Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick

MINIREVIEW Adhesins in Human Fungal Pathogens: Glue with Plenty of Stick Piet W. J. de Groot,a Oliver Bader,b Albert D. de Boer,a Michael Weig,b Neeraj Chauhanc,d Regional Center for Biomedical Research, Albacete Science and Technology Park, University of Castilla—La Mancha, Albacete, Spaina; Institute for Medical Microbiology and German National Reference Center for Systemic Mycoses, University Medical Center Göttingen, Göttingen, Germanyb; Public Health Research Institutec and Department of Microbiology and Molecular Genetics,d New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA P athogenic fungi are an important cause of superficial mucosal and disseminated infections in humans. In the nosocomial setting, invasive fungal infections, which are difficult to diagnose, are increasingly common and cause high morbidity and mortality. Those most frequently occurring are infections caused by Candida spp. (candidiasis), but many other species, including Cryptococcus neoformans, Aspergillus fumigatus, and dimorphic fungi causing endemic mycoses (e.g., Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Paracoccidioides brasiliensis), are medically important (1). Candida albicans is the most frequent cause of candidiasis, but in recent years non-albicans species have caused significant disease. Candida glabrata, for example, in some studies has been encountered in 20 to 24% of the human bloodstream infections that were caused by Candida (2, 3). One of the striking characteristics of Candida spp. and other pathogenic fungi is their ability to adhere tightly to different surfaces, including the human skin, and to endothelial and epithelial mucosal host tissues. Adhesion is considered an important first step in the establishment of fungal infections. Candida spp. also stick to inert abiotic surfaces such as intravascular and urinary catheters, prosthetic cardiac valves, and denture prostheses (4, 5). In addition, interaction between Candida, a normal inhabitant of the human microflora, and other host microbes as well as between different Candida cells (“flocculation”) occurs. Altogether, this may result in the formation of large surface-attached multi- or monospecies communities, designated biofilms. This form of Candida growth is a significant medical problem due to reduced susceptibility to antifungal substances of cells inside biofilms (6). Both C. albicans and C. glabrata owe their success as a pathogen, in part, to a large repertoire of adhesins present on the cell surface (7–9). Fungal adhesins have been recognized as major virulence factors that contribute to pathogenesis of these organisms (10–14). The main focus of this review is on the biosynthesis, structure, and function of adhesins reported in pathogenic Candida spp. However, adhesion in additional pathogenic fungi is starting to be addressed, and, where data already exist, adhesins from other fungal pathogens are also discussed. Comparisons are made with studies in the model yeast Saccharomyces cerevisiae, which contains proteins that are involved in flocculation and agglutination in contrast to the adhesins in pathogenic fungi that are involved in binding to host tissues or abiotic medical devices. 470 ec.asm.org Eukaryotic Cell ADHESINS ARE OUTER-SURFACE COMPONENTS OF THE FUNGAL CELL WALL The cell wall of a fungal cell is responsible for its shape and provides a number of essential functions, including protection against environmental stresses. An extensive literature exists on cell wall structure and biosynthesis of baker’s yeast, C. albicans, and some other species (15–20). Approximately 60 to 70% of the total cell wall mass in Candida spp. is accounted for by the carbohydrates ␤-1,3- and ␤-1,6-glucan and chitin. In addition, the cell walls of many fungi, including Candida spp., contain a diversity of glycoproteins. In Candida, on average about 80 to 90% of the cell wall protein mass are mannose residues added by N-glycosylation, O-glycosylation, and/or glycosylphosphatidylinositol (GPI) anchoring. The majority of the cell wall proteins are GPI proteins that are covalently bound to ␤-1,6-glucan via a remnant of their GPI anchor. These proteins are mostly present in the outer part of the cell wall, and among them are several proteins that govern primary host-pathogen interactions, such as superoxide dismutases, aspartyl proteases, phospholipases, and adhesins. Most known fungal adhesins are GPI-modified wall proteins. The primary structure of GPI protein precursors includes conserved features, which therefore can be used to identify putative adhesins by bioinformatic means. At their N terminus, they have a signal peptide for entry into the endoplasmic reticulum (ER), and at their C-terminal end they have a peptide for anchoring to a preformed GPI lipid in the membrane of the ER (Fig. 1). Mature GPI proteins lack transmembrane domains. Most known mature adhesins are large proteins (usually ⬎800 amino acids [aa]) with a modular structure; their N-terminal domain has a high complexity and mediates specific protein-protein, protein-sugar, or other protein-ligand interactions. These are believed to be largely responsible for the specific interactions with their substrates, e.g., host cell surface proteins or carbohydrates (14, 21, 22). It is followed by a variable domain of low complexity that often is rich in serine/threonine (Ser/Thr) and usually contains tandem repeats (TRs). The repeat regions are subject to significant intraspecies Published ahead of print 8 February 2013 Address correspondence to Neeraj Chauhan, . Copyright © 2013, American Society for Microbiology. All Rights Reserved. doi:10.1128/EC.00364-12 p. 470 – 481 April 2013 Volume 12 Number 4 Downloaded from http://ec.asm.org/ on November 15, 2019 by guest Understanding the pathogenesis of an infectious disease is critical for developing new methods to prevent infection and diagnose or cure disease. Adherence of microorganisms to host tissue is a prerequisite for tissue invasion and infection. Fungal cell wall adhesins involved in adherence to host tissue or abiotic medical devices are critical for colonization leading to invasion and damage of host tissue. Here, with a main focus on pathogenic Candida species, we summarize recent progress made in the field of adhesins in human fungal pathogens and underscore the importance of these proteins in establishment of fungal diseases. Minireview the latter especially taking place in the low-complexity domain, is not depicted for simplicity reasons. EtN-P, ethanolamine phosphate; Glc, glucose; GlcN, glucosamine; Man, mannose; PM, plasma membrane; PI, phosphatidylinositol. length polymorphisms due to slippage and/or recombination events during DNA replication (14, 23–25), which leads to removal or addition of repeat units. Longer repeat regions can confer greater adherence, while shorter repeat regions may result in dec (...truncated)