SUMMARY Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like Zn. The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7 and the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H+ channel function and triggered reactive oxygen species (ROS) generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function.

The dramatic increase in fungal diseases in recent years can be attributed to the increased aggressiveness of medical therapy and other human activities. Immunosuppressed patients are at risk of contracting fungal diseases in healthcare settings and from natural environments. Increased prescribing of antifungals has led to the emergence of resistant fungi, resulting in treatment challenges. These concerns, together with the elucidation of the mechanisms of protective immunity against fungal diseases, have renewed interest in the development of vaccines against the mycoses. Most research has used murine models of human disease and, as we review in this article, the knowledge gained from these studies has advanced to the point where the development of vaccines targeting human fungal pathogens is now a realistic and achievable goal.For many years, the concept of developing vaccines against fungal diseases attracted little interest, but this has changed in the past fifteen years (reviewed in REFS 1-6 ) because of the dramatic increase in the incidence rates of fungal diseases worldwide. Carbohydrate and, especially, protein antigens that exert protective immunity against various fungal diseases have now been identified. Fungal carbohydrates can induce the production of antibodies that enhance host resistance in many ways and, fuelled by advances in cellular and molecular biology, numerous fungal proteins that trigger T-cell-mediated immunity and that are immunogenic in murine models of fungal disease have been identified (TABLE 1). A vaccine based on one or more of these candidate antigens could prevent disease by inducing protective antibodies, T-cell-mediated immunity or a combination of both of these aspects of the host immune response. In this Review, we will assess the state of fungal vaccine development, both prophylactic and therapeutic. Overview of the immune response to fungiSuccessful resolution of the diseases caused by pathogenic fungi is crucially dependent on the coordinated interactions of many constituents of the host immune response. The host response to these organisms varies, as would be expected for such a heterogeneous group of pathogens, which differ morphologically, genetically and biochemically. Therefore, the effector molecules and cells that are important for combating opportunistic fungi such as Candida and Aspergillus spp. are less important for primary pathogens such as Coccidioides spp. and Histoplasma capsulatum (BOX 1). The innate response to fungiAs with all pathogens, the innate immune system is a crucial determinant in the antifungal response (FIG. 1) The non-cellular effectors of innate immunity comprise collectins, complement and natural antibodies. These molecules mediate opsonization and therefore promote the ingestion of fungi by phagocytes. One member of the collectin family, pentraxin 3, is necessary for the response to Aspergillus spp. 23 , and the pulmonary collectins surfactant proteins A and D not only cause aggregation of fungi but also have fungicidal activity ...

Only a handful of the more than 100,000 fungal species on our planet cause disease in humans, yet the number of life-threatening fungal infections in patients has recently skyrocketed as a result of advances in medical care that often suppress immunity intensely. This emerging crisis has created pressing needs to clarify immune defense mechanisms against fungi, with the ultimate goal of therapeutic applications. Herein, we describe recent insights in understanding the mammalian immune defenses deployed against pathogenic fungi. The review focuses on adaptive immune responses to the major medically important fungi and emphasizes how dendritic cells and subsets in various anatomic compartments respond to fungi, recognize their molecular patterns, and signal responses that nurture and shape the differentiation of T cell subsets and B cells. Also emphasized is how the latter deploy effector and regulatory mechanisms that eliminate these nasty invaders while also constraining collateral damage to vital tissue.