title: Protective role of the neuropeptide urocortin II against experimental sepsis and leishmaniasis by direct killing of pathogens.
abstract: We currently face an alarming resurgence in infectious diseases characterized by antimicrobial resistance and therapeutic failure. This has generated the urgent need of developing new therapeutic approaches that include agents with nontraditional modes of action. A recent interest focused on approaches based on our natural immune defenses, especially on peptides that combine innate antimicrobial activity against diverse pathogens and immunoregulatory functions. In this study, to our knowledge, we describe for the first time the antimicrobial activity of the neuropeptide urocortin II (UCNII) against a panel of Gram-positive and Gram-negative bacteria and tropical parasites of the genus Leishmania. Importantly, this cytotoxicity was selective for pathogens, because UCNII did not affect mammalian cell viability. Structurally, UCNII has a cationic and amphipathic design that resembles antimicrobial peptides. Using mutants and UCNII fragments, we determined the structural requirements for the interaction between the peptide and the surface of pathogen. Following its binding to pathogen, UCNII caused cell death through different membrane-disrupting mechanisms that involve aggregation and membrane depolarization in bacteria and pore formation in Leishmania. Noteworthily, UCNII killed the infective form of Leishmania major even inside the infected macrophages. Consequently, UCNII prevented mortality caused by polymicrobial sepsis and ameliorated pathological signs of cutaneous leishmaniasis. Besides its presence in body physical and mucosal barriers, we found that innate immune cells produce UCNII in response to infections. Therefore, UCNII could be considered as an ancient highly-conserved host peptide involved in the natural antimicrobial defense and emerge as an attractive alternative to current treatments for microbial disorders with associated drug resistances.
authors.affiliation: Institute of Parasitology and Biomedicine "López-Neyra," Spanish National Research Council, Granada 18016, Spain;
authors.forename: Jenny
authors.initials: J
authors.lastname: Campos-Salinas
authors.forename: Marta
authors.initials: M
authors.lastname: Caro
authors.forename: Antonio
authors.initials: A
authors.lastname: Cavazzuti
authors.forename: Irene
authors.initials: I
authors.lastname: Forte-Lago
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
authors.forename: Francisco
authors.initials: F
authors.lastname: O'Valle
authors.forename: Elena
authors.initials: E
authors.lastname: Gonzalez-Rey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D007113:Immunity, Innate; D007416:Intestinal Perforation / Q000150:complications / Q000382:microbiology; D007891:Leishmania / Q000187:drug effects* / Q000648:ultrastructure; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D008070:Lipopolysaccharides / Q000737:chemistry; D008264:Macrophages / Q000469:parasitology; D008564:Membrane Potentials / Q000187:drug effects; D008807:Mice, Inbred BALB C; D016982:Micrococcus luteus / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010538:Peritonitis / Q000209:etiology / Q000382:microbiology; D011485:Protein Binding; D011487:Protein Conformation; D044205:Pseudomonas pseudoalcaligenes / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology; D013295:Streptococcus mutans / Q000187:drug effects; D054832:Urocortins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D010446:Peptide Fragments; C576814:UCN protein, human; C426705:UCN2 protein, human; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone