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Chapter 10 : Signal Transduction in the Interactions of Fungal Pathogens and Mammalian Hosts
Category: Fungi and Fungal Pathogenesis
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This chapter highlights both the generalities and the unique features of signaling pathways controlling interactions between fungal pathogens and mammalian hosts. Of the common fungal pathogens of humans, Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have been the most extensively investigated. Although many different signal transduction cascades mediate responses of pathogens to their hosts, the most extensively investigated networks involve cAMP, MAPK, two-component histidine kinase (HK), pH pathways, and Ca2+/calmodulin signaling. The pathways can mediate different environmental conditions, such as temperature, stress, and presence of serum, within the different pathogens and induce different responses, including changes in cell morphology and expression of particular virulence factors. TLR2 and TLR4 appear to be the most important for the recognition of fungal pathogens. Both TLR2 and TLR4 play a role in the recognition of A. fumigatus and C. albicans, while C. neoformans, through its polysaccharide capsule consisting of glucuronoxylomannan, appears to be recognized uniquely by TLR4. The developing tools of knockout mice, genome sequences, cultured cell lines, and DNA microarrays have a profound impact on one's ability to define the interaction between mammalian host cells and fungal pathogens. The tools to address such questions are here or soon to arrive, the questions themselves are exciting and answerable, and the potential payoffs for understanding the signaling pathways in fungal pathogens are profound.
Cell types and developmental stages of the fungal pathogens C. albicans (A), C. neoformans (B), and A. fumigatus (C).
cAMP signaling pathways in C. albicans.
cAMP signaling pathways in C. neoformans.
cAMP signaling pathways in A. fumigatus.
MAPK pathways in C. albicans.
MAPK pathways in C. neoformans.
MAPK and two-component signaling pathways in A. fumigatus.
Two-component signaling pathways in C. albicans.
pH-regulatory pathways in C. albicans.
Ca2+/calcineurin signaling pathways in C. neofor-mans and C. albicans.
Recognition and TLR signaling involved in host detection and response to fungal pathogens. Many mammalian cell surface molecules are involved in the identification of fungal pathogens. These include proteins such as TLR2 and TLR4, which are connected to intracellular signaling pathways, and a variety of recognition proteins that interact primarily with components of fungal surfaces. These recognition receptors can be highly specific; recent evidence has been provided that dectin-1 on the surface of macrophages can distinguish hyphal from yeast forms of C. albicans. The signaling pathways involve protein-protein interactions; TIR domains on the TLRs interact with homologous domains on the MyD88 molecule, which in turn associates with IRAK serine/threonine kinase family members through shared motifs called death domains. Activated IRAKs signal through TRAF6 to transcription regulators such as AP1 and NF-kB. The relative importance of the surface receptors differs depending on the specific host cell type and the fungal pathogen detected.