidium formation from specialized conidiogenous cell (phialide). (C) Conidium formation by hyphal fragmentation. (D) Conidium formation by conversion (more...)
Despite the absence of meiosis during the life cycle of these imperfect fungi, recombination of hereditary properties and genetic variation still occur by a mechanism called parasexuality. The major events of this process (Fig. 73-7) include the production of diploid nuclei in a heterokaryotic, haploid mycelium that results from plasmogamy and karyogamy; multiplication of the diploid along with haploid nuclei in the heterokaryotic mycelium; sorting out of a diploid homokaryon; segregation and recombination by crossing over at mitosis; and haploidization of the diploid nuclei. Sexual and parasexual cycles are not mutually exclusive. Some fungi that reproduce sexually also exhibit parasexuality.
The parasexual cycle (genetic recombination without meiosis). Stages of the parasexual cycle are numbered as follows (1) Hyphal conjugation (plasmogamy). (2) Heterokaryosis. (3) Nuclear fusion (karyogamy). (4) Mitotic recombination and nondisjunction. (more...)
An extensive foundation of knowledge on the basic biology of fungi is at hand, including fungi that cause superficial, deep-seated, and systemic infections of humans and other animals. Much less is known, however, of the intricacies of interactions between these largely opportunistic pathogens and their hosts. Many areas of research in medical mycology are still in their infancy and offer formidable challenges and potential rewards. The current application of methods of recombinant DNA technology to problems of fungus-host interactions, especially the identification of pathogenicity genes, holds promise for significant contributions to our knowledge of medically important fungi.
Chapter 74Disease of Mechanisms of Fungi
George S. Kobayashi.
General Concepts
Entry
Fungi rarely cause disease in healthy immunocompetent hosts. Disease results when fungi accidentally penetrate host barriers or when immunologic defects or other debilitating conditions exist that favor fungal entry and growth.
Adaptation and Propagation
Fungi often develop both virulence mechanisms (e.g., capsule and ability to grow at 37oC) and morphologic forms (e.g., yeasts, hyphae, spherules, and sclerotic bodies) that facilitate their multiplication within the host.
Dissemination
Dissemination of fungi in the body indicates a breach or deficiency of host defenses (e.g., endocrinopathies and immune disorders).
Host Factors
Healthy, immunologically-competent individuals have a high degree of innate resistance to fungi. Resistance to fungi is based primarily upon cutaneous and mucosal physical barriers. Severity of disease depends on factors such as inoculum, magnitude of tissue destruction, ability of fungus to multiply in the tissue, and the immune status of the host.
Fungal Factors
Enzymes such as keratinase, the presence of capsule in Cryptococcus neoformans, the ability to grow at 37°C, dimorphism, and other as yet undefined factors contribute to fungal pathogenesis which involves a complex interplay of many fungal and host factors.
Introduction
Fungi are ubiquitous in nature and exist as free-living saprobes that derive no obvious benefits from parasitizing humans or animals. Since they are widespread in nature and are often cultured from diseased body surfaces, it may be difficult to assess whether a fungus found during disease is a pathogen or a transient environmental contaminant. Before a specific fungus can be confirmed as the cause of a disease, the same fungus must be isolated from serial specimens and fungal elements morphologically consistent with the isolate must be observed in tissues taken from the lesion. In general, fungal infections and the diseases they cause are accidental. A few fungi have developed a commensal relationship with humans and are part of the indigenous microbial flora (e.g., various species of Candida, especially Candida albicans, and Malassezia furfur). Although a great deal of information is available concerning the molecular basis of bacterial pathogenesis, little is known about mechanisms of fungal pathogenesis. Infection is defined as entry into body tissues followed by multiplication of the organism. The infection may be clinically inapparent or may result in disease due to a cellular injury from competitive metabolism, elaboration of toxic metabolites, replication of the fungus, or an immune response. Immune responses may be transient or prolonged and may be cell-mediated, humoral (with production of specific antibody to components of the infecting organism), or both. Successful infection may result in disease, defined as a deviation from or interruption of the normal structure or function of body parts, organs, or systems (or combinations thereof) that is marked by a characteristic set of symptoms and signs and whose etiology, pathology, and prognosis are known or unknown.
Entry
Fungi infect the body through several portals of entry (Table 74-1). The first exposure to fungi that most humans experience occurs during birth, when they encounter the yeast C. albicans while passing through the vaginal canal. During this process the fungus colonizes the buccal cavity and portions of the upper and lower gastrointestinal tract of the newborn, where it maintains a life-long residence as a commensal.
Table 74-1
Summary of Disease Mechanisms of Fungi.
Source of Fungus | Clinical classification | Mechanism of entry |
Endogenous | Opportunistic | iatrogenic (indwelling lines, catheters,etc.) |
Exogenous | Superficial Cutaneous Subcutaneous Systemic Opportunistic | Trauma (personal hygiene?) Trauma Trauma Inhalation Inhalation (iatrogenic, trauma) |
Another fungus, Malassezia furfur, is common in areas of skin rich in sebaceous glands. How it colonizes the skin is not known, but both M furfur and C albicans are the only fungi that exist as commensals of humans and are considered part of the indigenous flora. Only under certain unusual circumstances have they caused disease. Other fungi that have been implicated in human diseases come from exogenous sources, where they exist as saprobes on decaying vegetation or as plant parasites. Fungi rarely cause disease in healthy, immuno-competent hosts, even though we are constantly exposed to infectious propagules. It is only when fungi accidentally penetrate barriers such as intact skin and mucous membrane linings, or when immunologic defects or other debilitating conditions exist in the host, that conditions favorable for fungal colonization and growth occur. When C albicans, for example, is implicated in disease processes, it may indicate that the patient has a coexisting immune, endocrine, or other debilitating disorder. In most cases, the underlying disorder must be corrected to effectively manage the fungal disease.
Adaptation and Propagation
Although most fungal diseases are the result of accidental encounters with the agent, many fungi have developed mechanisms that facilitate their multiplication within the host. For example, the dermatophytes that colonize skin, hairs, and nails elaborate enzymes that digest keratin. Candida albicans as a commensal organism exists in a unicellular yeastlike morphology, but when it invades tissues it becomes filamentous; conversely, the systemic fungi Histoplasma capsulatum, Blastomyces dermatitidis, and Paracoccidoides brasiliensis exist as molds in nature and change to a unicellular morphology when they cause disease. Other properties, such as capsule production by C neoformans and the adherence properties of Candida species to host tissues, also contribute to their pathogenicity. In general, the fungi that cause systemic disease must be able to grow and multiply at 37°C.
Dissemination
Disseminated fungal diseases usually indicate a breach in host defenses. Such a breach may be caused by endocrinopathies or immune disorders, or it may be induced iatrogenically. Effective management of the fungal infection requires a concerted effort to uncover and correct the underlying defects.
Host Factors
The high degree of innate resistance of humans to fungal invasion is based primarily on the various protective mechanisms that prevent fungi from entering host tissues. Fungal growth is discouraged by the intact skin and factors such as naturally occurring long-chain unsaturated fatty acids, pH competition with the normal bacterial flora, epithelial turnover rate, and the desiccated nature of the stratum corneum. Other body surfaces, such as the respiratory tree, gastrointestinal tract, and vaginal vault, are lined with mucous membranes (epithelium) bathed in fluids that contain antimicrobial substances, and some of these membranes are lined with ciliated cells that actively remove foreign materials. Only when these protective barriers are breached can fungi gain access to, colonize, and multiply in host tissues. Fungi gain access to host tissues by traumatic implantation or inhalation. The severity of disease caused by these organisms depends upon the size of the inoculum, magnitude of tissue destruction, the ability of the fungi to multiply in tissues, and the immunologic status of the host.
Fungal Factors
Most of the fungi that infect humans and cause disease are classified by tissue or organ levels that are primary sites of colonization. These are discussed below.
Superficial Fungal Infections
Superficial fungal infections involve only the outermost layers of the stratum corneum of the skin ( Phaeoannellomyces werneckii [syn. Exophiala werneckii] and M furfur) or the cuticle of the hair shaft (Trichosporon beigelii and Piedraia hortae). These infections usually constitute cosmetic problems and rarely elicit an immune response from the host (except occasionally M furfur infections). Recently T beigelii and M furfur were implicated as opportunistic agents of disease, particularly in immunosuppressed or otherwise debilitated patients. Patients are accidentally infected with these common organisms via indwelling catheters or intravenous lines. Virtually nothing is known concerning the pathogenic mechanisms of these fungi.
Dermatophyte Infections
The dermatophytes are fungi that colonize skin, hair, and nails on the living host. These fungi possess greater invasive properties than those causing superficial infections, but they are limited to the keratinized tissues. They cause a wide spectrum of diseases that range from a mild scaling disorder to one that is generalized and highly inflammatory. Studies have shown that the disease-producing potential of these agents depends on various parasite and host factors, such as the species of organism, immunologic status of the host, type of clothing worn, and type of footwear used. Trauma plays an important role in infection. These organisms gain entry and establish themselves in the cornified layers of traumatized or macerated skin and its integument and multiply by producing keratinase to metabolize the insoluble, tough fibrous protein. The reason why these agents spread no deeper is not known, but it has been speculated that factors such as cell-mediated immunity and the presence of transferrin in serum inhibit fungal propagation to the deeper tissue layers and systemic disease does not occur. Some dermatophytes have evolved a commensal relationship with the host and are isolated from skin in the absence of disease. Little is known about specific pathogenic mechanisms of the dermatophytes, but they do not cause systemic disease.
Subcutaneous Mycoses
The fungi that have been implicated in the subcutaneous mycoses are abundant in the environment and have a low degree of infectivity. These organisms gain access to the subcutaneous tissues through traumatic implantation. Again, little is known about mechanisms of pathogenesis. Histopathologic evidence indicates that these organisms survive in the subcutaneous tissue layers by producing proteolytic enzymes and maintaining a facultative microaerophilic existence because of the lowered redox potential of the damaged tissue. In eumycotic mycetoma there is extensive tissue damage and production of purulent fluid, which exudes through numerous intercommunicating sinus tracts. Microabscesses are common in chromoblastomycosis, but the clinical manifestation of disease indicates a vigorous host response to the organism, as seen by the intense tissue reaction that characterizes the disease (pseudoepitheliomatous hyperplasia).
Although most of the fungi implicated in this category of disease exist in a hyphal morphology, the agents of chromoblastomycosis and sporotrichosis are exceptions. Chromoblastomycosis is caused by a group of fungi that have several features in common. They are all darkly pigmented (dematiaceous) and exhibit a pleomorphism consisting of two distinct morphologies: the organism may exist in a mycelial state or as a thick-walled spherical cell that divides by cleavage. The latter cell morphology, called a muriform cell, sclerotic cell or Medlar body, is the pathologic morphology seen in tissue sections. However, transition to the sclerotic morphology may not be a crucial requirement for pathogenesis. Several dematiaceous fungi cause a disease called phaeohyphomycosis, which clinically consists of a broad group of diseases characterized by the presence of various darkly pigmented yeastlike to hyphal elements, but not sclerotic cells, in pathologic specimens. Alternatively, the immune reaction of the host may dictate the morphology that the organism assumes. Again, there is no information about mechanisms or the role of morphogenesis in the pathogenesis of this group of fungi.
Sporotrichosis is caused by Sporothrix schenckii, which grows as a mold in nature or when cultured at 25°C, but as yeastlike cells when found in tissues. The clinical manifestations of disease caused by S schenckii vary, depending on the immune status of the patient. The classic condition, subcutaneous lymphanigitic sporotrichosis, is characterized by numerous nodules, abscesses, and ulcerative lesions that develop along the lymphatics that drain the primary site of inoculation. The disease does not extend beyond the regional lymph nodes that drain the site of the original infection. Alternatively, infection may result in solitary lesions or pulmonary disease. Clinical manifestations of pulmonary infections vary depending on the immune status of the patient. The immunocompetent individual has a high degree of innate resistance to disease, and when infection occurs the organism is often a secondary colonizer of old infarcted or healed cavities of the lungs. If the patient is immunocompromised, dissemination can occur. There is no information about mechanisms of pathogenesis of this dimorphic fungus.
Systemic Mycoses
Of all the fungi that have been implicated in human disease, only the six agents that cause the systemic mycoses have the innate ability to cause infection and disease in humans and other animals. The primary site of infection is the respiratory tract. Conidia and other infectious particles are inhaled and lodge on the mucous membrane of the respiratory tree or in the alveoli, where they encounter macrophages and are phagocytosed. To successfully colonize the host these organisms must be able to survive at the elevated temperature of the body and either elude phagocytosis, neutralize the hostility they encounter, or adapt in a manner that will allow them to multiply.
Several factors contribute to infection and pathogenesis of these organisms. Of the six systemic agents, five,Histoplasma capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, andPenicillium marneffei are dimorphic, changing from a mycelial to a unicellular morphology when they invade tissues, except C immitis that forms spherules. The change from mycelial to yeast morphology in H. capsulatum appears critical for pathogenicity. Several physiologic changes occur in the fungus during the transition, which is induced by the temperature shift to 37°C. The triggering event is a heat-related insult: the temperature rise causes a partial uncoupling of oxidative phosphorylation and a consequent decline in the cellular ATP level, respiration rate, and concentrations of electron transport components. The cells enter a period of dormancy, during which spontaneous respiration is maintained at a decreased level. Then there is a shift into a recovery phase, during which transformation to yeast morphology is completed. Mycelial cells of H capsulatum that are unable to undergo this morphologic transition are avirulent. Similar observations have been made when mycelia of B dermatitidis and P brasiliensis are shifted from 25°C to 37°C, and it has been implied that transformation to the yeast morphology is critical for infection.
Coccidioides immitis is also dimorphic, but its parasitic phase is a spherule. Little is known about the role of morphologic transformation in infection and disease of this organism. Dimorphism does not appear to play a role in C neoformans pathogenesis since the organism is an encapsulated yeast both at 25°C and in host tissues. The sexual phase of C neoformans, Filobasidiella neoformans, is known, and the organism assumes a filamentous morphology, producing small basidiospores. It has been suggested that these propagules are relevant in infection.
In addition to adjustment to the elevated temperature of the host, the infectious propagules must deal with the hostile cellular environment of the lungs. Studies with mutants of C neoformans have shown that the acidic mucopolysaccharide capsule is important in pathogenesis. Acapsular variants of the yeast are either avirulent or markedly deficient in pathogenicity. Since these mutants were obtained by mutagenesis, it is difficult to rule out the contribution of other genetic defects to their decreased pathogenicity. However, at the cellular level, the capsular polysaccharide inhibits phagocytosis of the yeast. Encapsulated C neoformans cells are highly resistant to phagocytosis by human neutrophils, whereas acapsular variants are effectively phagocytosed. The active component of the capsular polysaccharide has been identified as glucoronoxylomannan. In addition, the capsular polysaccharide is poorly immunogenic in humans and laboratory animals, and the glucoronoxylomannan component persists for extended periods in the host.
In addition to the capsular polysaccharide, elaboration of phenyl oxidase (an enzyme that catalyzes the oxidation of various phenols to dopachrome) by C neoformans appears to be a determinant of virulence, although the role of this enzyme in virulence is unknown. The infectious propagules of H capsulatum, B dermatitidis, P brasiliensis, and C immitis are readily phagocytosed by alveolar macrophages. To survive phagocytosis and to multiply, these fungi must neutralize the effects of the phagocytes. The production of reactive oxygen metabolites by phagocytic cells is an important host defense against microorganisms. Studies have shown that the yeast phase of H capsulatum fails to trigger release of reaction oxygen metabolites in unprimed murine macrophages despite extensive phagocytosis. How they avoid destruction by the fungicidal mechanisms within lysosomes is unclear. Arthroconidia of C immitis inhibit phagosome-lysosome fusion and survive within normal murine peritoneal macrophages. Phagosome-lysosome fusion takes place after H capsulatum infection, but the yeast cells survive in the phagolysosome. It has been speculated that the fungus neutralizes the fungicidal components of the lysosome by a mechanism not yet elucidated.
There is very little information about mechanisms of fungal pathogenicity, in contrast to what is known about molecular mechanisms of bacterial pathogenesis. Fungal pathogenesis is complex and involves the interplay of many factors. Studies to elucidate these mechanisms are needed because of the increasing incidence of opportunistic infections.
Taken from CHAPTER 73-74, MEDICAL MICROBIOLOGY BY SAMUEL BARON
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