Although fungal infections contribute substantially to human morbidity and mortality, the impact of these diseases on human health is not widely appreciated. Moreover, despite the urgent need for efficient diagnostic tests and safe and effective new drugs and vaccines, research into the pathophysiology of human fungal infections lags behind that of diseases caused by other pathogens. In this Review, we highlight the importance of fungi as human pathogens and discuss the challenges we face in combating the devastating invasive infections caused by these microorganisms, in particular in immunocompromised individuals.

The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1-Syk-CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (T(H)-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of T(H)-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent T(H)-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of T(H)-17 responses to some pathogens.

Abstractβ-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for β-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for β-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like patternrecognition receptor required for the induction of protective immune responses.Infections with normally nonpathogenic fungi such as Candida albicans are an emerging problem resulting from modern medical interventions and the increasing prevalence of acquired immunodeficiency1. The high incidence of morbidity and mortality associated with such diseases, especially once the fungus has disseminated, demonstrates deficiencies in both present antifungal therapies and understanding of the host immune response. Protection against such organisms is mediated mainly by phagocytic cells that recognize, ingest and kill the invading pathogen, inducing a T helper type 1 immune response, which in turn activates fungicidal effector mechanisms, such as the respiratory burst1. Although cells such as neutrophils and macrophages are thought to be crucial in that process, the mechanism underlying the recognition and initiation of the protective responses to these pathogens remains unclear. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2007 July 01. Published The cell walls of fungi consist mainly of carbohydrates, including mannose-based structures (the mannoproteins), β-glucan and chitin. For immune systems of infected hosts, such polysaccharides serve as pathogen-associated molecular patterns (PAMPs) that can be recognized by a variety of host-expressed pattern-recognition receptors, including the Tolllike receptors (TLRs), although the precise functions of each of the myriad receptors that can respond to these pathogens and contribute to the induction of protective responses have not been fully elucidated.Historically, the cell walls of fungi were shown to be covered by a layer of mannoproteins, which prompted much interest in mannose-based recognition systems2. Subsequent evidence has suggested that this model may be too simplistic and that other PAMPs, particularly β-glucans, are exposed on the cell surface and therefore are potentially important in immune recognition3. In fungi such as C. albicans and Saccharomyces cerevisiae, β-glucans can comprise up to 50% of the dry weight of the fungal cell wall and are essential structural components that ...

The ability of fungal-derived β-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF-α in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-α in response to fungi, a critical step required for the successful control of these pathogens.

The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease (IBD). Here we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility t chemically-induced colitis, which was the result of altered responses to indigenous fungi. In humans we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together our findings reveal a novel eukaryotic fungal community in the gut (the “mycobiome”) that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.