The nature and extent of the impairment of host defence mechanisms influence the manifestation and severity of fungal infections, such that the clinical forms of the disease depend on a patient's immune response.
Host defence mechanisms against fungi involve innate immunity and adaptive immunity. The two systems are intimately linked and controlled by sets of molecules and receptors that act to generate a highly coordinate and unitary process for protection against fungal pathogens.
It is known that host defence mechanisms influence the manifestation and severity of fungal infections, such that the clinical forms of the disease depend on a patient's immune response. For example, the host immune system is a major determinant of which particular form of disease will develop after exposure to the ubiquitous organism Aspergillus fumigatus8 or whether transition from commensalism to infection will occur with Candida albicans9,10. The host defence mechanisms against fungi are numerous, and range from protective mechanisms that were present early in the evolution of multicellular organisms ('innate immunity') to sophisticated adaptive mechanisms, which are specifically induced during infection and disease ('adaptive immunity'). The T HELPER 1 (TH1)/TH2 dichotomy has shed light on the general principle that diverse effector functions are required for eradication of different fungal infections11,12,13,14.
Traditionally considered only as a first line of defence, innate immunity has recently received renewed attention because, despite a certain lack of specificity, it effectively distinguishes self from non-self and activates adaptive immune mechanisms by the provision of specific signals15. The constitutive mechanisms of innate defence are present at sites of continuous interaction with fungi and include the barrier function of body surfaces and the mucosal epithelial surfaces of the respiratory, gastrointestinal and genito-urinary tracts (reviewed in Ref. 16). Microbial antagonism (lactobacilli and bifidobacteria have shown efficacy in the biotherapy of candidiasis), DEFENSINS and COLLECTINS indicate the marked pathogen specificity of the constitutive mechanisms17,18,19. Most host defence mechanisms, however, are inducible after infection and, therefore, their activation requires that invariant molecular structures shared by large groups of pathogens (also known as pathogen-associated molecular patterns, PAMPs) are recognized by a set of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), as discussed later.
Mammalian innate antifungal defences are mediated by cells, cellular receptors and several humoral factors. Professional phagocytes, consisting of neutrophils, mononuclear leukocytes (monocytes and macrophages) and dendritic cells (DCs) have an essential role. Natural killer (NK) cells, γδ T CELLS and non-haematopoietic cells, such as epithelial and endothelial cells, are also important16. However, their relative contributions largely depend on the site of infection. The innate response to fungi serves two main purposes: a direct antifungal effector activity by carrying out pathogen destruction through either a phagocytic process, which provides an immediate innate cellular immune response against fungi residing intracellularly, or through the secretion of microbicidal compounds against uningestible fungal elements; and an instructive role on cells of the adaptive immune system, through the production of pro-inflammatory mediators, including chemokines and cytokines, the induction of co-stimulatory activity by phagocytic cells, and antigen uptake and presentation. Although a division of labour exists among the cellular mediators of the innate system, the perception is that they might share the ability to serve both functions of the innate immune response. This might allow for full use of redundancy and compensatory mechanisms under specific conditions of infection and disease.
Several cell-wall components of fungi might act as PAMPs that are recognized by TLRs expressed by phagocytes and DCs (Fig. 1). TLR2 signalling leads to the prevalent production of inflammatory cytokines, such as tumour-necrosis factor (TNF) and IL-1β, although IL-10 is also produced occasionally24,25,26,27,28. Signalling through TLR2 by zymosan occurs together with the β-glucan receptor dectin-1 (Ref. 26), which indicates collaborative recognition of distinct microbial components by different classes of innate immune receptors. Although not formally proven, dectin-1 also seems to mediate the recognition of Pneumocystis carinii β-glucan, which is known to signal through the MYD88-dependent pathway29. It is of interest that Aspergillus hyphae, unlike CONIDIA, seem to be sensed by human monocytes through TLR4 and CD14 (Ref. 30), which indicates that TLRs discriminate between distinct fungal morphotypes. However, as Aspergillus hyphae might also evade TLR recognition31, this indicates that TLR recognition of only selected fungal morphotypes might contribute to the survival of fungi in vivo. TLR4 and CD14 also mediate the recognition of Saccharomyces cerevisiae- and C. albicans-derived mannan32 and of glucoronoxylomannan33 (a major component of the capsule of Cryptococcus neoformans). The finding that glucoronoxylomannan only partially activates TLR-dependent signal transduction pathways might account for its immunosuppressive and immunodysregulatory effects on the host. Although TNF and IL-1β production in response to C. albicans might also occur in a TLR4-independent manner, resistance to infection is decreased in TLR4-deficient mice, together with the release of chemokines25. Therefore, TLR2 and TLR4 are both involved in inducing host defences to the fungus, a finding that exemplifies the recruitment of different TLRs by one microbial species. Our own studies indicate that the MYD88-dependent pathway in DCs is required for adaptive TH1-cell-mediated resistance to C. albicans and A. fumigatus34. The MYD88-dependent pathway is also essential for innate resistance to C. albicans, but not to A. fumigatus, which is in line with the unaltered handling of the fungus by MYD88-deficient macrophages35. Intriguingly, Drosophila Myd88, although required for antifungal defence, is unable to induce expression of the antifungal peptide drosomycin in the absence of other adaptors36. The contribution of individual TLRs to the immune response might vary depending on fungal species, fungal morphotypes and route of infection. For example, signalling by C. albicans essentially occurs through IL-1R (a finding that is consistent with the occurrence of IL-1 in infection16) and by A. fumigatus through TLR4, and TLR2 and TLR4 are both implicated in different ways in the control of disseminated or mucosal infections with C. albicans34.
Macrophages are a heterogeneous population of tissue-resident cells that express the machinery for antigen presentation; however, their main contribution to antifungal defence is phagocytosis and killing of fungi37,46. Not surprisingly, therefore, fungi have various mechanisms or putative virulence factors to evade phagocytosis, escape destruction and survive inside macrophages38,47,48,49,50,51. Macrophages serve as a protected environment in which the dimorphic fungi multiply and disseminate from the lungs to other organs. Histoplasma capsulatum is an example of a successful intracellular pathogen of mammalian macrophages50.
There is marked plasticity in the T-cell response to fungi. The heterogeneity of the CD4+ and CD8+ T-cell repertoire might account for the multiplicity and redundancy of effector mechanisms through which T cells participate in the control of fungal infections. These include direct antifungal activity87, release of antimicrobial peptides from CD8+ T cells88, lysis of fungus-containing phagocytes89, and effector functions resulting from dynamic interactions with T cells that express selected members of the Vβ families of the T-cell receptor90. This functional plasticity indicates the potential of vaccines in conditions of immunodeficiency, as highlighted by the ability of CD8+ T cells to compensate for CD4+ T-cell deficiency in experimental models of vaccine-induced resistance to endemic fungi91,92. The flexible programme of T cells leads to the production of many mediators, including cytokines. Due to their action on circulating leukocytes, the cytokines produced by fungus-specific T cells are instrumental in mobilizing and activating antifungal effectors, so providing prompt and effective control of infectivity after the fungus has established itself in tissues or spread to internal organs. Therefore, host resistance to fungi seems to depend on the induction of cellular immunity, mediated by T cells, cytokines and effector phagocytes (Fig. 3).
Most fungi are detected and destroyed within hours by innate defence mechanisms mediated by phagocytes and opsonins through the involvement of distinct pattern-recognition receptors (PRRs). These mechanisms act immediately and are followed some hours later by an early induced inflammatory response, which must be activated by infection but does not generate lasting protective immunity. These early phases help to keep infection under control. In vertebrates, however, if the infectious organism can breach these early lines of defence, an adaptive immune response will ensue, with the generation of antigen-specific T helper (TH) effector cells, regulatory T (TReg) cells and B cells that specifically target the pathogen and induce memory cells that prevent subsequent infection with the same microorganism. Dendritic cells sample fungi at the site of colonization/infection, transport them to the draining lymph nodes and activate disparate TH and TReg cells in a morphotype- and tissue-dependent manner. As the different TH-cell subsets release a distinct panel of cytokines, capable of delivering activating and inhibitory feedback signals to effector phagocytes, the activation of the appropriate TH-cell subset is instrumental in the generation of a successful immune response to fungi. Counter-regulatory TReg cells might serve to dampen the excessive inflammatory reactions and contribute to the development of memory antifungal immunity. Solid and broken lines refer to positive and negative signals, respectively. IFN-γ, interferon-γ; IL, interleukin; TCR, T-cell receptor; TGF-β, transforming growth factor-β; TNF, tumour-necrosis factor. 2b1af7f3a8