Michael J. Kennedy

Models for studying the role of fungal attachment in colonization and pathogenesis

Fungal adhesion and aggregation is considered an important event in human, animal and plant disease as well as in the ecology of fungi in nature (e.g., in mating reactions and the dispersion of fungal propagules). Because of this, numerous models have been developed to study fungal adhesion and aggregation mechanisms over the last decade. Unfortunately, however, nearly all of the work in this area has been carried out in simple in vitro models and has focused its attention on that of the attachment process alone, while realitively little effort has been made toward understanding the role adhesion and aggregation plays in colonization or pathogenesis. The emphasis on adhesion and aggregation mechanisms appears, therefore, to have somewhat obscured the study of the interaction of adhesion with other factors that may be of equal or greater importance in these processes and to the development of more complex adhesion models to explore the relationship between adhesion and colonization. Moreover, because it has not generally been appreciated that several methodologic pitfalls accompany the use of simple in vitro adhesion models, there is now emerging a confused literature base with regard to: (i) the nature of the cell wall component(s) of Candida albicans that mediates its attachment to, for example, epithelial cells; (ii) the mechanism(s) of invasion of mucosal and endothelial surfaces; and (iii) the role certain adhesive reactions observed in vitro play in colonization and pathogenesis by this fungus. Therefore, with an emphasis on C. albicans, this paper will attempt to put into perspective the uses and limitations of models for studying the role of fungal attachment in colonization and pathogenesis. In addition, factors that can modify fungal adhesion data will be discussed and the beginnings of a standardized assay to study the adhesion of C. albicans to buccal epithelial cells will be described.

Disseminated trichosporonosis in a neutropenic murine model

Life-threatening disseminated infection withTrichosporon beigelii (trichosporonosis) is a rare mycosis most commonly seen in patients with hematologic malignancies made neutropenic by cytotoxic therapy. This infection is usually resistant to conventional antifungal therapies. Poor correlation between therapeutic outcome of trichosporonosis and in vitro susceptibility of clinical isolates ofT. beigelii to antifungal agents is often reported. To obtain a better understanding of its pathogenesis, and to aid in the future study of the therapy of this disease, a murine model of trichosporonosis was developed. The in vitro growth of clinical isolates ofT. beigelii was first studied. Subsequently, mice made neutropenic with cyclophosphamide were inoculated intravenously with the fungus to produce the disease model. Inoculum size which produced 100% mortality, yet allowed an apparent therapeutic window (6×106) was determined. Tissue distribution and burden of organism during the course of infection was examined by viability and histopathologic studies.T. beigelii disseminated rapidly in this model, involving numerous organs including the heart, brain, kidneys, lungs, and liver. The heart and kidneys of the infected animals showed evidence of infection as early as 6 hours following inoculation. Further understanding of the pathogenesis of trichosporonosis in the neutropenic host was imparted by this study. This will aid in the future study of antibiotic treatment of this disease and its untreated progression.

Candida Blastospore Adhesion, Association, and Invasion of the Gastrointestinal Tract of Vertebrates

Survival, implantation, and dissemination from the alimentary tract by Candida species, and Candida albicans in particular, may play an important role in human and animal health. Recurrent vaginitis and systemic candidosis, for instance, have both been linked to colonization of the gastrointestinal (GI) tract by C. albicans (Krause et al., 1969; Stone, 1974; Miles et al., 1977; Myerowitz et al., 1977; Nystatin Multicenter Study Group, 1986), and the alimentary tract is now regarded by some as the proximate source of infection in these and other types of infections caused by Candida species (Odds, 1988). The “overgrowth” of C. albicans in the GI tract, and its subsequent passage through the gut mucosa into the host bloodstream is thus believed to be the primary mechanism leading to systemic candidosis in severely compromised patients (Stone et al., 1974). This type of “autoinoculation” or “self-inoculation” appears to be particularly prevalent among individuals with acute leukemia (Myerowitz et al., 1977). Similarly, colonization of the GI tract by C. albicans and other Candida species may also lead to involvement in a number of other disease syndromes that include esophageal, gastric, and intestinal thrush, gastric and intestinal ulceration, GI bleeding, diarrhea, peritonitis, perianal itch, napkin dermatitis, chronic “irritable bowel” syndrome, autobrewery syndrome, and growth depression in food-producing animals (Odds, 1988; Rippon, 1988).