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Chapter 17 : Reactive Oxygen Intermediates, pH, and Calcium
Category: Clinical Microbiology; Fungi and Fungal Pathogenesis
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Reactive oxygen intermediates (ROIs), pH exacerbations, and calcium fluxes can act together to effect fungal killing at the level of the phagocyte; therefore, resilience in the face of rapid environmental alterations is necessary to promote fungal survival within the susceptible host. With such goals in mind the scientific community has pursued an understanding of innate immune defenses against Aspergillus fumigatus spores and hyphae. The threat posed by ROIs to cellular structures and functions is an unavoidable consequence of anaerobic respiration; thus, aerobic organisms have evolved mechanisms to neutralize ROIs resulting from normal physiological processes. The search for an antimicrobial mechanism such as superoxide production by phagocytic cells, had been prompted by several observations. First, dramatic increases in neutrophil oxygen uptake had been observed during phagocytosis of multiple microorganisms. Second, the occurrence of superoxide dismutase enzymes, which provide a cellular defense against the harmful effects of superoxide, was evident in aerobic but not in anaerobic cells. Finally, myeloperoxidase (MPO)-catalyzed peroxidation of halides failed to fully account for the microbicidal activity of leukocytes, as evidenced by the largely asymptomatic presentation of congenital MPO deficiency in humans, suggesting an alternative mechanism of oxygen-dependent microbial killing. A rise in intracellular calcium is not required for uptake of microorganisms through phagocytosis, but it is necessary for killing of ingested prey. Under circumstances in which A. fumigatus escapes from the phagocytic vacuole, appropriate adaptation to the impaired phagolysosomal environment is an important aspect of survival in the host.
Four-step reduction of molecular oxygen and resulting ROIs. The Lewis dot diagram depicts the stepwise reduction of O2. Complete reduction of molecular oxygen to water involves the addition of four protons and four electrons. The hydroxyl radical is the strongest ROI, being capable of indiscriminate oxidation of organic compounds such as biological macromolecules.
ROI production during phagocytosis. Shown is a schematic view of an A. fumigatus spore during phagocytosis and concomitant generation of ROIs. The spatially segregated NADPH-oxidase molecular components gp91 phox , p22 phox ,p67 phox , p47 phox , p40 phox , and p21 rac -GTP (represented by ovals) assemble into an active NADPH-oxidase complex in the phagosomal membrane of activated phagocytes. Transfer of electrons from cytosolic NADPH to dissolved molecular oxygen at the cell surface (and/or in the forming phagolysosome) generates the highly unstable superoxide anion (O2 -). Dismutation of superoxide (via superoxide dismutase [SOD]) generates hydrogen peroxide (H2O2), a progenitor of HOCl (via MPO-mediated halide oxidation), singlet oxygen (1O2), and hydroxyl radicals (OH7). Microbicidal enzymes are delivered to the phagosome from subcellular organelles called granules, coincident with, or soon after, the phagocytic event.
Schematic representation of plasma and endosomal membrane associations with pH signaling and ESCRT complexes. Molecules having demonstrated roles in pH signaling in S. cerevisae are shaded dark gray. Those leading to partially constitutive pH signaling in S. cerevisiae are shaded light gray. Links between ESCRTs are not shown.