Manipulation of innate immunity by a bacterial secreted peptide: Lantibiotic nisin Z is selectively immunomodulatory

Abstract

Innate immunity is triggered by a variety of bacterial molecules, resulting in both protective and potentially harmful pro-inflammatory responses. Further, innate immunity also provides a mechanism for the maintenance of homeostasis between the host immune system and symbiotic or non-pathogenic microorganisms. However, the bacterial factors that mediate these protective effects have been incompletely defined. Here, it was demonstrated that the lantiobiotic nisin Z is able to modulate host immune responses and mediate protective host immunity. Nisin Z induced the secretion of the chemokines MCP-1, IL-8 and Gro-α, and significantly reduced TNF-α induction in response to bacterial LPS in human PBMC. The results correlated with the ability of nisin Z to confer protection against both the Gram-positive organism Staphylococcus aureus, and the Gram-negatives Salmonella enterica sv. Typhimurium and Escherichia coli in murine challenge models. Mechanistic studies revealed that nisin Z modulates host immunity through similar mechanisms as natural host defense peptides, engaging multiple signal transduction pathways and growth factor receptors. The results presented herein demonstrate that, in addition to nisin Z, other bacterial cationic peptides and, in particular, the lantibiotics, could represent a new class of secreted bacterial molecule with immunomodulatory activities.

Efficacy of Lantibiotic Treatment of Staphylococcus aureus-Induced Skin Infections, Monitored byIn VivoBioluminescent Imaging

“…Lantibiotics are able to induce chemokines involved in wound healing. Interleukin 8, growth-related oncogene ␣, and monocyte chemoattractant protein 1 are induced by nisin and gallidermin, with nisin treatment resulting in stronger induction of these chemokines (20). Nisin and gallidermin are classified into different groups, namely, nisin-like and epiderminlike lantibiotics, respectively.…”

“…The immune response triggered by nisin is able to protect the host against infection caused by Gram-positive and Gram-negative bacteria. This response is unexpected, as nisin displays antimicrobial activity toward Gramnegative bacteria only when combined with a chelating agent or when the outer membrane has been damaged (20,21). In an unrelated study, Heunis and coworkers (14) observed accelerated wound healing when S. aureus-induced skin infections were treated with nisin incorporated into nanofibers.…”

“…Antimicrobial peptides, such as cathelicidin LL-37 and defensins, play an important role in immunity by acting as antimicrobials and/or immunomodulatory molecules to resolve infection and speed up the recovery process (18). Lantibiotics are also able to modulate the innate immune system, with nisin showing promising immunomodulatory activity (19,20). The immune response triggered by nisin is able to protect the host against infection caused by Gram-positive and Gram-negative bacteria.…”

Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection

“…Additionally, eukaryotic AMPs possess immunomodulatory functions or inhibit proinflammatory responses induced by microbial components (16)(17)(18). Such immunomodulatory activity has also been reported for the lantibiotic nisin Z and synthetic AMP derivates (19)(20)(21). These properties open up alternative approaches to combat microbial infections (15).…”

Nisin Augments Doxorubicin Permeabilization and Ameliorates Signaling Cascade during Skin Carcinogenesis

“…Previously also, inhibition of TNF-α by various cancer preventive agents like green tea polyphenols, tamoxifen, and aspirin has been reported to be associated with recession of various cancers [27]. Moreover, the immuno-modulatory efficacy of nisin [28] as well as various other peptide-drug combinations [29] has been well documented. The present study reports that down regulation of these crucial players of carcinogenesis and inflammation is a prominent route by which nisin-DOX combination might exert a synergetic anti-cancer effect.…”