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Exploring Iron Withholding by the Innate Immune Protein Human Calprotectin.

ABSTRACT: Calprotectin (CP) is a versatile player in the metal-withholding innate immune response, a process termed "nutritional immunity." CP is a heterooligomer of the polypeptides S100A8 and S100A9 and houses two transition-metal-binding sites at its S100A8/S100A9 heterodimer interface. During infection, CP is released from host cells and sequesters "bioavailable" transition metal ions in the extracellular space, thereby preventing microbial acquisition of these essential nutrients. For many years, the role of CP in nutritional immunity was interpreted in the contexts of Mn(II) and Zn(II) limitation, but recent work has broadened our understanding of its contributions to this process. We uncovered that CP provides a form of nutritional immunity that has previously received little attention: the battle between host and microbe for ferrous iron (Fe(II)). In this Account, we present our current understanding of Fe(II) coordination by CP and its role in Fe(II) withholding as well as considerations for future discovery. Nutritional immunity was first described in the context of host-microbe competition for ferric iron (Fe(III)). The battle for Fe(II) has received comparably little attention because the abundance of Fe(II) at infection sites and the importance of Fe(II) acquisition for microbial pathogenesis were recognized only recently. Several years ago, we discovered that human CP sequesters Fe(II) at its His6 site with subpicomolar affinity and thus hypothesized that it provides a means for Fe(II) limitation by the host during microbial infection. Fe(II) coordination by CP is unprecedented in biology because of its novel hexahistidine coordination sphere and its high-affinity binding, which surpasses that of other known Fe(II)-binding proteins. CP is also capable of shifting the Fe redox equilibrium by stabilizing Fe(II) in aerobic solution and can thereby sequester Fe in both reducing and nonreducing environments. These coordination chemistry studies allowed us to hypothesize that CP provides a means for Fe(II) limitation by the host during microbial infection. While investigating this putative Fe(II)-sequestering function, we discovered that CP withholds Fe from diverse bacterial pathogens. Recent studies by our lab and others of the bacterial pathogens Pseudomonas aeruginosa and Acinetobacter baumannii have shown that, by preventing sufficient Fe acquisition, CP induces Fe starvation responses in these organisms. As a result, CP affects bacterial virulence and metabolism. We also elucidated a complex interplay between CP and secondary metabolites produced by P. aeruginosa during the competition for Fe. Our work provides a foundation for understanding how CP affects Fe homeostasis during microbial infection. We believe that understanding how bacterial physiology is altered when challenged with Fe(II) withholding by CP will likely reveal crucial determinants of bacterial survival within the host.

SUBMITTER: Zygiel EM

PROVIDER: S-EPMC6702060 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Exploring Iron Withholding by the Innate Immune Protein Human Calprotectin.

Zygiel Emily M EM Nolan Elizabeth M EM

Accounts of chemical research 20190805 8

Calprotectin (CP) is a versatile player in the metal-withholding innate immune response, a process termed "nutritional immunity." CP is a heterooligomer of the polypeptides S100A8 and S100A9 and houses two transition-metal-binding sites at its S100A8/S100A9 heterodimer interface. During infection, CP is released from host cells and sequesters "bioavailable" transition metal ions in the extracellular space, thereby preventing microbial acquisition of these essential nutrients. For many years, the ...[more]

PMID: 31381301

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Project description:To combat infections, the mammalian host limits availability of essential transition metals such as iron (Fe), zinc (Zn), and manganese (Mn) in a strategy termed "nutritional immunity." The innate immune protein calprotectin (CP) contributes to nutritional immunity by sequestering these metals to exert antimicrobial activity against a broad range of microbial pathogens. One such pathogen is Pseudomonas aeruginosa, which causes opportunistic infections in vulnerable populations, including individuals with cystic fibrosis. CP was previously shown to withhold Fe(II) and Zn(II) from P. aeruginosa and induce Fe and Zn starvation responses in this pathogen. In this work, we performed quantitative, label-free proteomics to further elucidate how CP impacts metal homeostasis pathways in P. aeruginosa. We report that CP induces an incomplete Fe starvation response, as many Fe-containing proteins that are repressed by Fe limitation are not affected by CP treatment. The Zn starvation response elicited by CP seems to be more complete than the Fe starvation response and includes increases in Zn transporters and Zn-independent proteins. CP also induces the expression of membrane-modifying proteins, and metal depletion studies indicate this response results from the sequestration of multiple metals. Moreover, the increased expression of membrane-modifying enzymes upon CP treatment correlates with increased tolerance to polymyxin B. Thus, the response of P. aeruginosa to CP treatment includes both single- and multimetal starvation responses and includes many factors related to virulence potential, broadening our understanding of this pathogen's interaction with the host. IMPORTANCE Transition metal nutrients are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed "nutritional immunity." While multimetal depletion by the host is appreciated, the majority of studies have focused on individual metals. Here, we use the innate immune protein calprotectin (CP), which complexes with several metals, including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogen Pseudomonas aeruginosa to investigate multimetal starvation. Using an unbiased label-free proteomics approach, we demonstrate that multimetal withholding by CP induces a regulatory response that is not merely additive of individual metal starvation responses, including the induction of lipid A modification proteins.

Dataset Information

Exploring Iron Withholding by the Innate Immune Protein Human Calprotectin.

Publications

Exploring Iron Withholding by the Innate Immune Protein Human Calprotectin.

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