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Antimicrobial Peptides and Antimicrobial Chemokines

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 20582

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Special Issue Editor

Dr. Loredana Frasca

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Guest Editor

Istituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy
Interests: psoriasis; antimicrobial peptides; immunology and microbiology medicine biochemistry, genetics and molecular biology chemistry physics and astronomy engineering materials science environmental science pharmacology, toxicology and pharmaceutics
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Special Issue Information

Dear Colleagues,

Antimicrobial peptides (AMPs) are natural antibiotics produced by epithelial cells or immune cells, and are active against viruses, bacteria and fungi. They are generally cationic, with hydrophobic residues making the folded peptide able to kill pathogens. However, AMPs also have pleiotropic effector functions which act on various cell types, including the cells of the immune system. Given the capacity to induce/regulate inflammatory pathways, some AMPs, such as cathelicidin LL37 or defensins, play a pathogenic role in autoimmune/auto-inflammatory diseases, such as psoriasis or systemic lupus erythematosus. Interestingly, antimicrobial chemokines also exist and can demonstrate similar structures, cationicities and functions. Several investigators have discovered various chemokines (for instance, CXCL7, CXCL10, CXCL4, CXCL6, CCL20) with antimicrobial properties. Among these, CXCL4 and CXCL10 are up-regulated in some autoimmune conditions, and CXCL4 mediates immune amplification in systemic sclerosis. Like the AMPs, antimicrobial chemokines can show a plethora of effector functions which act between antimicrobial activity and inflammation. Improving our understanding of the AMPs/anti-microbial chemokines effects in autoimmunity helps the identification of new biomarkers and therapy targets.

This Special Issue calls for original research papers and reviews on the molecular mechanisms underlying AMPs/antimicrobial chemokines’ involvement in the pathogenesis of human autoimmune/auto-inflammatory diseases. Appropriate animal studies on chronic disease models are also of interest.

Dr. Loredana Frasca
Guest Editor

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Keywords

antimicrobial peptides
antimicrobial chemokines
chronic inflammatory diseases
autoimmunity
biomarkers
therapy targets
inflammation
immune regulation
innate immunity
adaptive immunity

Published Papers (8 papers)

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Research

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19 pages, 3243 KiB

Open AccessArticle

Systematical Screening of Intracellular Protein Targets of Polyphemusin-I Using Escherichia coli Proteome Microarrays

by Pramod Shah and Chien-Sheng Chen

Int. J. Mol. Sci. 2021, 22(17), 9158; https://doi.org/10.3390/ijms22179158 - 25 Aug 2021

Cited by 4 | Viewed by 1736

Abstract

With their wide repertoire of mechanisms, antimicrobial peptides (AMPs) are promising alternatives to fight against varied pathogenic microorganisms (bacteria, fungi, viruses, parasites, etc.). AMPs, novel components of the innate immune defense system, are secreted by all organisms. The aquatic environment represents a huge population and an enormous source of varied AMPs. Polyphemusin-I, a marine AMP isolated from hemocytes of an American horseshoe crab, possesses high antimicrobial activities. Studies on polyphemusin-I have verified the intracellular mechanisms of action, however, its intracellular targets are not yet explored. In this study, we employed Escherichia coli proteome microarrays to systematically screen the entire intracellular protein targets of polyphemusin-I. A total of 97 protein targets of polyphemusin-I were statistically analyzed from the quadruplicate Escherichia coli proteome microarrays assays. Among these identified protein targets, 56 proteins had cellular location inside the cell (i.e., cytoplasm), one in the plasma membrane, one in the periplasm and the rest 39 proteins had no specified cellular location. The bioinformatics analysis of these identified protein targets of polyphemusin-I in gene ontology (GO) enrichment category of molecular function revealed significant enrichment in nucleic acid related GO terms i.e., “RNA binding”, “nucleotide binding”, “nuclease activities”, “uracil DNA N-glycosylase activities” and others. Moreover, enrichment in GO category of biological process also depicted enrichment in nucleic acid related GO terms, such as “nucleic acid phosphodiester bond hydrolysis”, “deoxyribonucleotide metabolism”, and others. In accordance to GO enrichment analysis, protein families (PFAM) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis also showed significant enrichment in nucleic acid terms. These enrichment results suggest that polyphemusin-I targets nucleic acid-associated proteins. Furthermore, to provide a comprehensive study, we compared the identified protein targets of polyphemusin-I with previously identified protein targets of four AMPs (P-Der, Lfcin B, PR-39, and Bac 7) using Escherichia coli proteome microarrays. The comparison study of five AMPs (polyhemusin-I, P-Der, Lfcin B, PR-39, and Bac 7) showed only nine common protein targets in all the five AMPs, whereas a total of 39 and 43 common protein targets were identified among the two marine AMPs (polyphemusin-I and P-Der) and three terrestrial AMPs (Lfcin B, PR-39 and Bac7), respectively. To further reveal the target pattern of marine and terrestrial AMPs, the enrichment results obtained from common protein targets of marine AMPs with terrestrial AMPs were compared. The comparison result indicated that AMPs have unique mechanism of action among marine or terrestrial AMPs. Hence, in this study, we have not only identified the intracellular protein targets of polyphemusin-I, but also revealed the protein target differences between marine AMPs and terrestrial AMPs. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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20 pages, 4132 KiB

Open AccessArticle

Symbiotic NCR Peptide Fragments Affect the Viability, Morphology and Biofilm Formation of Candida Species

by Bettina Szerencsés, Attila Gácser, Gabriella Endre, Ildikó Domonkos, Hilda Tiricz, Csaba Vágvölgyi, János Szolomajer, Dian H. O. Howan, Gábor K. Tóth, Ilona Pfeiffer and Éva Kondorosi

Int. J. Mol. Sci. 2021, 22(7), 3666; https://doi.org/10.3390/ijms22073666 - 1 Apr 2021

Cited by 6 | Viewed by 2522

Abstract

The increasing rate of fungal infections causes global problems not only in human healthcare but agriculture as well. To combat fungal pathogens limited numbers of antifungal agents are available therefore alternative drugs are needed. Antimicrobial peptides are potent candidates because of their broad activity spectrum and their diverse mode of actions. The model legume Medicago truncatula produces >700 nodule specific cysteine-rich (NCR) peptides in symbiosis and many of them have in vitro antimicrobial activities without considerable toxicity on human cells. In this work we demonstrate the anticandidal activity of the NCR335 and NCR169 peptide derivatives against five Candida species by using the micro-dilution method, measuring inhibition of biofilm formation with the XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) assay, and assessing the morphological change of dimorphic Candida species by microscopy. We show that both the N- and C-terminal regions of NCR335 possess anticandidal activity as well as the C-terminal sequence of NCR169. The active peptides inhibit biofilm formation and the yeast-hypha transformation. Combined treatment of C. auris with peptides and fluconazole revealed synergistic interactions and reduced 2-8-fold the minimal inhibitory concentrations. Our results demonstrate that shortening NCR peptides can even enhance and broaden their anticandidal activity and therapeutic potential. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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20 pages, 1886 KiB

Open AccessArticle

The Multifunctional Sactipeptide Ruminococcin C1 Displays Potent Antibacterial Activity In Vivo as Well as Other Beneficial Properties for Human Health

by Clarisse Roblin, Steve Chiumento, Cédric Jacqueline, Eric Pinloche, Cendrine Nicoletti, Hamza Olleik, Elise Courvoisier-Dezord, Agnès Amouric, Christian Basset, Louis Dru, Marie Ollivier, Aurélie Bogey-Lambert, Nicolas Vidal, Mohamed Atta, Marc Maresca, Estelle Devillard, Victor Duarte, Josette Perrier and Mickael Lafond

Int. J. Mol. Sci. 2021, 22(6), 3253; https://doi.org/10.3390/ijms22063253 - 23 Mar 2021

Cited by 13 | Viewed by 3092

Abstract

The world is on the verge of a major antibiotic crisis as the emergence of resistant bacteria is increasing, and very few novel molecules have been discovered since the 1960s. In this context, scientists have been exploring alternatives to conventional antibiotics, such as ribosomally synthesized and post-translationally modified peptides (RiPPs). Interestingly, the highly potent in vitro antibacterial activity and safety of ruminococcin C1, a recently discovered RiPP belonging to the sactipeptide subclass, has been demonstrated. The present results show that ruminococcin C1 is efficient at curing infection and at protecting challenged mice from Clostridium perfringens with a lower dose than the conventional antibiotic vancomycin. Moreover, antimicrobial peptide (AMP) is also effective against this pathogen in the complex microbial community of the gut environment, with a selective impact on a few bacterial genera, while maintaining a global homeostasis of the microbiome. In addition, ruminococcin C1 exhibits other biological activities that could be beneficial for human health, as well as other fields of applications. Overall, this study, by using an in vivo infection approach, confirms the antimicrobial clinical potential and highlights the multiple functional properties of ruminococcin C1, thus extending its therapeutic interest. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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17 pages, 13098 KiB

Open AccessArticle

Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus

by Roberto Lande, Immacolata Pietraforte, Anna Mennella, Raffaella Palazzo, Francesca Romana Spinelli, Konstantinos Giannakakis, Francesca Spadaro, Mario Falchi, Valeria Riccieri, Katia Stefanantoni, Curdin Conrad, Cristiano Alessandri, Fabrizio Conti and Loredana Frasca

Int. J. Mol. Sci. 2021, 22(4), 1650; https://doi.org/10.3390/ijms22041650 - 6 Feb 2021

Cited by 11 | Viewed by 2906

Abstract

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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19 pages, 7493 KiB

Open AccessArticle

Transgenic Mice Overexpressing PG1 Display Corneal Opacity and Severe Inflammation in the Eye

by Min-Kyeung Choi, Minh Thong Le, Hye-Sun Cho, Juyoung Lee, Hyoim Jeon, Se-Yeoun Cha, Manheum Na, Taehoon Chun, Jin-Hoi Kim, Hyuk Song and Chankyu Park

Int. J. Mol. Sci. 2021, 22(4), 1586; https://doi.org/10.3390/ijms22041586 - 4 Feb 2021

Cited by 3 | Viewed by 2210

Abstract

Antimicrobial peptides (AMPs) are of interest as alternatives to antibiotics or immunomodulators. We generated and characterized the phenotypes of transgenic mice overexpressing protegrin 1 (PG1), a potent porcine cathelicidin. No obvious differences were observed between PG1 transgenic and wild-type mice in terms of growth, development, general behaviour, and the major immune cell population. However, PG1 transgenic mice intranasally infected with Staphylococcus aureus resulted in a reduction in microscopic pulmonary injury, improved clearance of bacteria, and lower proinflammatory cytokine secretion, compared to those of wild-type mice. On the other hand, approximately 25% of PG1 transgenic mice (n = 54/215) showed corneal opacity and developed inflammation in the eye, resulting ultimately in phthisis bulbi. Immunohistochemical analyses revealed that PG1 and its activator, neutrophil elastase, localized to the basal cells of the cornea and glands in eyelids, respectively. In addition, apoptosis indicated by a Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive signal was detected from flat cells of the cornea. Our study suggests that the expression regulation or localization of AMPs such as PG1 is important to prevent their adverse effects. However, our results also showed that the cytotoxic effects of PG1 on cells could be tolerated in animals, except for the eyes. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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13 pages, 3009 KiB

Open AccessArticle

Antipseudomonal and Immunomodulatory Properties of Esc Peptides: Promising Features for Treatment of Chronic Infectious Diseases and Inflammation

by Floriana Cappiello, Veronica Carnicelli, Bruno Casciaro and Maria Luisa Mangoni

Int. J. Mol. Sci. 2021, 22(2), 557; https://doi.org/10.3390/ijms22020557 - 8 Jan 2021

Cited by 1 | Viewed by 2231

Abstract

Persistent infections, such as those provoked by the Gram-negative bacterium Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients, can induce inflammation with lung tissue damage and progressive alteration of respiratory function. Therefore, compounds having both antimicrobial and immunomodulatory activities are certainly of great advantage in fighting infectious diseases and chronic inflammation. We recently demonstrated the potent antipseudomonal efficacy of the antimicrobial peptide (AMP) Esc(1-21) and its diastereomer Esc(1-21)-1c, namely Esc peptides. Here, we confirmed this antimicrobial activity by reporting on the peptides’ ability to kill P. aeruginosa once internalized into alveolar epithelial cells. Furthermore, by means of enzyme-linked immunosorbent assay and Western blot analyses, we investigated the peptides’ ability to detoxify the bacterial lipopolysaccharide (LPS) by studying their effects on the secretion of the pro-inflammatory cytokine IL-6 as well as on the expression of cyclooxygenase-2 from macrophages activated by P. aeruginosa LPS. In addition, by a modified scratch assay we showed that both AMPs are able to stimulate the closure of a gap produced in alveolar epithelial cells when cell migration is inhibited by concentrations of Pseudomonas LPS that mimic lung infection conditions, suggesting a peptide-induced airway wound repair. Overall, these results have highlighted the two Esc peptides as valuable candidates for the development of new multifunctional therapeutics for treatment of chronic infectious disease and inflammation, as found in CF patients. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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17 pages, 3604 KiB

Open AccessArticle

Lasso Peptide Microcin J25 Effectively Enhances Gut Barrier Function and Modulates Inflammatory Response in an Enterotoxigenic Escherichia coli-Challenged Mouse Model

by Xiuliang Ding, Haitao Yu and Shiyan Qiao

Int. J. Mol. Sci. 2020, 21(18), 6500; https://doi.org/10.3390/ijms21186500 - 5 Sep 2020

Cited by 22 | Viewed by 2637

Abstract

Bacterial resistance leads to severe public health and safety issues worldwide. Alternatives to antibiotics are currently needed. A promising lasso peptide, microcin J25 (MccJ25), is considered to be the best potential substitute for antibiotics to treat pathogen infection, including enterotoxigenic Escherichia coli (ETEC). This study evaluated the efficacy of MccJ25 in the prevention of ETEC infection. Forty-five female BALB/c mice of clean grade (aged seven weeks, approximately 16.15 g) were randomly divided into three experimental groups as follows: (i) control group (uninfected); (ii) ETEC infection group; (iii) MccJ25 + ETEC group. Fifteen mice per group in five cages, three mice/cage. MccJ25 conferred effective protection against ETEC-induced body weight loss, decrease in rectal temperature and increase in diarrhea scores in mice. Moreover, in ETEC-challenged mice model, MccJ25 significantly improved intestinal morphology, decreased intestinal histopathological scores and attenuated intestinal inflammation by decreasing proinflammatory cytokines and intestinal permeability, including reducing serum diamine oxidase and D-lactate levels. MccJ25 enhanced epithelial barrier function by increasing occludin expression in the colon and claudin-1 expression in the jejunum, ultimately improving intestinal health of host. MccJ25 was further found to alleviate gut inflammatory responses by decreasing inflammatory cytokine production and expression via the activation of the mitogen-activated protein kinase and nuclear factor κB signaling pathways. Taken together, the results indicated that MccJ25 protects against ETEC-induced intestinal injury and intestinal inflammatory responses, suggesting the potential application of MccJ25 as an excellent antimicrobial or anti-inflammation agent against pathogen infections. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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Review

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14 pages, 1375 KiB

Open AccessReview

Use of Photodynamic Therapy Associated with Antimicrobial Peptides for Bacterial Control: A Systematic Review and Meta-Analysis

by Luana Mendonça Dias, Túlio Morandin Ferrisse, Karine Sousa Medeiros, Eduardo Maffud Cilli and Ana Claudia Pavarina

Int. J. Mol. Sci. 2022, 23(6), 3226; https://doi.org/10.3390/ijms23063226 - 17 Mar 2022

Cited by 14 | Viewed by 2477

Abstract

Considering the challenges related to antimicrobial resistance, other strategies for controlling infections have been suggested, such as antimicrobial photodynamic therapy (aPDT) and antimicrobial peptides (AMP). This study aims to perform a systematic review and meta-analysis to obtain evidence on the antimicrobial effectiveness of aPDT associated with AMP and establish in vitro knowledge on this topic for further study designs. The PubMed, Scopus, Web of Science, Science Direct, Scielo, and Cochrane Library databases were searched. Two independent and calibrated researchers (Kappa = 0.88) performed all the systematic steps according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The odds ratio (OR) was used as the effect measure. The Peto method was used to perform the meta-analysis due to the sparse data. Twenty studies were included in the present review. The result was significant (OR = 0.14/p = 0.0235/I-squared = 0%), showing better outcomes of aPDT associated with peptides than those of aPDT alone for controlling the microbial load. Only 20% of the studies included evaluated this approach in a biofilm culture. Combined treatment with aPDT and AMP highly increased the ability of microbial reduction of Gram-positive and Gram-negative bacteria. However, additional blind studies are required to evaluate the efficacy of this therapy on microbial biofilms. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Antimicrobial Chemokines)

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