The principal mediators of innate immunity against fungi are neutrophils and macrophages. Patients with neutro-penia are extremely susceptible to opportunistic fungal infections. Phagocytes and dendritic cells sense fungal organisms by TLRs and lectin-like receptors called dectins (see Chapter 4). Neutrophils presumably liberate fungi-cidal substances, such as reactive oxygen species and lysosomal enzymes, and phagocytose fungi for intracel-lular killing. Virulent strains of Cryptococcus neoformans inhibit the production of cytokines such as TNF and IL-12 by macrophages and stimulate production of IL-10, thus inhibiting macrophage activation.
Cell-mediated immunity is the major mechanism of adaptive immunity against fungal infections. Histoplasma capsulatum, a facultative intracellular parasite that lives in macrophages, is eliminated by the same cellular mechanisms that are effective against intracellular bacteria. CD4+ and CD8+ T cells cooperate to eliminate the yeast forms of C. neoformans, which tend to colonize the lungs and brain in immunodeficient hosts. Many extracellular fungi elicit strong TH17 responses, which are driven in part by the activation of dendritic cells by fungal glucans binding to dectin-1, a receptor for this fungal polysac-charide, and this results in the production of TH17-inducing cytokines (IL-6, IL-23) from the dendritic cells (see Chapter 9). The TH17 cells stimulate inflammation, and the recruited neutrophils and monocytes destroy the fungi. Candida infections often start at mucosal surfaces, and cell-mediated immunity is believed to prevent spread of the fungi into tissues. TH1 responses are protective in intracellular fungal infections, such as histoplasmosis, but these responses may elicit granulomatous inflammation, which is an important cause of host tissue injury in these infections (see Chapter 18). Fungi also elicit specific antibody responses that are of protective value.
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