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 non-traditional modes of action. A recent interest focused on approaches based on our natural immune defenses, especially on peptides which combine innate antimicrobial activity against diverse pathogens and immunoregulatory functions. Here, 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. Noteworthy, UCNII killed the infective form of L. 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.

Anti-leishmanial activity of Brevinin 2R and its Lauric acid conjugate type against L. major: In vitro mechanism of actions and in vivo treatment potentials

“…donovani infection in an experimental model [ 13 ]. Other types of AMPs like Urocortin II [ 14 ] and Vasoactive Intestinal peptide (VIP) analogs, were capable of controlling infection in the cutaneous form of the disease in Balb/c mice [ 15 ]. Recently, our data about HNP1 from Defensin superfamily of AMPs also showed remarkable effect on limiting L .…”

Lulling immunity, pain, and stress to sleep with cortistatin

“…Therefore, it is plausible that CST, at least through the GHSR1, could regulate this factor. Finally, ghrelin, VIP, or urocortin have been shown to have direct antimicrobial actions in vitro and in vivo , on the basis of their structural conformation and sequence . However, CST does not show properties characteristic of host antimicrobial peptides and failed to kill a variety of bacteria (unpublished observations).…”

Peptides to Tackle Leishmaniasis: Current Status and Future Directions

“…The work of Campos-Salinas et al [ 65 ] presented the action of urocortin II in vivo. This peptide is produced in the human body as part of the innate immune system; therefore, it has a highly conserved primary structure with anti-pathogenic activity.…”