TRENDSin Microbiology Vol.10 No.1 January 2002 25 Review http://tim.trends.com 0966-842X/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0966-842X(01)02258-2 T. Tristan Brandhorst Thomas D. Sullivan Dept of Pediatrics, Peggy J. Rooney Dept of Medical Microbiology & Immunology, Bruce S. Klein* Depts of Pediatrics, Internal Medicine, Medical Microbiology & Immunology and the Comprehensive Cancer Care Center, University of Wisconsin Medical School, Madison, WI 53792, USA. *e-mail: bsklein@facstaff.wisc.edu Blastomyces dermatitidis is a pathogenic Ascomycete (Onygenaceae family) that exists in nature as a sporulating mold [1] and converts to a large (15–20 μm), thick-walled yeast form at elevated temperatures.This dimorphic fungus is closely related to Histoplasma capsulatum, Chrysosporium parvum, Coccidioides immitis [2,3] and Par acocci di oi des brasiliensis [4]. Although the ecology of B.dermatitidis is still the subject of debate [5],these phylogenetic relatives of B. dermatitidis gr ow naturally in soils, often involving or requiring the presence of animal excreta. The favored substrate of B.dermatitidis appears to be material with a high organic content, with the assumption frequently being made that it, too, must grow within the soil.Some studies suggest that decaying wood might be its reservoir [5,6], however, and others have pointed out the strong association between bodies of water and the exogenous sapr ophyt ic sour ce of B. dermatitidis [7]. Conidia constitute the infectious form of this organism.After inhalation into the lungs of animals or humans, the conidia swell and germinate into yeast, the form required for pathogenicity and proliferation [5].Unchecked proliferation in turn results in blastomycosis, a systemic mycosis that can become life-threatening when undiagnosed or untreated. Acute blastomycosis is occasionally self- limiting, but more frequently progresses to produce severe pulmonary disease, with the potential for dissemination to other organs, skin and bone [8]. These tissues become inflamed as neutrophils and mononuclear phagocytes are recruited to control the infection. Despite this robust response, phagocytosis by macrophages does not inhibit yeast replication [9] and in some cases, it can be stimulatory [10]. Several weeks after the onset of an infection, the host develops a delayed-type hypersensitivity response with activated T-cell proliferation.In a murine model of blastomycosis, these T cells confer protection when transferred into naive animals whereas serum does not, suggesting that antigen-specific T cells are the key to an effective host response [9,11]. B. dermatitidis is endemic in the central United States in and around the Ohio and Mississippi River Valleys, although blastomycosis has also been reported in parts of Canada and the southeastern United States. The 100th meridian is commonly cited as the westernmost boundary of this endemic area, but the actual extent of its range is uncertain as mycoses are frequently unreported in the United States and Canada. Sporadic cases have been verified in other regions throughout the world, but these are usually deemed to have stemmed from exposure during time spent in endemic areas, or exposure to contaminated materials originating in endemic areas [5,12].African varieties of B. dermatitidis have been isolated and described, but these strains lack antigens characteristic of North American B. dermatitidis [13,14] and produce a variant pattern of blastomycosis consisting largely of chronic cutaneous lesions [15,16]. It has been suggested that African B. dermatitidis might in fact be a separate species, bearing a closer taxonomic resemblance to P. br asi l i ensi s [16,17]. The pathogenesis of B. dermatitidis Thermally regulated dimorphism is the single-most defining trait of B. dermatitidis and related systemic dimorphic fungi.These agents reversibly differentiate between mold and yeast phases via a morphological transition that can be controlled and induced in vitro by growing the fungi at 25°C (mold) or 37°C (yeast). Medoff and colleagues [18–22] demonstrated that the temperature-induced transition is accompanied by a shared and well-characterized sequence of biochemical events: after an increase in the temperature from 25°C t o 37°C, there is a rapid decline in intracellular ATPthat follows the uncoupling of oxidative phosphorylation.This is followed by a progressive decrease in respiration rate (stage 1). After 24–40 hours, cells enter a dormant period (stage 2) that can last as long as 4–6 days. I n st age 3, cyt ochr ome component s ar e r est or ed, nor mal Fungal pathogens have emerged as a public health menace owing to the expanding population of vulnerable patients and a heightened exposure to fungi in our environment, particularly for the systemic dimorphic fungi that inhabit soil worldw ide. A better understanding of these invaders and their pathogenic mechanisms is badly needed to further research into therapeutic options. Advances in the molecular tools available for genetic manipulation of Blastomyces dermatitidis have enhanced our ability to study this poorly understood dimorphic fungal pathogen.Recent refinements in gene-transfer techniques, new selection markers, reliable reporter fusions and successes in gene targeting have shed light upon the importance of the mycelium-to-yeast transition and the crucial and complex role the BAD1 adhesin plays in pathogenesis. Using new genetic tools to study the pathogenesis of Blastomyces dermatitidis T. Tristan Brandhorst, Peggy J. Rooney, Thomas D. Sullivan and Bruce S. Klein F U N G A L P A T H O G E N S