Abstract: The mammalian innate immune system provides non-specific and immediate responses to microbial invasion, constituting a primitive defense mechanism that modulates host/pathogen interactions and prevents the onset of disease. Ribosomally-synthesized antimicrobial peptides are ubiquitous components of the innate immune response, protecting mucosal surfaces from bacterial invasion. Following release into the extracellular space, many antimicrobial peptides exert non-specific antibacterial action by penetrating and disrupting the outer membranes of bacterial cells. We believe that additional and unrecognized roles for these peptides exist and we are motivated to elucidate how antimicrobial peptides contribute to host physiology prior to their extracellular release. Based on structures and cellular localizations, we hypothesize that select antimicrobial peptides are key players in regulating zinc homeostasis. A central goal of this proposal is to identify and investigate synergies between ribosomal peptide-based antibiotics and zinc at the molecular and physiological levels. We present a multifaceted experimental program that draws upon inorganic chemistry and cell biology to (i) address interactions between peptides, metal ions, other biomolecules and putative cellular targets, and (ii) decipher the downstream physiological consequences for the host and microbial pathogens. This initiative is significant and innovative because it provides a completely new framework for considering antimicrobial peptides and metal ion stores, that latter of which are essential but oftentimes overlooked in the contexts of the immune response and antibacterial therapeutic development. These studies will enhance our understanding of fundamental mechanisms that underlie metal ion physiology and the host/pathogen interaction and thereby impact the fields of biomedicine, medicinal chemistry, and public health. ) Public Health Relevance: This research initiative lies at the chemistry/biology/medicine interface, addresses fundamental mechanisms of human innate immunity and mucosal defense, and seeks to establish unrecognized connections between antimicrobial peptides and zinc biology. The outcomes of the proposed investigations will afford important new insights into the mammalian immune response, the host/pathogen interaction, and metal ion physiology. This basic research is relevant to public health;elucidating the chemistry and biology that underlies physiology is essential for improving our understanding of human health and combating disease.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZGM1-NDIA-O (01))
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Basavappa, Ravi
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Chairatana, Phoom; Nolan, Elizabeth M (2017) Human ?-Defensin 6: A Small Peptide That Self-Assembles and Protects the Host by Entangling Microbes. Acc Chem Res 50:960-967
Chairatana, Phoom; Nolan, Elizabeth M (2017) Defensins, lectins, mucins, and secretory immunoglobulin A: microbe-binding biomolecules that contribute to mucosal immunity in the human gut. Crit Rev Biochem Mol Biol 52:45-56
Shabab, Mohammed; Arnold, Markus F F; Penterman, Jon et al. (2016) Disulfide cross-linking influences symbiotic activities of nodule peptide NCR247. Proc Natl Acad Sci U S A 113:10157-62
Chairatana, Phoom; Chu, Hiutung; Castillo, Patricia A et al. (2016) Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human ?-Defensin Peptide. Chem Sci 7:1738-1752
Stephan, Jules R; Nolan, Elizabeth M (2016) Calcium-induced Tetramerization and Zinc Chelation Shield Human Calprotectin from Degradation by Host and Bacterial Extracellular Proteases. Chem Sci 7:1962-1975
Nakashige, Toshiki G; Stephan, Jules R; Cunden, Lisa S et al. (2016) The Hexahistidine Motif of Host-Defense Protein Human Calprotectin Contributes to Zinc Withholding and Its Functional Versatility. J Am Chem Soc 138:12243-51
Cunden, Lisa S; Gaillard, Aleth; Nolan, Elizabeth M (2016) Calcium Ions Tune the Zinc-Sequestering Properties and Antimicrobial Activity of Human S100A12. Chem Sci 7:1338-1348
Gagnon, Derek M; Brophy, Megan Brunjes; Bowman, Sarah E J et al. (2015) Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysis. J Am Chem Soc 137:3004-16
Chileveru, Haritha R; Lim, Shion A; Chairatana, Phoom et al. (2015) Visualizing attack of Escherichia coli by the antimicrobial peptide human defensin 5. Biochemistry 54:1767-77
Nakashige, Toshiki G; Zhang, Bo; Krebs, Carsten et al. (2015) Human calprotectin is an iron-sequestering host-defense protein. Nat Chem Biol 11:765-71

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