Review
The impact of metal availability on immune function during infection

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Highlights

  • During inflammation, nutrient metals are redistributed to starve and/or intoxicate invading pathogens.

  • The availability of nutrient metals influences the response of innate immune cells to pathogens during infection.

  • Metal-sequestering proteins have pleotropic functions at the host–pathogen interface that dictate disease outcome.

Nutrient transition metals are required cofactors for many proteins to perform functions necessary for life. As such, the concentration of nutrient metals is carefully maintained to retain critical biological processes while limiting toxicity. During infection, invading bacterial pathogens must acquire essential metals, such as zinc, manganese, iron, and copper, from the host to colonize and cause disease. To combat this, the host exploits the essentiality and toxicity of nutrient metals by producing factors that limit metal availability, thereby starving pathogens or accumulating metals in excess to intoxicate the pathogen in a process termed ‘nutritional immunity’. As a result of inflammation, a heterogeneous environment containing both metal-replete and -deplete niches is created, in which nutrient metal availability may have an underappreciated role in regulating immune cell function during infection. How the host manipulates nutrient metal availability during infection, and the downstream effects that nutrient metals and metal-sequestering proteins have on immune cell function, are discussed in this review.

Introduction

The concentration of nutrient transition metals is carefully maintained to avoid both deficiency and toxicity, because nutrient metals, such as zinc, manganese, iron, and copper, are required cofactors for many proteins that are critical for life. Therefore, pathogens have evolved strategies to acquire essential transition metals from the host to colonize and cause disease. To combat pathogens, the host either accumulates metals in excess to intoxicate the pathogen or produces factors that sequester and starve the pathogen of essential metals through a process termed ‘nutritional immunity’ [1,2]. By exploiting the essentiality and toxicity of nutrient metals, the distribution of metals is altered dramatically through systemic and local changes that modulate the accessibility of metals to invading pathogens. However, immune cells must also operate in these same environments; therefore, changes in metal concentrations have an underappreciated but valuable role in regulating immune cell function during infection. In this review, we focus on the strategies in which the host manipulates nutrient metal availability, and the downstream implications that nutrient metal and metal-sequestering proteins have on immune cell function.

Section snippets

S100 proteins

S100 proteins are EF-hand calcium-binding proteins, a subset of which is released extracellularly and has a key antimicrobial role in host defense through metal sequestration. The S100 protein complex calprotectin is a heterodimer of S100A8 and S100A9 that binds and sequesters zinc, manganese, iron, and nickel [3., 4., 5.]. It is abundant in neutrophils, forming nearly 50% of the cytosolic protein content [6] and, therefore, is one of the most abundant immune proteins at the host–pathogen

Metal mobilization to combat pathogens in the phagosome

Upon engaging many pathogens, professional phagocytes internalize the pathogen into phagosomal compartments. In an effort to prevent intracellular replication within the phagosome, host phagocytes mobilize the subcellular distribution of metals to exploit both the essentiality and toxicity of nutrient metals. Zinc [62,63] and copper [64., 65., 66., 67.] are actively accumulated within the phagosomal compartment through a process referred to as the ‘brass dagger’, while iron, manganese, and

The influence of nutrient metal on immune cells

The role that nutrient transition metals play in influencing immune cell function at the host pathogen interface is complex. The impact of zinc, iron/heme, manganese, and copper, on immune cell antibacterial functions (Figure 1) and signal transduction within immune cells (Figure 2) is discussed below.

The intersection between DAMP activity and nutritional immunity

Many metal-sequestering proteins have pleotropic roles in the immune response by acting as a damage-associated molecular pattern (DAMP) and/or opsonin during infection. For example, calprotectin not only binds nutrient metals, but is also a potent DAMP that activates toll-like receptor 4 (TLR4) [156], receptor for advanced glycation end products (RAGE) [157], and CD33 [158]. As a result, it acts as a powerful chemoattractant for myeloid cells during inflammation [159,160]. The biological

Concluding remarks

The role of metals at the host–pathogen interface is complicated and many questions still exist (see Outstanding questions). While significant progress has been made to determine how zinc and iron/heme regulate immune cell function, less is understood regarding how other metals, such as manganese and copper, influence the immune response. As such, there is a significant gap in our understanding of metal biology at the host–pathogen interface. Additionally, much of the work assessing how

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