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Author (up) Mozzi, A.; Forni, D.; Clerici, M.; Cagliani, R.; Sironi, M. url  doi
  Title The Diversity of Mammalian Hemoproteins and Microbial Heme Scavengers Is Shaped by an Arms Race for Iron Piracy Type Journal Article
  Year 2018 Publication Frontiers in Immunology Abbreviated Journal Front Immunol  
  Volume 9 Issue Pages 2086  
  Keywords Animals; Bacterial Proteins/*chemistry/metabolism; Cation Transport Proteins/*chemistry/metabolism; Haemophilus influenzae/chemistry/metabolism; Haptoglobins/*chemistry/metabolism; Hemopexin/*chemistry/metabolism; Humans; Iron/*chemistry/metabolism; Neisseria meningitidis/chemistry/metabolism; Protozoan Proteins/*chemistry/metabolism; Receptors, Cell Surface/*chemistry/metabolism; Staphylococcus aureus/chemistry/metabolism; Trypanosoma brucei brucei/chemistry/metabolism; *hemoglobin; *hemopexin; *iron piracy; *nutritional immunity; *positive selection  
  Abstract Iron is an essential micronutrient for most living species. In mammals, hemoglobin (Hb) stores more than two thirds of the body's iron content. In the bloodstream, haptoglobin (Hp) and hemopexin (Hpx) sequester free Hb or heme. Pathogenic microorganisms usually acquire iron from their hosts and have evolved complex systems of iron piracy to circumvent nutritional immunity. Herein, we performed an evolutionary analysis of genes coding for mammalian heme-binding proteins and heme-scavengers in pathogen species. The underlying hypothesis is that these molecules are engaged in a molecular arms race. We show that positive selection drove the evolution of mammalian Hb and Hpx. Positively selected sites in Hb are located at the interaction surface with Neisseria meningitidis heme scavenger HpuA and with Staphylococcus aureus iron-regulated surface determinant B (IsdB). In turn, positively selected sites in HpuA and IsdB are located in the flexible protein regions that contact Hb. A residue in Hb (S45H) was also selected on the Caprinae branch. This site stabilizes the interaction with Trypanosoma brucei hemoglobin-haptoglobin (HbHp) receptor (TbHpHbR), a molecule that also mediates trypanosome lytic factor (TLF) entry. In TbHpHbR, positive selection drove the evolution of a variant (L210S) which allows evasion from TLF but reduces affinity for HbHp. Finally, selected sites in Hpx are located at the interaction surface with the Haemophilus influenzae hemophore HxuA, which in turn displays fast evolving sites at the Hpx-binding interface. These results shed light into host-pathogens conflicts and establish the importance of nutritional immunity as an evolutionary force.  
  Address Scientific Institute, IRCCS E. Medea, Bioinformatics, Lecco, Italy  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1664-3224 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:30271410 Approved no  
  Call Number Medea @ manuela.sironi @ Serial 46105  
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