Shaping Up for Battle: Morphological Control Mechanisms in Human Fungal Pathogens

Many pathogenic and non-pathogenic fungi possess the ability to alter their morphology. The major fungal pathogens can grow vegetatively in multiple morphologies, including yeast, pseudohyphae, and hyphae. Yeast are typically round or oval-shaped single cells, while the filamentous morphologies, pseudohyphae and hyphae, are comprised of elongated cells attached end to end. Pseudohyphae are ellipsoidal in shape, possess constrictions at septal junctions, and are typically highly branched. Hyphae, in contrast, have parallel-sided walls, possess true septa (lacking constrictions), and often show a smaller filament width than pseudohyphae [1]. Pathogenic genera in the phylum zygomycota (e.g., Absidia, Mucor, Rhizopus, Rhizomucor, Saksenaea, and Cunninghamella) primarily grow as coenocytic (aseptate) hyphae or hyphae with only rudimentary septa. In addition, certain fungi (e.g., the pathogens Aspergillus fumigatus and Penicillium marneffei) also form distinctive reproductive structures on their hyphae, termed conidiophores, which generate asexual single-celled spores called conidia [2]. The ability to undergo a reversible transition from yeast to filamentous form is required for virulence of the major human fungal pathogen Candida albicans. Initial studies indicated that C. albicans mutants locked in either the yeast or filamentous form were avirulent in a mouse model of systemic candidiasis [3,4]. More convincing evidence came from a later study using a strain in which the timing of the morphological transition could be controlled during the course of an infection [5]. When locked in the yeast form, this strain was avirulent, but the virulence defect could be reversed by allowing the strain to transition to filaments at various post-infection time points. An additional study provided further evidence by demonstrating that a strain showing increased hyphal formation could promote virulence in a mouse model of systemic candidiasis [6]. In C. albicans and other fungal pathogens, hyphal formation is known to be important for a variety of virulence-related processes, including tissue invasion, breaching of epithelial and endothelial cell layers, immune evasion, lysis of macrophages, biofilm formation, and thigmotropism (contact guidance) [7–9]. The C. albicans yeast form also plays an important role in several virulence-related processes, including adhesion to host cells, rapid dissemination through the bloodstream, and biofilm formation [10]. In addition, a recent genetic study has identified a variety of C. albicans mutants which are defective for infectivity but not morphogenesis (and vice versa) [11], suggesting that the relationship between filamentation and pathogenicity is not always precise and that yeast may be more important for pathogenesis than previously expected. Interestingly, dimorphic fungal pathogens, such as Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides brasiliensis, P. marneffei, Blastomyces dermatitidis, Wangiella dermatitidis, and Sporothrix schenkii are typically found as hyphae in the soil. Conidia derived from hyphal phase growth of these species are inhaled by the host (S. schenkii infections initiate after trauma) and differentiate to the infectious yeast form (or spherules for C. immitis) [2,12]. Unlike C. albicans, these pathogens undergo a complete morphological conversion in vivo. Chemically blocking the hyphal–yeast transition renders H. capsulatum avirulent [13]. H. capsulatum yeast cells are known to multiply in macrophages, which promotes dissemination to several host organs, including the liver and spleen [14]. The large size of B. dermatitidis yeast cells has also been shown to prevent engulfment by polymorphonuclear neutrophils (PMNs) [15]. In addition, a-(1,3) glucan in the yeast cell wall of at least one of these species is known to block recognition by the macrophage b-glucan receptor dectin-1 [16]. Because of the importance of morphology for both virulence and virulence-related processes in a wide variety of pathogenic fungi, a significant amount of research has focused on determining the mechanisms by which morphological transitions are controlled. A comprehensive and detailed understanding of morphology regulation, in turn, may not only provide a better understanding of how certain fungal pathogens promote virulence in response to host environmental cues but also information leading to the development of novel and more effective antifungal strategies. Therefore, in the remainder of this review we will highlight and discuss several key morphological control mechanisms in pathogenic fungi. The recent discovery of these mechanisms has had a significant impact on the field, raising many new and interesting questions and opening up a variety of avenues for future research.