Peptides from non-immune proteins target infections through antimicrobial and immunomodulatory properties, 2024, Torres et al.

Peptides from non-immune proteins target infections through antimicrobial and immunomodulatory properties
Marcelo D.T. Torres; Angela Cesaro; Cesar de la Fuente-Nunez

Encrypted peptides (EPs) have been recently described as a new class of antimicrobial molecules. They have been found in numerous organisms and have been proposed to have a role in host immunity and as alternatives to conventional antibiotics. Intriguingly, many of these EPs are found embedded in proteins unrelated to the immune system, suggesting that immunological responses extend beyond traditional host immunity proteins.

To test this idea, we synthesized and analyzed representative peptides derived from non-immune human proteins for their ability to exert antimicrobial and immunomodulatory properties. Most of the tested peptides from non-immune proteins, derived from structural proteins as well as proteins from the nervous and visual systems, displayed potent in vitro antimicrobial activity.

These molecules killed bacterial pathogens by targeting their membrane, and those originating from the same region of the body exhibited synergistic effects when combined. Beyond their antimicrobial properties, nearly 90% of the peptides tested exhibited immunomodulatory effects, modulating inflammatory mediators, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). Moreover, eight of the peptides identified, collagenin-3 and 4, zipperin-1 and 2, and immunosin-2, 3, 12, and 13, displayed anti-infective efficacy in two different preclinical mouse models, reducing bacterial infections by up to four orders of magnitude.

Altogether, our results support the hypothesis that peptides from non-immune proteins may have a role in host immunity. These results potentially expand our notion of the immune system to include previously unrecognized proteins and peptides that may be activated upon infection to confer protection to the host.


Link | PDF (Trends in Biotechnology) [Open Access]

 

Introduction (reformatted) —

The innate immune system traditionally has been thought to be orchestrated by immune proteins. Computational and artificial intelligence (AI) tools have recently been used to identify novel antimicrobial molecules encoded within genomes and proteomes; the presence of these molecules suggests that there is much dark matter still to be explored for antibiotic discovery. EPs [encrypted peptides] were discovered as a result of such efforts. EPs are fragments of natural proteins that were initially identified by algorithms that consider amino acid, sequence, and physicochemical features of previously described antimicrobial peptides (AMPs).

These molecules have now been identified across the tree of life, including in the human proteome. Many EPs have been found to have potent antimicrobial properties. Intriguingly, many of these peptides are derived from non-immune proteins. For instance, many human proteins with defined physiological roles, such as thrombin, protein C3, lactoferrin, pepsinogen A, CUB and EGF-like domain-containing protein, von Willebrand factor, and apolipoproteins, were demonstrated to harbor precursor forms of AMPs that are released through cleavage by either host or bacterial proteases.

Altogether, these findings led us to formulate the ‘Cross-talk Hypothesis’ to test the notion that non-immune proteins are communicating or interacting with the immune system in ways previously unrecognized, contributing to its overall function.