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IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of Clostridioides difficile infection.

ABSTRACT: Clostridioides difficile infection is currently the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. Cathelicidins, a major group of natural antimicrobial peptides, have antimicrobial and immunomodulatory activities in Clostridioides difficile infection. Here, we have shown that cytokine IL-27 induced human cathelicidin antimicrobial peptide (LL-37) expression in primary human colonic epithelial cells. IL-27 receptor-deficient mice had impaired expression of cathelicidin-related antimicrobial peptide (CRAMP, mouse homolog for human LL-37) after Clostridioides difficile infection, and restoration of CRAMP improved Clostridium difficile clearance and reduced mortality in IL-27 receptor-deficient mice after Clostridioides difficile challenge. In clinical samples from 119 patients with Clostridioides difficile infection, elevated levels of IL-27 were positively correlated with LL-37 in the sera and stools. These findings suggest that IL-27 may be involved in host immunity against Clostridioides difficile infection via induction of LL-37/CRAMP. Therefore, IL-27-LL-37 axis may be a valuable pathway in the development of immune-based therapy.

SUBMITTER: Xu B

PROVIDER: S-EPMC8405154 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purpose: The world is heading to a post-antibiotic era where the treatment of bacterial infections will not be possible even with well-known last-line antibiotics. Unfortunately, the emergence of multidrug resistant bacterial strains is uncontrollable, and the humanity will face a life-threatening fate unless new antimicrobial agents with new bacterial target sites are promptly developed. Herein, we design a hybrid antimicrobial peptide (B1) from helical parts taken from the parent peptides: LL-37 and BMAP-27. The purpose of this design is to improve the potency and enhance the toxicity profile of the parent peptides. Methods: Rational design was used to hybridize two antimicrobial peptides, in which two helical parts from the bovine analog BMAP-27, and the human cathelicidin LL-37 were used to generate a novel peptide (B1). The physicochemical properties were checked using in silico methods. The antimicrobial activities were tested against nine control and resistant strains of Gram-positive and Gram-negative bacteria. On the other hand, the antibiofilm activities were tested against four resistant strains. The cytotoxicity on mammalian cells was tested using HEK293, and the hemolysis activity was also investigated on human blood. Finally, synergistic studies were performed with four conventional antibiotics against four resistant strains of Gram-positive and Gram-negative bacteria. Results: The new peptide B1 exhibited broad-spectrum activities against all tested strains. The concentration against planktonic cells ranged between 10 and 20 µM. However, 40-60 µM were needed to eradicate the biofilms. B1 showed reduced toxicity toward mammalian cells with minimal hemolysis risk. On the other hand, the synergistic studies showed improved activities for the combined conventional antibiotics with a huge reduction in their minimum inhibitory concentration values. The concentrations of B1 peptide combined with the tested antibiotics were also decreased markedly down to 0.5 µM in some cases. Conclusion: B1 is a hybrid peptide from two cathelicidin peptides. It showed an improved activity compared to parent peptides. The hybridization was successful in this study. It generated a new potent broad-spectrum antimicrobial. The toxicity profile was improved, and the synergism with the convention antibiotics showed promising results.

Project description:Clostridioides difficile infection (CDI) creates an imbalance in the intestinal microbiota due to the interaction of the components making up this ecosystem, but little is known about the impact of this disease on other microbial members. This work has thus been aimed at evaluating the taxonomic composition, potential gene-associated functions, virulence factors, and antimicrobial resistance profiles of gut microbiomes. A total of 48 DNA samples obtained from patients with health care facility-acquired (HCFO) and community-onset (CO) diarrhea were distributed in the following four groups according to CDI status: HCFO/+ (n = 13), HCFO/- (n = 8), CO/+ (n = 13), and CO/- (n = 14). These samples were subjected to shotgun metagenomics sequencing. Although the CDI groups' microbiota had microbiome alterations, the greatest imbalance was observed in the in the HCFO+/- groups, with an increase in common pathogens and phage populations, as well as a decrease in beneficial microorganisms that leads to a negative impact on some intestinal homeostasis-related metabolic processes. A reduction in the relative abundance of butyrate metabolism-associated genes was also detected in the HCFO groups (P < 0.01), with an increase in some virulence factors and antibiotic-resistance markers. A set of 51 differentially abundant species in the groups with potential association to CDI enabled its characterization, leading to their spatial separation by onset. Strong correlations between phages and some archaeal and bacterial phyla were identified. This highlighted the need to study the microbiota's various components since their imbalance is multifactorial, with some pathogens contributing to a greater or lesser extent because of their interaction with the ecosystem they inhabit. IMPORTANCE Clostridioides difficile infection represents a serious public health problem in different countries due to its high morbi-mortality and the high costs it represents for health care systems. Studies have shown the impact of this infection on intestinal microbiome homeostasis, mainly on bacterial populations. Our research provides evidence of the impact of CDI at both the compositional (bacteria, archaea, and viruses), and functional levels, allowing us to understand that the alterations of the microbiota occur systemically and are caused by multiple perturbations generated by different members of the microbiota as well as by some pathogens that take advantage of the imbalance to proliferate. Likewise, the 51 differentially abundant species in the study groups with potential association to CDI found in this study could help us envisage future treatments against this and other inflammatory diseases, improving future therapeutic options for patients.

Project description:Rationale: Biomarkers for the diagnosis of heart failure (HF) are clinically essential. Circulating antimicrobial peptides LL-37 has emerged as a novel biomarker in cardiovascular disease, however, its relevance as a biomarker for acute HF are undetermined. Methods: Acute HF patients were enrolled in this study and the serum levels of LL-37/CRAMP (cathelicidin-related antimicrobial peptide) were measured by ELISA. The receiver-operator characteristic (ROC) curve was used to determine if serum LL-37 could be a biomarker for acute HF. Mouse CRAMP (mCRAMP, mouse homolog for human LL-37) was also determined in both heart and serum samples of, transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced HF mice models, and phenylephrine (PE) and angiotensin II (AngII)-induced neonatal mouse cardiomyocytes (NMCMs) hypertrophic models, both intracellular and secreted, by ELISA. The protective effects of mCRAMP were determined in TAC, ISO, and AngII-induced HF in mice while whether HF was exacerbated in AngII-infused animals were checked in mCRAMP knockout mice. The underlying mechanism for protective effects of CARMP in pathological hypertrophy was determined by using a NF-κB agonist together with rCRAMP (rat homolog for human LL-37) in AngII or PE treated neonatal rat cardiomyocytes (NRCMs). Results: Serum levels of LL-37 were significantly decreased in acute HF patients (area under the curve (AUC) of 0.616), and negatively correlated with NT-proBNP. We further confirmed that mCRAMP was decreased in both heart and serum samples of TAC- and ISO-induced HF mice models. Moreover, in PE and AngII-induced NMCMs hypertrophic models, both intracellular and secreted mCRAMP levels were reduced. Functionally, mCRAMP could attenuate TAC, ISO, and AngII-induced HF in mice while CRAMP deficiency exacerbated HF. Mechanistically, the anti-hypertrophy effects of CRAMP were mediated by NF-κB signaling. Conclusions: Collectively, serum LL-37 is associated with acute HF and increasing CRAMP is protective against deleterious NF-κB signaling in the rodent.

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IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of Clostridioides difficile infection.

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