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Pathogenesis of Candida infections
CUTANEOUS YEAST INFECTIONS PRESEi'ilED AT THE "INTE~ATIONALSL1\1MIT ON CUTAJ.'\"EO{;S ANTIFUNGAL THERAPY," SUPPORTED BY EDUCATIONAL GRANTS FROM JANSSEN PHARMACEUTICA; ORlHO PHARMACEUTICAL CORPORATION-DERMATOLOGICAL DIVISION; ROERIG-A DIVISION OF PFIZER; AND SANDOZ PHARMACEUTICALS CORPORATION.
Pathogenesis of Candida infections Frank C. Odds, PhD, MRCPath Beerse, Belgium Candida infections of the skin and superficial mucosal sites are the result of an interplay between fungal virulence and host defenses. Epidermal proliferation and T -lymphocyte immune responses are expressed by the host to combat fungal invasion, but inflammatory responses and nonspecific inhibitors also probably playa role. Candida albicans can express at least three types of surface adhesion molecules to colonize epithelial surfaces, plus an aspartyl proteinase enzyme able to facilitate initial penetration of keratinized cells. Deeper penetration of keratinized epithelia is assisted by hypha fonnation, and C. albicans hyphae may use contact sensing (thigmotropism) as a guiding mechanism. Pathogenesis requires differential expression ofvirulence factors at each new stage of the process: a propensity for rapid alteration of the expressed phenotype in C. albicans may therefore be a significant factor in establishing the comparatively high pathogenic potential of this species. (J AM ACAD DERMATOL 1994;31:52-S5.)
Candida albicans is the species most frequently responsible for Candida infections of the skin or mucous membranes. However, other species such as Candida glabrata, Candida kefyr, Candida krusei, Candida parapsilosis, and Candida tropicalis are occasional causative agents. 1,2 In vaginal Candida infections, other Candida species may sometimes be involved, and vaginal infections clinically equivalent to Candida infections have been attributed to Saccharomyces cerevisiae. 3 These various yeasts differ in their potential to colonize and invade epithelial and epidermal sites; C. albicans has the greatest virulence. Host resistance to yeast invasion is reduced at epidermal sites that are occluded or macerated and is also decreased in patients whose cellular immunity is impaired. This allows commensal yeasts to penetrate the corneal layer. Penetration beyond the horny layer is normally not seen even in patients with defective T-Iymphocyte responses. The nature of virulence in Candida is now becoming better underFrom the Department of Bacteriology and Mycology, Janssen Research Foundation. Reprint requests: Frank C. Odds, PhD, Department of Bacteriology and Mycology, Janssen Research Foundation, B-2340, Beerse, Belgium. Copyright @) 1994 by the American Academy of Dermatology, fnc. 0190-9622/94 $3.00 + 0
82
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stood at the cellular and molecular levels. This article reviews the host and yeast factors that may play a role in the pathogenesis of superficial Candida infections. HOST DEFENSES AGAINST CANDIDA
Epidermal and external epithelial surfaces are normally defended against microbial invasion by a range of factors (Table 1), two of which stand out as particularly significant anti-Candida defenses: Tlymphocyte immune responses and epidermal (also epithelial?) proliferation. The evidence for the importance of cellular immunity in defense against Candida infections comes from the simple observation that in persons with definable T-cell defects and in patients with low CD4 cell counts resulting from HIV infection, chronic cutaneous and mucosal Candida infections frequently occur. In HIVnegative patients with chronic mucocutaneous Candida infections, the mouth, skin, nails, and (in women) the vagina may also be affected.! In HIVinfected patients, the mouth and esophagus are the principal sites of invasion, with less or no evidence of skin and nail infection. 4 These widely repeated clinical observations stress not only the importance of T-lymphocytes in the defense of external epithelial and epidermal surfaces against Candida, but the different locations associated with the two types
Journal of the American Academy of Dermatology Volume 31, Number 3, Part 2
of T-lymphocyte defect suggest a subtle interplay between host leukocytes and yeast pathogen. Langerhans' cells may play a role in the generation of T-lymphocyte responses to cutaneous Candida infection; such a role has been demonstrated experimentally for dermatophyte fungal infections. 5 In classic chronic mucocutaneous Candida infections, epidermal proliferation sometimes results in the formation of grotesque cutaneous crusts, once called "granulomas." Histopathologic examination of the crusts shows that the fungus remains confined to the corneal layer,6 suggesting that the massive hyperkeratosis occurs at a rate equal to or greater than the rate of fungal penetration of the epidermis. Sohnle and Kirkpatrick7 have demonstrated an increase in basal cell turnover rate and epidermal thickening in mice experimentally infected with C. albieans. It is likely that increased proliferation of epithelial cells in sites such as the mouth and vagina occurs in response to Candida infection, but little direct evidence exists for such a response. Other host factors that play a role in defense against Candida are the presence, particularly in locations such as the mouth and the vagina, of an indigenous microbial flora that competes with Candida for epithelial colonization sites. Epithelia and epidermal cells are also routinely coated with a fluid layer containing potential inhibitors of Candida growth that may be nonspecific (e.g., various acids and lipids contained in secretions) or specific (e.g., secretory IgA molecules). Keratinocytes are capable of phagocytosing C. albieans cells. 8, 9 The nature of superficial lesions caused by Candida species is of course not uniform. The lesions that arise on occluded skin are frequently erythematous and pustular. These may form subcutaneous abscesses, which may be sterile, presumably provoked by soluble components from the fungilO that lead to complement activation and an influx of polymorphonuclear leukocytes. I I, 12 In oral and vaginal lesions, the white "plaques" characteristic of a Candida infection contain a mixture of fungi and host material and may well result from a desquamatory process analogous to epidermal proliferation. The inflammatory component of oral and vaginal lesions is based on polymorphonuclear leukocyte influx analogous to that in cutaneous Candida intertrigo. CANDIDA VIRULENCE FACTORS
Table I lists a number of C. albicans attributes that are possible factors of virulence in the coloniza-
Odds
83
Table 1. Possible C. albicans virulence attributes and host epidermal/epithelial defenses involved in the pathogenesis of Candida infections of skin and external mucosae C. albicans virulence attributes
Host-defense attributes
Hypha formation Contact sensing (thigmotropism) Surface adhesion factors
Epidermal proliferation T-cell immunity (Langerhans' cells?) Phagocytosis by
Surface hydrophobicity
Antifungal substances in secretions Secretory immunoglobulins Other microbial flora
Lytic enzymes (e.g., acid proteinase) Propensity to switch phenotype
keratinocytes
tion and invasion of cutaneous and mucosal sites. Adhesion, the first essen tial step in colonization of an epithelial site, is dependent on surface components of the fungal cells with a specific affinity for epithelial receptors. Candida adhesion molecules appear to be of three general types. In one type the protein moiety of a surface glycoprotein binds to arginineglycine-aspartate (RGD) sequences common to flbronectin, vitronectin, collagens, laminin, and other extracellular matrix glycoproteins. In the second, the protein moiety of a surface glycoprotein binds in a lectin-like manner to the sugar portion of host membrane glycoproteins. In the third and the least well characterized, the polysaccharide moiety of a Candida surface mannoprotein binds to unknown host receptors. These various adhesions have been reviewed in detail by Calderone and Braun. 13 Production of a secreted aspartyl proteinase by C. albieans has long been suggested as a likely virulence attribute in this species. I Some evidence suggests a role for this enzyme in the colonization of oral epithelia. 14 A direct role for the proteinase in early invasion of the corneal layer was indicated by the experiments of Ray and Payne, 15 in which C. albicans yeast cells formed pits in mouse corneocytes ex vivo, a process arrested in the presence of pepstatin, which inhibits the aspartyl proteinase enzyme. It was natable that pepstatin did not inhibit initial attachment of C. albicans to the corneocytes, only penetration, which suggests that adhesion to and colonization of epidermal cells is not mediated by the proteinase. It was also notable that the proteinase-dependent penetration of corneocytes required no morphologic transformation of the Candida yeast cells to hyphae. Hypha formation has long been considered an at-
84 Odds tribute of virulence and tissue penetration in C. a/bieans, although little or no firm evidence exists for the traditional dogma that C. albicans hyphae are the sale participants in invasive processes, whereas yeast forms are associated with commensal colonization. It has been well established that hyphal forms adhere more readily to buccal epithelia than do yeast forms of Candida,1 but this property may confer on hyphae the role of a stable, attached colonizer from which new infectious propagules (budding yeast cells) are generated. Such a concept differs from the classic role of penetration normally attributed to Candida hyphal forms. Hyphal penetration ofepidermal and buccal or vaginal epithelial surfaces is the most usual and consistent histopathologic finding in superficial Candida infections, but the experiments of Ray and Payne l5 indicate that hypha formation is not an obligatory property for invasion of epidermal cells by C. albieans. Recent experiments in vitro have shown that C. albicans hyphae have the property of contact sensing, or thigmotropism. 16 In histopathologic sections of C. albicans-infected tissues, the hyphae most often appear to be randomly distributed. However, in keratinized epithelial layers, the hyphae sometimes appear to be distributed in patterns either predominantly along the keratinocyte strata or perpendicular to the strata, although such patterns are never so consistent or clearcut as with some plant pathogenic fungal species that always grow precisely parallel or perpendicular to cell boundaries. Semiregular orientations of C. a/bieans hyphae might result simply from a tendency to grow in the direction of freely available nutrients, but it is a theoretic possibility that such hyphal arrangements result from their thigmotropic responses to the microsurfaces found in the keratinized layer. Surface hydrophobicity is a nonspecific factor that can govern mutual adhesion of cell types via van der Waals forces. l7 C. alMeans cells have different degrees of hydrophobicity according to their growth temperature,18 and these differences correspond with differences in epithelial cell adhesion 19 and virulence in terms of mouse lethality. IS Fluctuations in hydrophobicity may therefore play a role in the pathogenesis of superficial Candida infections, although such a possibility has not yet been studied. The possible virulence factors described for C. albicans are unlikely to be expressed consistently and continuously by Candida cells in all possible microenvironments. There is now evidence to show
Journal of the American Academy of Dermatology September 1994
that C. albicans has a high potential for rapid switching of its expressed phenotype,20 probably through transcriptional regulation of gene expression.2 1This phenomenon may enhance the potential for C. a/bicans cells to adapt rapidly to new microniches, for example, when yeast cells are transferred from the anus to the vagina. 22 Such adaptability may be a factor regulating the appropriate expression of virulence attributes during the various stages of colonization and tissue penetration necessary to establish a pathologic infection. STAGES OF PATHOGENESIS OF EPITHELIAL INFECfIONS BY CANDIDA
The pathogenesis ofinfections by C. albicans (and other Candida species) occurs in stages at which different host and fungal factors playa critical role. For initial colonization of an epithelial or epidermal site, the surface adhesion components of the fungus will determine whether it succeeds in establishing itself. The host defenses against colonization (apart from physical factors such as flushing mechanisms) are other competing microbes and substances at the site capable of inhibiting Candida growth. Once the fungal cells have begun to embed themselves in epithelial or epidermal surfaces-a process made difficult by the innate mechanical resistance of keratinized surfaces but facilitated by fungal hydrolytic enzymes and maceration-they may begin to form hyphae, which, by means of contact sensing, are guided to penetrate deeper into the epithelia. At this stage the host calls a variety of defenses into play, including epidermal and epithelial proliferation, direct phagocytosis of Candida by keratinocytes, and activation of an inflammatory response. T-Iymphocytes may be involved as specific defenses against any or all three stages of pathogenesis. This entirely speculative scenario seeks to integrate the present fragmentary knowledge of possible host and fungal factors involved in a descriptive natural history of the pathogenesis of superficial Candida infections. The techniques for study of expression of microbial virulence attributes in vivo are now embryonic but are actively under development. REFERENCES I. Odds Fe. Candida and candidosis. 2nd ed. London: BailIiere Tindall, 1988. 2. Agatensi L, Franchi F, Mondello F, et al. Vaginopathic and proteolytic Candida species in outpatients attending a gynecology clinic. J Clin Pathol 1991 ;44:826-30.
Journal of the American Academy of Dermatology y olume 31, Number 3, Part 2
3. Sobel JD, VazquezJ, Lynch M, Meriwether C, Zervos MJ. Vaginitis due to Saccharomyces cerevisiae-epidemiology, clinical aspects, and therapy. Clin Infect Dis 1993;16:93-9. 4. Mackenzie DWR, Cauwenbergh 0, Van Cutsem J, Drouhet E, Dupont B. Mycoses in AIDS patients: an overview. In: Vanden Bossche H, ed. Mycoses in AIDS patients. New York: Plenum Press, 1990:27-53. 5. Braathen LR, Kaaman T. Human epidermal Langerhans' cells induce cellular immune response to Trichophyton in dermatophytosis. Br J Dermatol 1983;109:295-300. 6. Rippon JW. Candidiasis and the pathogenic yeasts. In: Rippon JW ed. Medical mycology. Philadelphia: WB Saunders, 1988:532-81. 7. SohnlePG, Kirkpatrick CH. Epidermal proliferation in the defense against experimental cutaneous candidiasis. J Invest Dermatol 1978;70: 130·3. 8. Csato M, Bozoky B, Hunyadi H, Dobozy A. Candida albicans phagocytosis by separated human epidermal cells. Arch Dermatol Res 1986;279:136-9. 9. Csato M, Kenderessy AS, Dobozy A. Enhancement of Candida albicallS killing activity of separated human epidermal cells by ultraviolet radiation. Br J Dermatol 1987; 116:469-75. 10. Maibach HI, Kligman AM. The biology of experimental human cutaneous moniliasis (Candida albicans). Arch Dermatol 1962;85:233-55. II. Ray TL, Wuepper KD. Experimental cutaneous candidiasis in rodents. J Invest Dermatol 1976;66:29-33. 12. Sohnle PG, Kirkpatrick CH. Study of possible mechanisms of basophil accumulation in experimental cutaneous candidiasis in guinea pigs. J Allergy Clin Immunol 1977; 59:171-7. 13. Calderone RA, Braun Pc. Adherence and receptor rcla-
Odds 85
14. 15.
16.
17. 18. 19.
20. 21. 22.
tionships of Candida albicans. Microbiol Rev 1991 ;55:120. Borg M, Ruchel R. Expression of extracellular acid proteinase by proteolytic Candida spp during experimental infection of the oral mucosa. Infect lmmun 1988;56:626-31. Ray TL, Payne CD. Scanning electron microscopy of epidermal adherence and cavitation in murine candidiasis: a role of Candida acid proteinase. Infect Immun 1988; 56:1942-9. Sherwood J, Gow NAR, Oooday OW, Gregory OW, Marshall D. Contact sensing in Candida albicans: a possible aid to epithelial penetration. J Med Vet Mycol 1992; 30:461-70. Klotz SA, Drutz DJ, Zajic E. Factors governing adherence of Candida species to plastic surfaces. Infect Immun 1985;50:97-101. Antley PP, Hazen KC. Role of yeast cell growth temperatureon Calldida albicans virulence in mice. Infect Immun 1988;56:2884-90. Hazen KC, Brawner DL, Riesselman MH, Jutila MA, Cutler JE. Differential adherence of hydrophobic and hydrophilic Candida albicans yeast cells to mouse tissues. Infect Immun 1991;59:907-12. Soli DR. High-frequency switching in Candida albicans. Clin Microbiol Rev 1992;5: 183-203. Soli DR, Morrow B, Srikantha T. High-frequency phenotypic switching in Candida albicans. Trend Genet 1993; 9:61-5. Soil DR, Galsask R, Schmid J, Hanna C, Mac K, Morrow B. Genetic dissimilarity of commensal strains of Candida spp carried in different anatomical locations of the same healthy women. J Clin Microbiol 199) ;29: 1702-10.
Pathogenesis of Candida infections Frank C. Odds, PhD, MRCPath Beerse, Belgium Candida infections of the skin and superficial mucosal sites are the result of an interplay between fungal virulence and host defenses. Epidermal proliferation and T -lymphocyte immune responses are expressed by the host to combat fungal invasion, but inflammatory responses and nonspecific inhibitors also probably playa role. Candida albicans can express at least three types of surface adhesion molecules to colonize epithelial surfaces, plus an aspartyl proteinase enzyme able to facilitate initial penetration of keratinized cells. Deeper penetration of keratinized epithelia is assisted by hypha fonnation, and C. albicans hyphae may use contact sensing (thigmotropism) as a guiding mechanism. Pathogenesis requires differential expression ofvirulence factors at each new stage of the process: a propensity for rapid alteration of the expressed phenotype in C. albicans may therefore be a significant factor in establishing the comparatively high pathogenic potential of this species. (J AM ACAD DERMATOL 1994;31:52-S5.)
Candida albicans is the species most frequently responsible for Candida infections of the skin or mucous membranes. However, other species such as Candida glabrata, Candida kefyr, Candida krusei, Candida parapsilosis, and Candida tropicalis are occasional causative agents. 1,2 In vaginal Candida infections, other Candida species may sometimes be involved, and vaginal infections clinically equivalent to Candida infections have been attributed to Saccharomyces cerevisiae. 3 These various yeasts differ in their potential to colonize and invade epithelial and epidermal sites; C. albicans has the greatest virulence. Host resistance to yeast invasion is reduced at epidermal sites that are occluded or macerated and is also decreased in patients whose cellular immunity is impaired. This allows commensal yeasts to penetrate the corneal layer. Penetration beyond the horny layer is normally not seen even in patients with defective T-Iymphocyte responses. The nature of virulence in Candida is now becoming better underFrom the Department of Bacteriology and Mycology, Janssen Research Foundation. Reprint requests: Frank C. Odds, PhD, Department of Bacteriology and Mycology, Janssen Research Foundation, B-2340, Beerse, Belgium. Copyright @) 1994 by the American Academy of Dermatology, fnc. 0190-9622/94 $3.00 + 0
82
16/0/57441
stood at the cellular and molecular levels. This article reviews the host and yeast factors that may play a role in the pathogenesis of superficial Candida infections. HOST DEFENSES AGAINST CANDIDA
Epidermal and external epithelial surfaces are normally defended against microbial invasion by a range of factors (Table 1), two of which stand out as particularly significant anti-Candida defenses: Tlymphocyte immune responses and epidermal (also epithelial?) proliferation. The evidence for the importance of cellular immunity in defense against Candida infections comes from the simple observation that in persons with definable T-cell defects and in patients with low CD4 cell counts resulting from HIV infection, chronic cutaneous and mucosal Candida infections frequently occur. In HIVnegative patients with chronic mucocutaneous Candida infections, the mouth, skin, nails, and (in women) the vagina may also be affected.! In HIVinfected patients, the mouth and esophagus are the principal sites of invasion, with less or no evidence of skin and nail infection. 4 These widely repeated clinical observations stress not only the importance of T-lymphocytes in the defense of external epithelial and epidermal surfaces against Candida, but the different locations associated with the two types
Journal of the American Academy of Dermatology Volume 31, Number 3, Part 2
of T-lymphocyte defect suggest a subtle interplay between host leukocytes and yeast pathogen. Langerhans' cells may play a role in the generation of T-lymphocyte responses to cutaneous Candida infection; such a role has been demonstrated experimentally for dermatophyte fungal infections. 5 In classic chronic mucocutaneous Candida infections, epidermal proliferation sometimes results in the formation of grotesque cutaneous crusts, once called "granulomas." Histopathologic examination of the crusts shows that the fungus remains confined to the corneal layer,6 suggesting that the massive hyperkeratosis occurs at a rate equal to or greater than the rate of fungal penetration of the epidermis. Sohnle and Kirkpatrick7 have demonstrated an increase in basal cell turnover rate and epidermal thickening in mice experimentally infected with C. albieans. It is likely that increased proliferation of epithelial cells in sites such as the mouth and vagina occurs in response to Candida infection, but little direct evidence exists for such a response. Other host factors that play a role in defense against Candida are the presence, particularly in locations such as the mouth and the vagina, of an indigenous microbial flora that competes with Candida for epithelial colonization sites. Epithelia and epidermal cells are also routinely coated with a fluid layer containing potential inhibitors of Candida growth that may be nonspecific (e.g., various acids and lipids contained in secretions) or specific (e.g., secretory IgA molecules). Keratinocytes are capable of phagocytosing C. albieans cells. 8, 9 The nature of superficial lesions caused by Candida species is of course not uniform. The lesions that arise on occluded skin are frequently erythematous and pustular. These may form subcutaneous abscesses, which may be sterile, presumably provoked by soluble components from the fungilO that lead to complement activation and an influx of polymorphonuclear leukocytes. I I, 12 In oral and vaginal lesions, the white "plaques" characteristic of a Candida infection contain a mixture of fungi and host material and may well result from a desquamatory process analogous to epidermal proliferation. The inflammatory component of oral and vaginal lesions is based on polymorphonuclear leukocyte influx analogous to that in cutaneous Candida intertrigo. CANDIDA VIRULENCE FACTORS
Table I lists a number of C. albicans attributes that are possible factors of virulence in the coloniza-
Odds
83
Table 1. Possible C. albicans virulence attributes and host epidermal/epithelial defenses involved in the pathogenesis of Candida infections of skin and external mucosae C. albicans virulence attributes
Host-defense attributes
Hypha formation Contact sensing (thigmotropism) Surface adhesion factors
Epidermal proliferation T-cell immunity (Langerhans' cells?) Phagocytosis by
Surface hydrophobicity
Antifungal substances in secretions Secretory immunoglobulins Other microbial flora
Lytic enzymes (e.g., acid proteinase) Propensity to switch phenotype
keratinocytes
tion and invasion of cutaneous and mucosal sites. Adhesion, the first essen tial step in colonization of an epithelial site, is dependent on surface components of the fungal cells with a specific affinity for epithelial receptors. Candida adhesion molecules appear to be of three general types. In one type the protein moiety of a surface glycoprotein binds to arginineglycine-aspartate (RGD) sequences common to flbronectin, vitronectin, collagens, laminin, and other extracellular matrix glycoproteins. In the second, the protein moiety of a surface glycoprotein binds in a lectin-like manner to the sugar portion of host membrane glycoproteins. In the third and the least well characterized, the polysaccharide moiety of a Candida surface mannoprotein binds to unknown host receptors. These various adhesions have been reviewed in detail by Calderone and Braun. 13 Production of a secreted aspartyl proteinase by C. albieans has long been suggested as a likely virulence attribute in this species. I Some evidence suggests a role for this enzyme in the colonization of oral epithelia. 14 A direct role for the proteinase in early invasion of the corneal layer was indicated by the experiments of Ray and Payne, 15 in which C. albicans yeast cells formed pits in mouse corneocytes ex vivo, a process arrested in the presence of pepstatin, which inhibits the aspartyl proteinase enzyme. It was natable that pepstatin did not inhibit initial attachment of C. albicans to the corneocytes, only penetration, which suggests that adhesion to and colonization of epidermal cells is not mediated by the proteinase. It was also notable that the proteinase-dependent penetration of corneocytes required no morphologic transformation of the Candida yeast cells to hyphae. Hypha formation has long been considered an at-
84 Odds tribute of virulence and tissue penetration in C. a/bieans, although little or no firm evidence exists for the traditional dogma that C. albicans hyphae are the sale participants in invasive processes, whereas yeast forms are associated with commensal colonization. It has been well established that hyphal forms adhere more readily to buccal epithelia than do yeast forms of Candida,1 but this property may confer on hyphae the role of a stable, attached colonizer from which new infectious propagules (budding yeast cells) are generated. Such a concept differs from the classic role of penetration normally attributed to Candida hyphal forms. Hyphal penetration ofepidermal and buccal or vaginal epithelial surfaces is the most usual and consistent histopathologic finding in superficial Candida infections, but the experiments of Ray and Payne l5 indicate that hypha formation is not an obligatory property for invasion of epidermal cells by C. albieans. Recent experiments in vitro have shown that C. albicans hyphae have the property of contact sensing, or thigmotropism. 16 In histopathologic sections of C. albicans-infected tissues, the hyphae most often appear to be randomly distributed. However, in keratinized epithelial layers, the hyphae sometimes appear to be distributed in patterns either predominantly along the keratinocyte strata or perpendicular to the strata, although such patterns are never so consistent or clearcut as with some plant pathogenic fungal species that always grow precisely parallel or perpendicular to cell boundaries. Semiregular orientations of C. a/bieans hyphae might result simply from a tendency to grow in the direction of freely available nutrients, but it is a theoretic possibility that such hyphal arrangements result from their thigmotropic responses to the microsurfaces found in the keratinized layer. Surface hydrophobicity is a nonspecific factor that can govern mutual adhesion of cell types via van der Waals forces. l7 C. alMeans cells have different degrees of hydrophobicity according to their growth temperature,18 and these differences correspond with differences in epithelial cell adhesion 19 and virulence in terms of mouse lethality. IS Fluctuations in hydrophobicity may therefore play a role in the pathogenesis of superficial Candida infections, although such a possibility has not yet been studied. The possible virulence factors described for C. albicans are unlikely to be expressed consistently and continuously by Candida cells in all possible microenvironments. There is now evidence to show
Journal of the American Academy of Dermatology September 1994
that C. albicans has a high potential for rapid switching of its expressed phenotype,20 probably through transcriptional regulation of gene expression.2 1This phenomenon may enhance the potential for C. a/bicans cells to adapt rapidly to new microniches, for example, when yeast cells are transferred from the anus to the vagina. 22 Such adaptability may be a factor regulating the appropriate expression of virulence attributes during the various stages of colonization and tissue penetration necessary to establish a pathologic infection. STAGES OF PATHOGENESIS OF EPITHELIAL INFECfIONS BY CANDIDA
The pathogenesis ofinfections by C. albicans (and other Candida species) occurs in stages at which different host and fungal factors playa critical role. For initial colonization of an epithelial or epidermal site, the surface adhesion components of the fungus will determine whether it succeeds in establishing itself. The host defenses against colonization (apart from physical factors such as flushing mechanisms) are other competing microbes and substances at the site capable of inhibiting Candida growth. Once the fungal cells have begun to embed themselves in epithelial or epidermal surfaces-a process made difficult by the innate mechanical resistance of keratinized surfaces but facilitated by fungal hydrolytic enzymes and maceration-they may begin to form hyphae, which, by means of contact sensing, are guided to penetrate deeper into the epithelia. At this stage the host calls a variety of defenses into play, including epidermal and epithelial proliferation, direct phagocytosis of Candida by keratinocytes, and activation of an inflammatory response. T-Iymphocytes may be involved as specific defenses against any or all three stages of pathogenesis. This entirely speculative scenario seeks to integrate the present fragmentary knowledge of possible host and fungal factors involved in a descriptive natural history of the pathogenesis of superficial Candida infections. The techniques for study of expression of microbial virulence attributes in vivo are now embryonic but are actively under development. REFERENCES I. Odds Fe. Candida and candidosis. 2nd ed. London: BailIiere Tindall, 1988. 2. Agatensi L, Franchi F, Mondello F, et al. Vaginopathic and proteolytic Candida species in outpatients attending a gynecology clinic. J Clin Pathol 1991 ;44:826-30.
Journal of the American Academy of Dermatology y olume 31, Number 3, Part 2
3. Sobel JD, VazquezJ, Lynch M, Meriwether C, Zervos MJ. Vaginitis due to Saccharomyces cerevisiae-epidemiology, clinical aspects, and therapy. Clin Infect Dis 1993;16:93-9. 4. Mackenzie DWR, Cauwenbergh 0, Van Cutsem J, Drouhet E, Dupont B. Mycoses in AIDS patients: an overview. In: Vanden Bossche H, ed. Mycoses in AIDS patients. New York: Plenum Press, 1990:27-53. 5. Braathen LR, Kaaman T. Human epidermal Langerhans' cells induce cellular immune response to Trichophyton in dermatophytosis. Br J Dermatol 1983;109:295-300. 6. Rippon JW. Candidiasis and the pathogenic yeasts. In: Rippon JW ed. Medical mycology. Philadelphia: WB Saunders, 1988:532-81. 7. SohnlePG, Kirkpatrick CH. Epidermal proliferation in the defense against experimental cutaneous candidiasis. J Invest Dermatol 1978;70: 130·3. 8. Csato M, Bozoky B, Hunyadi H, Dobozy A. Candida albicans phagocytosis by separated human epidermal cells. Arch Dermatol Res 1986;279:136-9. 9. Csato M, Kenderessy AS, Dobozy A. Enhancement of Candida albicallS killing activity of separated human epidermal cells by ultraviolet radiation. Br J Dermatol 1987; 116:469-75. 10. Maibach HI, Kligman AM. The biology of experimental human cutaneous moniliasis (Candida albicans). Arch Dermatol 1962;85:233-55. II. Ray TL, Wuepper KD. Experimental cutaneous candidiasis in rodents. J Invest Dermatol 1976;66:29-33. 12. Sohnle PG, Kirkpatrick CH. Study of possible mechanisms of basophil accumulation in experimental cutaneous candidiasis in guinea pigs. J Allergy Clin Immunol 1977; 59:171-7. 13. Calderone RA, Braun Pc. Adherence and receptor rcla-
Odds 85
14. 15.
16.
17. 18. 19.
20. 21. 22.
tionships of Candida albicans. Microbiol Rev 1991 ;55:120. Borg M, Ruchel R. Expression of extracellular acid proteinase by proteolytic Candida spp during experimental infection of the oral mucosa. Infect lmmun 1988;56:626-31. Ray TL, Payne CD. Scanning electron microscopy of epidermal adherence and cavitation in murine candidiasis: a role of Candida acid proteinase. Infect Immun 1988; 56:1942-9. Sherwood J, Gow NAR, Oooday OW, Gregory OW, Marshall D. Contact sensing in Candida albicans: a possible aid to epithelial penetration. J Med Vet Mycol 1992; 30:461-70. Klotz SA, Drutz DJ, Zajic E. Factors governing adherence of Candida species to plastic surfaces. Infect Immun 1985;50:97-101. Antley PP, Hazen KC. Role of yeast cell growth temperatureon Calldida albicans virulence in mice. Infect Immun 1988;56:2884-90. Hazen KC, Brawner DL, Riesselman MH, Jutila MA, Cutler JE. Differential adherence of hydrophobic and hydrophilic Candida albicans yeast cells to mouse tissues. Infect Immun 1991;59:907-12. Soli DR. High-frequency switching in Candida albicans. Clin Microbiol Rev 1992;5: 183-203. Soli DR, Morrow B, Srikantha T. High-frequency phenotypic switching in Candida albicans. Trend Genet 1993; 9:61-5. Soil DR, Galsask R, Schmid J, Hanna C, Mac K, Morrow B. Genetic dissimilarity of commensal strains of Candida spp carried in different anatomical locations of the same healthy women. J Clin Microbiol 199) ;29: 1702-10.