Nutritional immunity: transition metals at the pathogen-host interface

Abstract

Transition metals occupy an essential niche in biological systems. Their electrostatic properties stabilize substrates or reaction intermediates in the active sites of enzymes, and their heightened reactivity is harnessed for catalysis. However, this heightened activity also renders transition metals toxic at high concentrations. Bacteria, like all living organisms, must regulate their intracellular levels of these elements to satisfy their physiological needs while avoiding harm. It is therefore not surprising that the host capitalizes on both the essentiality and toxicity of transition metals to defend against bacterial invaders. This Review discusses established and emerging paradigms in nutrient metal homeostasis at the pathogen-host interface.

Figure 1. Fe limitation and Fe acquisition during bacterial infections

a. Overview of Fe limitation strategies in the vertebrate host. Fe³⁺ is stored intracellularly in complex with ferritin (F), bound by serum transferrin (TF) or bound by lactoferrin (LTF) at mucosal surfaces. In the blood, Fe²⁺ is complexed with haem, which is bound by haemoglobin within red blood cells (RBCs). Upon red cell lysis, haemoglobin is bound by haptoglobin (Hpt) and free haem is scavenged by haemopexin (Hpx). In addition to these haem-binding proteins, neutrophil gelatinase-associated lipocalin (NGAL) binds and sequesters bacterial siderophores. b. Representative Fe acquisition systems expressed by Gram-negative and Gram-positive pathogens. Both Gram-negative and Gram-positive pathogens possess systems to acquire Fe³⁺-siderophores, Fe²⁺-haem, Fe³⁺ from transferrin and/or free Fe²⁺. Not all systems are expressed by the same organism. TF, transferrin; SIP, siderophore interacting protein; HO, haem oxygenase; Hpt, haptoglobin; OM, outer membrane; P, periplasm; IM, inner membrane; CW, cell wall; CM, cytoplasmic membrane.

Figure 2. Mn and Zn homeostasis at the pathogen-host interface

a. Zn²⁺ and Mn²⁺ sequestration by S100 family proteins at epithelial surfaces and within tissue abscesses. S100A7 is released at epithelial surfaces, where it inhibits bacterial invasion through chelation of Zn²⁺. In deep tissues, infection leads to recruitment of neutrophils, which deliver calprotectin (S100A8/A9) to the infection site. Calprotectin inhibits bacterial growth through chelation of Mn²⁺ and Zn²⁺ and is thought to be transported away from the abscess by an as-yet-unknown mechanism. Engulfment of bacteria by macrophages leads to decreased Zn²⁺ uptake and increased Zn²⁺ efflux from the cytoplasm and efflux of Mn²⁺ and Fe from the phagosome by NRAMP1. b. Representative Mn²⁺ and Zn²⁺ uptake systems expressed by pathogenic bacteria. c. Proposed mechanisms of Zn²⁺ intoxication employed by the host and Zn²⁺ detoxification systems expressed by pathogens. Upon infection, Zn accumulates in the phagolysosome where it is toxic to bacteria. Gram-negative and Gram-positive bacteria primarily alleviate Zn toxicity through efflux of excess Zn from the cytoplasm. d. Proposed mechanism for Zn toxicity in bacteria. When the extracellular Zn²⁺: Mn²⁺ ratio is high, Zn²⁺ binds the SBP of Mn²⁺-specific transporters, preventing Mn²⁺ binding and uptake.

Figure 3. New insights into the roles for Cu in innate immunity

a. Mechanisms of Cu intoxication within macrophages. Following phagocytosis of bacteria, interferon gamma induces expression of the Cu⁺ importer Ctr1. Cu is bound by Atox1 and shuttled to the phagosomal Cu⁺ transporter, ATP7A. Accumulation of copper within the phagolysosome contributes to bacterial killing through multiple mechanisms including disruption of Fe-S cluster-containing bacterial proteins and possibly through the generation of reactive oxygen species. This leads to inhibition of bacterial metabolic processes and damage to DNA, proteins and lipids. b. Cu detoxification systems expressed by pathogenic bacteria. Bacteria encode multiple mechanisms to detoxify the cytoplasm or periplasm from excess Cu⁺ including expression of Cu⁺ efflux systems, periplasmic multicopper oxidases and cytoplasmic Cu chaperones. Many bacteria express several independently regulated Cu detoxification systems, which provide a graded response to Cu toxicity.

Figure 4

a | Mn²⁺ and Zn²⁺ uptake systems in pathogenic Gram-negative bacteria. b | Mn²⁺ and Zn²⁺ uptake systems in pathogenic Gram-positive bacteria. c | Proposed mechanisms of Zn²⁺ detoxification by Gram-negative pathogens. On infection, Zn²⁺ accumulates in the phagolysosome, where it is toxic to bacteria. Gram-negative bacteria alleviate this Zn²⁺ toxicity primarily through efflux of excess Zn²⁺ from the cytoplasm. d | Proposed mechanisms of Zn²⁺ and Mn²⁺ detoxification by Gram-positive pathogens. Zn²⁺ can be exported from the bacterial cytoplasm by dedicated transporters. Mn²⁺ is usually imported by the ABC family pneumococcal surface adhesin (Psa) system, but when the extracellular Zn²⁺/Mn²⁺ ratio is high, Zn²⁺ binds PsaA, the substrate-binding protein of this Mn²⁺-specific transporter, preventing Mn²⁺ binding and uptake. CDF, cation diffusion facilitator; CM, cytoplasmic membrane; IM, inner membrane; MntH, Mn transport H; OM, outer membrane; Znu, Zn uptake protein.

Figure 5

a | Mechanisms of Cu⁺ intoxication within macrophages. Following phagocytosis of bacteria, interferon-γ induces expression of the Cu⁺ importer Cu⁺ transport protein 1 (CTR1). Cu⁺ is bound by ATOX1 and shuttled to the phagosomal Cu⁺ transporter, ATP7A. Accumulation of Cu⁺ within the phagolysosome contributes to bacterial killing through multiple mechanisms, including the disruption of Fe–S cluster-containing bacterial proteins, and possibly the generation of reactive oxygen species. This leads to inhibition of bacterial metabolic processes and damage to DNA, proteins and lipids. b | Pathogenic bacteria encode multiple systems to detoxify the cytoplasm or periplasm when there is excess Cu⁺, including Cu⁺ efflux systems (such as the RND family transporter CusABC), periplasmic multicopper oxidases (such as blue Cu oxidase (CueO)) and cytoplasmic Cu⁺ chaperones (such as metallothionein (MymT)). Many bacteria express several independently regulated Cu⁺ detoxification systems, providing a graded response to Cu⁺ toxicity. CM, cytoplasmic membrane; IM, inner membrane; OM, outer membrane; TCA, tricarboxylic acid.