The Innate Immunity The Art of Microbe Sensing and Shaping of Specific Immunity

The innate immune system distinguishes self from nonself and activates adaptive immune mechanisms by provision of specific signals. The constitutive mechanisms of defense 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 genitourinary tracts. Microbial antagonism (lactobacilli and bifidobacteria have shown efficacy in the biotherapy of candidiasis, i.e. probiotics), defensins, and collectins comprise the major constitutive mechanisms of fungal immunity (Romani, 2004a).

Antigen-independent recognition of fungi by the innate immune system leads to the immediate mobilization of immune effector and regulatory mechanisms that provide the host with three crucial survival advantages: (i) rapid initiation of the immune response and creation of the inflammatory and co-stimulatory environment for antigen recognition; (ii) establishment of a first line of defense, which holds the pathogen in check during the maturation of the adaptive immune response; and (iii) steering of the adaptive immune response towards the cellular or humoral elements that are most appropriate for protection against the specific pathogen. Therefore, in order to achieve optimal activation of antigen-specific adaptive immunity, it is first necessary to activate the pathogen-detection mechanisms of the innate immune response.

The bulwark of the mammalian innate antifungal defense system is built upon effector mechanisms mediated by cells, cellular receptors, and a number of humoral factors (Romani, 2004a; Mansour & Levitz, 2002). The professional phagocytes, consisting of polymorphonuclear leukocytes (neutrophils), mononuclear leukocytes (monocytes and macrophages) and DC play an essential role. The antifungal effector functions of phagocytes include fungicidal and growth-inhibiting mechanisms, as well as processes to resist fungal infectivity, including inhibitory effects on dimorphism and promotion of phenotypic switching. The optimal restriction of fungal growth occurs via a combination of oxidative and complementary nonoxida-tive mechanisms, the latter consisting of intracellular or extracellular release of effector molecules, defensins, neutrophil cationic peptides, and iron sequestration. Enzymes such as the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and inducible nitric oxide synthase initiate the oxidative pathways known as the respiratory burst. Myeloperoxidase, a lysosomal hemoprotein found in azurophilic granules of neutrophils and monocytes, but not macrophages, is also a mediator in the oxygen-dependent killing of fungi. Patients with inherited X-linked chronic granulomatous disease (CGD), resulting from a deficiency in formation of activated oxygen radicals due to an NADPH-oxidase deficiency, have increased susceptibility to aspergillosis (Segal et al., 2000). However, transplantation of bone marrow cells transfected with the NADPH-oxidase gene has been shown to restore fungicidal activity of CGD patients (Barese et al., 2004). Myeloperoxidase deficiency predisposes to pulmonary candidiasis and aspergillosis, although it has not been shown to play an isolated role in fungal host defense in the absence of the NADPH oxidase.

The fact that both quantitative and qualitative defects of neutrophils are associated with an undue susceptibility to major disseminated fungal infections points to the important role that neutrophils play in the protective immunity to fungal diseases (Romani, 2004a; Fradin et al., 2006). Their functions may well go beyond microbicidal activity, and also include an immunoregulatory role in adaptive immunity (Romani et al., 1996). Myeloid suppressor cells are responsible for the immunosuppression observed in pathologies as dissimilar as tumor growth, immunosuppression, overwhelming infections, graft-versus-host disease, and pregnancy.

The reciprocal relationship of neutrophils and T lymphocytes further implies that the immune resistance to fungi is a highly coordinated and unitary process.

Macrophages are a heterogeneous population of tissue resident cells possessing the machinery for antigen presentation; however, their main contribution to antifungal defense is through phagocytosis and killing of fungi and immunomodulation (Vazquez-Torres & Balish, 1997; Cortez et al., 2006). Not surprisingly, therefore, fungi have exploited a variety of mechanisms or putative virulence factors to evade phagocytosis, escape destruction and survive inside macrophages (Woods, 2003; Alvarez & Casadevall, 2006). Macrophages serve as a protected environment in which the dimorphic fungi multiply and disseminate from the lung to other organs. H. capsulatum is a teaching example of a successful intracellular pathogen of mammalian macrophages.

Humoral factors contribute to and enhance the innate defense mechanisms. Mannose-binding protein or lectins (MBL), collectins, complement (a group of proteins activated in cascading fashion) and antibodies promote binding (opsonization) of the fungal organism and represent a recognition mechanism carried out by a variety of receptors and PRR that have a hierarchical organization. The collectin pentraxin 3 has shown a nonredundant role in antifungal resistance to A. fumigatus by promoting conidial recognition and phagocytosis, as well as activation of effector phagocytes (Garlanda et al., 2002). The specific biological activities of the complement system and antibodies, which contribute to host resistance are multifaceted and interdependent (Romani & Kaufmann, 1998 and references therein). For example, antibodies greatly contribute to the activation of the complement system by fungi and complement is essential for antibody-mediated protection. Each receptor on phagocytes not only mediates distinct downstream intracellular events related to clearance, but it also participates in complex and disparate functions related to immunomodulation and activation of immunity, depending on cell type. The receptors below are teaching examples. Engagement of CR3 (also known as CD11b/CD18) is one most efficient means of engulfing opsonized fungi, but it also has the remarkable characteristic of a broad recognition capacity of diverse fungal ligands. The multiplicity of binding sites and the existence of different activation states enable CR3 to engage in disparate (positive and negative) effector activities against fungi. Thus, because signaling through CR3 may not lead to phagocyte activation without the concomitant engagement of receptors for the Fc portion of immunoglobulins (FcR), this may contribute to intracellu-lar fungal parasitism. It is of interest, therefore, that H. capsulatum uses this receptor for entry into macrophages, where it survives, and not into DC, where it is rapidly degraded. Likewise, Candida exploits entry through CR3 to survive inside DC. In contrast, ligation of FcR is usually sufficient to trigger phagocytosis, a vigorous oxidative burst, and the generation of pro-inflammatory signals. Ultimately, recognition of antibody-opsonized particles represents a high-level threat.

The absence of an association between deficits in antibodies and susceptibility to fungal infections and the presence of specific antibodies in patients with progressive fungal infections have been the main arguments against a protective role of antibodies in fungal infections. Recent advances have demonstrated that both protective and nonprotective antibodies against fungi can be demonstrated, the relative composition and proportion of which may vary greatly in infections (Cassone et al., 2005). As a matter of fact, antibodies to HSP90 are associated with recovery from C. albicans infections, protection against disseminated disease in patients with AIDS, and synergize with antifungal chemotherapy (Pachl et al., 2006). Complement, antibodies and collectins not only fulfill the requirement of a first line of defense against fungi, but have also an impact on the inflammatory and adaptive immune responses, through several mechanisms, including regulation of cytokine secretion by and costimulatory molecule expression on phagocytes. The local release of these effector molecules regulates cell trafficking in various types of leukocytes, thus initiating an inflammatory response, activates phagocytic cells to a microbicidal state, and directs Th/Treg-cell development (Romani, 2004b).

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