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Key Points The term dysbiosis has been used to describe disruptions of microbial communities that lead to a shift in steady-state composition that is distinct from that induced by infections. Recent work has suggested that, in addition to bacterial dysbiosis, fungal dysbiosis might contribute to the pathology of several immune-mediated conditions of non-infectious origin. Fungal dysbiosis is observed in human diseases affecting different barrier surfaces, including the mouth, vagina, skin, lungs and gut. The mucosal immune system can respond to changes in fungal communities; several antifungal immunity pathways such as C-type lectin receptors, and the IL-1β and inflammasome pathways, might have a role in sensing these fluctuations. The interaction between fungi and the host immune system has mainly been studied in the context of infection. However, fungal communities reside on the barrier surfaces of various mammals and are dynamic and responsive to environmental and pathophysiological changes. The mammalian gut is a unique site in which fungal infections are rare but fungal dysbiosis occurs frequently. Dysbiosis probably affects all communities of the microbiota, including bacterial and fungal species. Changes in the composition of the microbiota — also known as dysbiosis — are important contributors to inflammatory diseases. In this Review, the authors explore how disruptions in fungal communities can influence host immunity, and how the immune system has evolved to distinguish between fungal infection and dysbiosis. Fungi and mammals share a co-evolutionary history and are involved in a complex web of interactions. Studies focused on commensal bacteria suggest that pathological changes in the microbiota, historically known as dysbiosis, are at the root of many inflammatory diseases of non-infectious origin. However, the importance of dysbiosis in the fungal community — the mycobiota — was only recently acknowledged to have a pathological role, as novel findings have suggested that mycobiota disruption can have detrimental effects on host immunity. Fungal dysbiosis and homeostasis are dynamic processes that are probably more common than actual fungal infections, and therefore constantly shape the immune response. In this Review, we summarize specific mycobiota patterns that are associated with fungal dysbiosis, and discuss how mucosal immunity has evolved to distinguish fungal infections from dysbiosis and how it responds to these different conditions. We propose that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and that can influence health and disease.

Key Points The fungal microbiota, or 'mycobiota', is an understudied component of the microflora that is found on all mucosal surfaces and on the skin. Like other microorganisms, fungi interact with the immune system at these surfaces in ways that are important both for host defence and for regulating the immune system. Investigators who study the mycobiota face both biological and bioinformatic challenges. The study of human genetic disorders and genetic polymorphisms teaches us about the mechanisms by which commensal and pathogenic fungi interact with the immune system. Research into the role of commensal microorganisms in influencing the immune system has mainly focused on bacterial communities. Here, the authors review recent studies that highlight the importance of commensal fungi and how the immune system interacts with these communities at different body sites. The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.

Key Points Several mechanisms exist by which fungi can delay or interfere with the processes used by phagocytic cells of the innate immune system to uptake and kill invading cells. Certain fungal species escape immune capture by generating cell types, such as Titan cells, elongated tubular hyphae or sporulating structures, known as spherules, that are too large to be taken up by phagocytic cells and cannot be killed by phagocytosis. Fungal cell wall layers are highly heterogeneous and include components such as hydrophobic proteins and α-glucan that do not activate immune receptors and hence cloak other wall components that would otherwise result in detection by the host immune system. Fungal pathogens can rapidly alter the composition of their cell walls when growing in the host where they are exposed to different nutrients and environmental conditions, or when undergoing morphogenesis. This makes them a moving target for immune detection. Many fungi are able to induce their own exocytosis after they have been taken up by macrophages. The formation of hyphae by Candida albicans is induced within phagosomes and this activates a modified form of programmed cell death known as pyroptosis. This process, and the physical rupture of the phagocyte membrane by growing hyphae, can eliminate a proportion of innate immune cells that would otherwise confer protection to the host. Some fungi interfere with the mechanism of phagosome maturation, preventing or delaying the fusion of vesicles which contain microbicidal compounds that are required for fungal killing. Phagocytes can detect and eliminate fungal pathogens, but fungi have evolved several mechanisms that enable them to subvert immune recognition, uptake and killing. In this Review, Erwig and Gow detail how fungi interact with the host innate immune system and describe the mechanisms of immune evasion used by fungal pathogens to promote infection. The surveillance and elimination of fungal pathogens rely heavily on the sentinel behaviour of phagocytic cells of the innate immune system, especially macrophages and neutrophils. The efficiency by which these cells recognize, uptake and kill fungal pathogens depends on the size, shape and composition of the fungal cells and the success or failure of various fungal mechanisms of immune evasion. In this Review, we describe how fungi, particularly Candida albicans , interact with phagocytic cells and discuss the many factors that contribute to fungal immune evasion and prevent host elimination of these pathogenic microorganisms.

Key Points Candida albicans is the most important fungal pathogen in humans, and it causes both mucosal and systemic fungal infections. Innate immune recognition by pattern recognition receptors (PRRs) is the first step for activation of host defence mechanisms during Candida infections. C-type lectin receptors (CLRs) are the main family of PRRs involved in recognition of Candida species, but Toll-like receptors, NOD-like receptors and RIG-I-like receptors are also involved in the antifungal response. Neutrophils, monocytes and macrophages are the main immune cell populations responsible for host defence against systemic candidiasis, whereas T helper 1 (T H 1) cells, T H 17 cells and innate lymphoid cells are mainly responsible for protection against Candida infections at mucosal surfaces. C. albicans and components from its cell wall, particularly β-glucans, have the capacity to induce epigenetic reprogramming of innate immune cells, generating a de facto innate immune memory that has been termed 'trained immunity'. Systems biology approaches combining innovative genomic, microbiome and functional data open new possibilities for identifying key mechanisms in the pathophysiology of fungal infections. Future efforts need to combine cutting-edge molecular and cell-biological techniques with translational approaches in order to gain a better understanding of the host immune response to Candida infections and enable the design of novel antifungal strategies. This Review describes the host immune response to Candida fungal infections. The authors detail the innate and adaptive immune mechanisms, as well as the non-immune mechanisms, that are involved in the antifungal response. They also discuss emerging evidence suggesting that both innate and adaptive immune cells contribute to immune memory against Candida species. The immune response to Candida species is shaped by the commensal character of the fungus. There is a crucial role for discerning between colonization and invasion at mucosal surfaces, with the antifungal host defence mechanisms used during mucosal or systemic infection with Candida species differing substantially. Here, we describe how innate sensing of fungi by pattern recognition receptors and the interplay of immune cells (both myeloid and lymphoid) with non-immune cells, including platelets and epithelial cells, shapes host immunity to Candida species. Furthermore, we discuss emerging data suggesting that both the innate and adaptive immune systems display memory characteristics after encountering Candida species.

Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C . albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1 , is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C . albicans . This suggests that Candidalysin-induced cell damage is a third mechanism of C . albicans -mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae. Phagocytic cells of the innate immune system play critical roles in defence against invading pathogens including the opportunistic pathogen Candida albicans . Here the authors show that C . albicans derived Candidalysin in addition to being a cell-damaging toxin to mononuclear phagocytes is a trigger of NLRP3 inflammasome activation in these cells.

The C-type lectin receptor–Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans . The cytokine IL-1β served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1β and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1β, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1β and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host–pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS. Innate immunity protects the central nervous system against fungal pathogens. Lionakis and colleagues identify Candidalysin, a Candida virulence factor that elicits microglial expression of the cytokine IL-1β and chemokine CXCL1 and facilitates neutrophil recruitment. Alteration of this pathway impairs antifungal responses.

Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, β-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/β-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases. Yeast form part of the host microbiome with known impact on host immunity. Here the authors identify and investigate the impact of commensal yeast-derived polysaccharides in modulating host inflammation, and show its potential for inhibiting inflammation in a number of models of inflammatory diseases.

Immunity to pathogens critically requires pattern-recognition receptors (PRRs) to trigger intracellular signaling cascades that initiate and direct innate and adaptive immune responses. For fungal infections, these responses are primarily mediated by members of the C-type lectin receptor family. In this Review, we highlight recent advances in the understanding of the roles and mechanisms of these multifunctional receptors, explore how these PRRs orchestrate antifungal immunity and briefly discuss progress in the use of these receptors as targets for antifungal and other vaccines.

Key Points Fungi can interact with humans in multiple ways, establishing symbiotic, commensal, latent or pathogenic relationships. Although the burdens of fungal diseases may rival those of many of the best-known bacterial diseases, humans have evolved with ubiquitous or commensal fungi in host–fungus relationships that for the most part are positive or neutral. The co-evolution of humans and fungi suggests that complex mechanisms exist to allow the host immune system to respond to fungi and, likewise, that fungi have developed sophisticated mechanisms to antagonize immune responses. Indeed, fungal diseases represent an important paradigm in immunology, as they can result either from lack of recognition or from overactivation of the inflammatory response. We are entering an exciting period of transition from studying the molecular and cellular bases of the virulence of fungal pathogens to determining the mechanisms of immune adaptations that maintain homeostasis with fungi. As the immune system cannot ignore fungi, a fine balance between pro- and anti-inflammatory signals is required for a stable host–fungus relationship, the disruption of which leads to pathological consequences. Thus, the challenge for future studies is to gain a better understanding of the control of inflammation, the molecular bases of regulation and rupture, and the way in which innocuous but opportunistic fungal pathogens maintain 'friendly' relationships, or evade or subvert host inflammation. The use of multidisciplinary approaches, including functional genomics, proteomics and bioinformatics, will have important biomedical implications. These may include the identification of new susceptibility genes, the identification of more accurate biomarkers that predict inflammatory fungal disorders, and the development of multi-pronged therapeutic approaches that target specific inflammatory or metabolic end points in fungal infections and diseases. In this article, Luigina Romani describes the immune mechanisms that have evolved to recognize and respond to fungi. She explains how the failure of either pro-inflammatory or tolerogenic immune responses can lead to the development of fungal diseases. Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host−fungus interactions in mammals.

Production of the proinflammatory cytokine IL-1β is crucial in host defense. Geijtenbeek and colleagues show that dectin-1 signaling in response to fungi and mycobacteria induces IL-1β maturation via a noncanonical caspase-8-dependent inflammasome. Production of the proinflammatory cytokine interleukin 1β (IL-1β) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1β through signaling routes mediated by the kinase Syk. Whereas the CARD9–Bcl-10–MALT1 scaffold directed IL1B transcription, the recruitment of MALT1–caspase-8 and ASC into this scaffold was crucial for processing of pro-IL-1β by caspase-8. In contrast to activation of the canonical caspase-1 inflammasome, which requires additional activation of cytosolic receptors, activation of the noncanonical caspase-8 inflammasome was independent of pathogen internalization. Thus, dectin-1 acted as an extracellular sensor for pathogens that induced both IL-1β production and maturation through a noncanonical caspase-8-dependent inflammasome for protective immunity.