FIG 6.

Proposed model of zinc utilization during neutrophil killing of GAS cells. (A) Intracellular zinc toxicity within human neutrophils. GAS cells are phagocytosed into the phagosome, which fuses with the zinc-rich lysosomes to form the phagolysosome. The azurophilic granules also degranulate, releasing their contents, which include zinc, into the phagolysosome. As a consequence, a high-zinc environment is formed within the phagolysosome that results in zinc toxicity to the GAS cells. Within the phagolysosome, a zinc export-deficient mutant (ΔczcD) is unable to export the excess zinc, and hence, it will experience zinc toxicity and cell death. (B) Extracellular zinc starvation (nutritional immunity) as a result of calprotectin. The abundance of zinc-chelating calprotectin released in neutrophil extracellular traps (NETs) results in an extracellular zinc-limiting environment. GAS cells can be trapped within NETs, and a zinc import deletion mutant (ΔadcA ΔadcAII) that is unable to acquire zinc for growth will therefore experience zinc starvation and cell death.