Metals as phagocyte antimicrobial effectors

Abstract

Transition metal ions are essential to bacterial pathogens and their hosts alike but are harmful in excess. In an effort to curtail the replication of intracellular bacteria, host phagocytes exploit both the essentiality and toxicity of transition metals. In the paradigmatic description of nutritional immunity, iron and manganese are withheld from phagosomes to starve microbial invaders of these nutrients. Conversely, the destructive properties of copper and zinc appear to be harnessed by phagocytes, where these metals are delivered in excess to phagosomes to intoxicate internalized bacteria. Here, we briefly summarize key players in metal withholding from intracellular pathogens, before focusing on recent findings supporting the function of copper and zinc as phagocyte antimicrobial effectors. The mechanisms of copper and zinc toxicity are explored, along with strategies employed by intracellular bacterial pathogens to avoid killing by these metals.

Figure 1.. Key metal-dependent strategies employed by phagocytes to inhibit survival of intracellular bacteria.

A schematic cartoon of the metal intoxication (left and lowercase letters) and starvation (right and uppercase letters) tactics used by the host to control the survival and replication of intracellular bacterial pathogens (green bacilli). During infection, ferroportin (Fpn; peach) is bound by hepcidin (black star), which targets Fpn for lysosomal degradation (A,B). Decreased Fpn expression leads to increased accumulation of Fe(II) within the phagocyte cytosol which, may promote growth of intracellular bacteria (C). To counteract Fe accumulation, Fpn expression is increased during intracellular infection, promoting extrusion of Fe (green circles) from the host cytosol (D). Additionally, Fe, Mn (cyan circles), and perhaps Zn (yellow circles) are effluxed from the phagosome by NRAMP1 (pink) (E). Free Zn, Cu (orange circles), and other heavy metals within the cytosol are sequestered by metallothioneins (MTs; black flowers) (F). Divalent metals in the external milieu are sequestered by calprotectin (CP; grey shapes) (G). ATP7A (yellow) associates primarily with the endoplasmic reticulum (ER) to populate cuproproteins with Cu (H). In using metal toxicity in the killing of intracellular bacteria, expression of the Cu importer CTR1 (grey) is increased, leading to Cu accumulation within the phagocyte (a). Cytosolic Cu is sequestered by the metallochaperone ATOX1 (salmon; b) and shuttled to the phagosomal membrane for transport into the vesicle by ATP7A (c). Once within the phagosome, free Cu poisons bacteria, in part through mismetallation of key metalloproteins (d). Similarly, Zn is likely transported into the phagocyte by a ZIP family importer (green; e). Cytosolic Zn is thought to be liberated from MTs through oxidative release, facilitated by phagocyte NADPH oxidase (pink; f). Zn is delivered to the phagosome by way of a ZnT family transporter (cyan; g) or through fusion with a zincosome (purple; h), where it intoxicates bacteria through mismetallation of key proteins/processes (i).