ABSTRACT
Human defensins are cysteine-rich peptides (Cys-rich peptides) of the innate immune system. Defensins contain an ancestral structural motif (i.e., γ-core motif) associated with the antimicrobial activity of natural Cys-rich peptides. In this study, low concentrations of human α- and ß-defensins showed microbicidal activity that was not associated with cell membrane permeabilization. The cell death pathway was similar to that previously described for human lactoferrin, also an immunoprotein containing a γ-core motif. The common features were (1) cell death not related to plasma membrane (PM) disruption, (2) the inhibition of microbicidal activity via extracellular potassium, (3) the influence of cellular respiration on microbicidal activity, and (4) the influence of intracellular pH on bactericidal activity. In addition, in yeast, we also observed (1) partial K+-efflux mediated via Tok1p K+-channels, (2) the essential role of mitochondrial ATP synthase in cell death, (3) the increment of intracellular ATP, (4) plasma membrane depolarization, and (5) the inhibition of external acidification mediated via PM Pma1p H+-ATPase. Similar features were also observed with BM2, an antifungal peptide that inhibits Pma1p H+-ATPase, showing that the above coincident characteristics were a consequence of PM H+-ATPase inhibition. These findings suggest, for the first time, that human defensins inhibit PM H+-ATPases at physiological concentrations, and that the subsequent cytosolic acidification is responsible for the in vitro microbicidal activity. This mechanism of action is shared with human lactoferrin and probably other antimicrobial peptides containing γ-core motifs.
Subject(s)
Cell Membrane , Proton-Translocating ATPases , Humans , Cell Membrane/metabolism , Cell Membrane/drug effects , Proton-Translocating ATPases/metabolism , Proton-Translocating ATPases/antagonists & inhibitors , Cell Membrane Permeability/drug effects , Anti-Infective Agents/pharmacology , Defensins/pharmacology , Defensins/metabolism , Hydrogen-Ion Concentration , Saccharomyces cerevisiae/metabolism , beta-Defensins/metabolism , beta-Defensins/pharmacology , Lactoferrin/pharmacology , Lactoferrin/metabolism , Potassium/metabolism , Microbial Sensitivity Tests , Candida albicans/drug effectsABSTRACT
Enterogenic infection is a common complication for patients with radiation injury and requires efficient therapeutics in the clinic. Herein, we evaluated the promising drug candidate T7E21RHD5, which is a peptide derived from intestinal Paneth cell-secreted human defensin 5. Oral administration of this peptide alleviated the diarrhea symptoms of mice that received total abdominal irradiation (TAI, γ-ray, 12 Gy) and improved survival. Pathologic analysis revealed that T7E21RHD5 elicited an obvious mitigation of ionizing radiation (IR)-induced epithelial damage and ameliorated the reduction in the levels of claudin, zonula occluden 1 and occludin, three tight junction proteins in the ileum. Additionally, T7E21RHD5 regulated the gut microbiota in TAI mice by remodeling ß diversity, manifested as a reversal of the inverted proportion of Bacteroidota to Firmicutes caused by IR. T7E21RHD5 treatment also decreased the abundance of pathogenic Escherichia-Shigella but significantly increased the levels of Alloprevotella and Prevotellaceae_NK3B31, two short-chain fatty acid-producing bacterial genera in the gut. Accordingly, the translocation of enterobacteria and lipopolysaccharide to the blood, as well as the infectious inflammatory responses in the intestine after TAI, was all suppressed by T7E21RHD5 administration. Hence, this versatile antimicrobial peptide possesses promising application prospects in the treatment of IR-induced enterogenic infection.
Subject(s)
Defensins , Peptides , Humans , Mice , Animals , Gamma Rays/adverse effectsABSTRACT
An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.
ABSTRACT
Recently, aging is considered a risk factor for various diseases. Although changes in the intestinal microbiota along with aging are thought to associate with the increased disease risk, mechanisms that cause age-related transition of the intestinal microbiota remain unknown. This study aims to clarify relationships between the amount of human defensin 5 (HD5), a Paneth cell α-defensin, which is known to regulate the intestinal microbiota, and age-related differences of the intestinal microbiota composition. Fecal samples from 196 healthy Japanese (35 to 81 years old) were collected and measured HD5 concentration. HD5 concentration in the elderly group (age > 70 years old) was significantly lower than the middle-aged group (age ≤ 70 years old). Furthermore, individual age was negatively correlated with HD5 concentration (r = - 0.307, p < 0.001). In ß-diversity, the intestinal microbiota of the elderly showed a significantly different composition compared to the middle-aged. At the genus level, relative abundance of Collinsella, Alistipes, Peptococcaceae; unassigned, Lactobacillus, Lactococcus, Weissella, Christensenellaceae R-7 group, Megasphaera, and [Eubacterium] eligens group was significantly higher, and Lachnospiraceae; unassigned, Blautia, Anaerostipes, Fusicatenibacter, Dorea, and Faecalibacterium was significantly lower in the elderly compared to the middle-aged. In addition, HD5 concentration was negatively correlated with Alistipes, Peptococcaceae; unassigned, and Christensenellaceae R-7 group and positively correlated with Lachnospiraceae; unassigned and Dorea. These results provide novel insights into the immunosenescence of enteric innate immunity, indicating low HD5 is suggested to contribute to the age-related differences in the intestinal microbiota and may relate to increased risk of diseases in elderly people.
Subject(s)
Gastrointestinal Microbiome , alpha-Defensins , Adult , Aged , Aged, 80 and over , Defensins , Feces , Humans , Japan , Middle Aged , alpha-Defensins/analysisABSTRACT
Human α-defensin 5 (HD5) is a host-defense peptide exhibiting broad-spectrum antimicrobial activity. The lipopolysaccharide (LPS) layer on the Gram-negative bacterial membrane acts as a barrier to HD5 insertion. Therefore, the pore formation and binding mechanism remain unclear. Here, the binding mechanisms at five positions along the bacterial membrane axis were investigated using Molecular Dynamics. (MD) simulations. We found that HD5 initially placed at positions 1 to 3 moved up to the surface, while HD5 positioned at 4 and 5 remained within the membrane interacting with the middle and inner leaflet of the membrane, respectively. The arginines were key components for tighter binding with 3-deoxy-d-manno-octulosonic acid (KDO), phosphates of the outer and inner leaflets. KDO appeared to retard the HD5 penetration.
Subject(s)
Anti-Infective Agents/metabolism , Cell Membrane/metabolism , Gram-Negative Bacteria/metabolism , Molecular Dynamics Simulation , alpha-Defensins/metabolism , Amino Acid Sequence , Anti-Infective Agents/chemistry , Arginine/metabolism , Humans , Hydrogen Bonding , Lipopolysaccharides/metabolism , Protein Binding , Protein Multimerization , Sugar Acids/metabolism , alpha-Defensins/chemistryABSTRACT
Human α-defensin 5 (HD5) is one of cationic antimicrobial peptides which plays a crucial role in an innate immune system in human body. HD5 shows the killing activity against a broad spectrum of pathogenic bacteria by making a pore in a bacterial membrane and penetrating into a cytosol. Nonetheless, its pore-forming mechanisms remain unclear. Thus, in this work, the constant-velocity steered molecular dynamics (SMD) simulation was used to simulate the permeation of a dimeric HD5 into a gram-negative lipopolysaccharide (LPS) membrane model. Arginine-rich HD5 is found to strongly interact with a LPS surface. Upon arrival, arginines on HD5 interact with lipid A head groups (a top part of LPS) and then drag these charged moieties down into a hydrophobic core resulting in the formation of water-filled pore. Although all arginines are found to interact with a membrane, Arg13 and Arg32 appear to play a dominant role in the HD5 adsorption on a gram-negative membrane. Furthermore, one chain of a dimeric HD5 is required for HD5 adhesion. The interactions of arginine-lipid A head groups play a major role in adhering a cationic HD5 on a membrane surface and retarding a HD5 passage in the meantime.
Subject(s)
Bacterial Outer Membrane/chemistry , alpha-Defensins/chemistry , Arginine/chemistry , Bacterial Outer Membrane/metabolism , Gram-Negative Bacteria/chemistry , Humans , Hydrogen Bonding , Lipopolysaccharides/chemistry , Molecular Dynamics Simulation , Protein Multimerization , alpha-Defensins/metabolismABSTRACT
Human ß defensin type 3 (hBD-3) is a cationic peptide having strong antimicrobial activities even at high salt concentrations. The conserved sequence is believed to contribute to its unique antibacterial activities. To design novel drugs based on hBD-3, predicting the binding free energy contribution of each residue on hBD-3 with bacterial membrane is important. Firstly, the stable binding structure of hBD-3 dimer in analog form bound on POPG lipid bilayer was predicted using NAMD simulations, which was confirmed by RMSD, buried surface area, hydrogen bonds, distance map, and insertion depth map calculations. Then, free energy perturbation (FEP) method was applied to calculate the binding free energy of each residue by mutating it into Alanine. It was found that the positively charged residues on the tail region of hBD-3 contribute significantly to its binding with membrane. The result emphasized the importance of electrostatic interactions to hBD-3's binding with bacterial membrane.
Subject(s)
Lipid Bilayers , Entropy , beta-DefensinsABSTRACT
Human beta-defensins (hBDs) play an important role in the host defense against various microbes, showing different levels of antibacterial activity and salt resistance in vitro. It is of interest to investigate whether can chimeric hBD analogs enhanced antibacterial activity and salt resistance. In this study, we designed a chimeric human defensin, named H4, by combining sequences of human beta-defensin-3 (hBD-3) and human beta-defensin-4 (hBD-4), then evaluated its antibacterial activity, salt resistance, and cytotoxic effects. The result showed that the antibacterial activity of H4 against most tested strains, including Klebsiella pneumonia, Enterococcus faecalis, Staphyloccocus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, and Acinetobacter baumannii was significantly improved compared to that of hBD-3 and hBD-4. Notably, H4 exhibited significantly better antibacterial activity against multidrug resistant isolate A. baumannii MDR-ZJ06 than commonly used antibiotics. Chimeric H4 still showed more than 80% antibacterial activity at high salt concentration (150 µM), which proves its good salt tolerance. The cytotoxic effect assay showed that the toxicity of H4 to Hela, Vero, A549 cells and erythrocytes at a low dose (<10 µg/ml) was similar to that of hBD-3 and hBD-4. In conclusion, given its broad spectrum of antibacterial activity and high salt resistance, chimeric H4 could serve as a promising template for new therapeutic antimicrobial agents.
Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Enterocytes/virology , Paneth Cells/virology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/virology , alpha-Defensins/physiology , Angiotensin-Converting Enzyme 2 , COVID-19 , Cell Culture Techniques , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Enterocytes/metabolism , Humans , Microscopy, Interference , Pandemics , Paneth Cells/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , SARS-CoV-2 , Virus AttachmentABSTRACT
The escalating predicament of multidrug resistant cancer cells and associated side effects of conventional chemotherapy necessitates the exploration of alternative anticancer therapies. The present study evaluated anticancer therapeutic potential of human defensin 5 (HD-5) against colon cancer. The in vivo anticancer efficacy of HD-5 against 1,2-dimethylhydrazine (DMH) induced colon cancer was elucidated in terms of tumor biostatistics, number of aberrant crypt foci (ACF), in situ apoptosis assay,changes in morphological as well as histological architecture of colon(s). The direct interaction of peptide was investigated by incubating peptide with normal and/or cancerous colonocytes followed by phase contrast, Hoechst 3342 and AO/PI staining as well as confocal microscopy. Changes in membrane dynamics were evaluated by MC 540 and N-NBD-PE staining. In vivo decrease(s) in tumor parameters, number of aberrant crypt foci along with marked increase in the rate of apoptosis was observed.H&E staining revealed neutrophils infiltration and restoration of normal architecture in treated colon(s) which was consistent with scanning electron microscopic observations. Furthermore, non-membranolytic mechanism was found to be acquired by peptide as it could traverse cell membrane gaining access to nucleus and cytoplasm thereby disintegrating cellular architecture. MC 540 and NBD-PE staining revealed that peptide could bind to cancerous cells by taking advantage of altered fluidity levels. Our results indicated that HD-5 exhibited strong cancer cell killing and does not affect normal host cells. The peptide can be exploited as promising option to combat developing menace of colon cancer and/or can at least be used as an adjunct to present day chemotherapies.
Subject(s)
Colonic Neoplasms/prevention & control , Peptide Fragments/pharmacology , alpha-Defensins/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carcinogens/toxicity , Colon/drug effects , Colon/pathology , Colonic Neoplasms/chemically induced , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Dimethylhydrazines/toxicity , Female , Random Allocation , Rats , Rats, Sprague-DawleyABSTRACT
Antimicrobial peptides (AMPs) that are able to neutralize toxins are promising antibiotics. In this study we investigated the role of structurally conserved amino acids in reduced human defensinâ 5 (HD5RED ), which is an endogenous peptide with antibacterial action and the ability to neutralize lipopolysaccharide (LPS). Cys residues and high Arg content, rather than Gly18 and Arg6 -Glu14 , were found to be indispensable for HD5RED binding to lipidâ A, for penetrating the bacterial outer and inner membranes, and for eliminating bacteria. Otherwise, all the conserved sites were requisite for HD5RED to block the interaction between LPS and LPS-binding protein and to suppress the TLR4-NF-κB signaling pathway initiated by LPS. Accordingly, we designed the acetamidomethylated Acm Cys-E21R-HD5RED , which was much more potent than HD5RED at eliminating bacteria and which can neutralize LPS. Acm Cys-E21R-HD5RED was also found to exhibit a synergistic effect with ciprofloxacin in killing multidrug-resistant Acinetobacter baumannii. The results of this study, in which multifunctional AMPs were designed based on structure-activity research, may help in the development of more peptide antibiotics.
Subject(s)
Anti-Infective Agents/chemistry , Arginine/metabolism , Cysteine/metabolism , Defensins/chemistry , Acinetobacter baumannii/drug effects , Acute-Phase Proteins/metabolism , Amino Acid Sequence , Animals , Anti-Infective Agents/pharmacology , Carrier Proteins/metabolism , Ciprofloxacin/chemistry , Ciprofloxacin/pharmacology , Defensins/pharmacology , Drug Resistance, Microbial , Humans , Lipopolysaccharides/metabolism , Membrane Glycoproteins/metabolism , Mice , Models, Molecular , Molecular Structure , NF-kappa B/metabolism , Protein Binding , Protein Conformation , RAW 264.7 Cells , Signal Transduction , Structure-Activity Relationship , Toll-Like Receptor 4/metabolismABSTRACT
Human α -defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits broad-spectrum antimicrobial activity and plays an essential role in innate immunity in the human gut and other organ systems. Although its antimicrobial mechanism of action remains unclear, the high salt concentration seems to attenuate the antimicrobial function of HD5 via an unknown mechanism. In this work, we employ Molecular Dynamics (MD) simulations to analyse the oligomerization behaviour of HD5 when exposed to different salt concentration. We demonstrate that the presence of salt, such as sodium chloride (NaCl), promotes HD5 to form higher-order oligomers (up to heptamers) in our simulations. In addition, we also analyse the electrostatic interactions between the two Glu residues (E14 and E21) and their neighbouring residues. Our data confirm that the E14 residue is essential for the structural integrity, whereas the E21 residue contributes to the dimerization of HD5, suggesting that these Glu residues are important for the antimicrobial function of this peptide.
Subject(s)
Molecular Dynamics Simulation , alpha-Defensins/chemistry , Humans , Sodium Chloride/chemistry , Solutions , Static Electricity , alpha-Defensins/chemical synthesisABSTRACT
Human α-defensin 5 (HD5) is one of the important antimicrobial peptides (AMPs) used against a broad-spectrum of pathogens, especially Gram-negative bacteria. HD5 kills by disrupting and making a pore in the bacterial membrane. The presence of lipopolysaccharide (LPS), located on a membrane surface, is found to have an impact on HD5's activity, where such binding mechanism in microscopic detail remains unclear. In this work, we therefore employed molecular dynamics (MD) simulations to investigate the binding mechanisms of HD5 on LPS in comparison to a bare DMPC lipid membrane. Two oligomers, dimer and tetramer, are studied here. Apparently, the membrane structure influences the protein binding affinity. HD5 binds tighter to a lipid membrane than LPS. Both dimeric and tetrameric HD5 can penetrate deeply into a phosphate layer in a lipid membrane, whereas only facial contacts are observed for LPS systems. The proteins appear to stay in the polar area instead of diving into a hydrophobic region. Furthermore, it happens in all cases that residues in the active region (A1, T2, R6, R13, R32) contribute to the membrane adsorption. The breakdown of tetramer into two dimers is also found. This implies that the dimer is more favorable for membrane binding. Moreover, both dimeric and tetrameric HD5 can significantly disrupt a LPS layer, whilst no serious distortion of lipid membrane is obtained. This emphasizes the importance of LPS on HD5 activity.
Subject(s)
Cell Membrane/chemistry , Gram-Negative Bacteria/cytology , Lipopolysaccharides/chemistry , Molecular Dynamics Simulation , alpha-Defensins/chemistry , Adsorption , Cell Membrane/metabolism , Humans , Lipopolysaccharides/metabolism , Protein Binding , Protein Conformation , alpha-Defensins/metabolismABSTRACT
Clostridioides difficile is the leading cause of worldwide antibiotics-associated diarrhea. In this study, we report the construction and evaluation of a novel bacteriophage lysin-human defensin fusion protein targeting C. difficile. The fusion protein, designated LHD, is composed of two parts connected by a 3-repeating unit linker "(GGGGS)3": the catalytic domain of a lysin protein from a C. difficile bacteriophage phiC2 (LCD), and the functional domain of a human defensin protein HD5. Lytic assays showed that LHD protein had a potent lytic activity against different types of clinical C. difficile strains, including the epidemic 027, 078, 012, and 087 strains. The minimum inhibitory concentration (MIC) of LHD was 0.78 µg/ml, which was lower than the MIC of the protein LCD (1.56 µg/ml), and the MICs of metronidazole (4 µg/ml) and vancomycin (4 µg/ml). In addition, the LHD protein could lyse C. different strains in different pHs (6.0, 7.0, and 8.0). Evaluation of LHD potency in vivo using mouse model of C. difficile infection (CDI) showed that administration of the LHD protein (twice daily for 7 days) was effective in mitigating the symptoms and reducing the death from CDI. Treatment with LHD also significantly decreased the number of C. difficile spores and the toxin level in feces from the infected mice. Our data suggest that this novel lysin-human defensin fusion protein has a potential on CDI control.
ABSTRACT
Computational prediction and design of membrane protein-protein interactions facilitate biomedical engineering and biotechnological applications. Due to their antimicrobial activity, human defensins play an important role in the innate immune system. Human defensins are attractive pharmaceutical targets due to their small size, broad activity spectrum, reduced immunogenicity, and resistance to proteolysis. Protein engineering based modification of defensins can improve their pharmaceutical properties. Here we present an approach to computationally probe defensins' oligomerization states in the membrane. First, we develop a novel docking and rescoring algorithm. Then, on the basis of the 3D structure of Sapecin, an insect defensin, and a model of its antimicrobial ion-channel, we optimize the parameters of our empirical scoring function. Finally, we apply our docking program and scoring function to the hBD-2 (human ß-defensin-2) molecule and obtain structures of four possible oligomers. These results can be used in higher level simulations.
Subject(s)
Defensins/chemistry , Membrane Proteins/chemistry , Models, Molecular , Protein Conformation , Protein Multimerization , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein BindingABSTRACT
We demonstrate for the first time a complete small protein characterization with the projection-decomposition approach, including full assignments as well as determination of the 3D fold. In TOCSY- and NOESY-type 4D experiments, pairing of signals from hydrogens and from their respective heavy atoms in decompositions represents a new problem. An approach, referred to as "DIADECOMP" (diagonal decomposition), is introduced to solve this problem; it consists of two separate decompositions of the input projections, differing in a 45° rotation of the spectral axes. While DIADECOMP requires a somewhat complex formulation, in practice it results in observing signals in the rotated decompositions that correspond to sums or differences of frequencies. When applied to a small protein, human defensin ß6, the analysis of a HCC(CO)NH-TOCSY with DIADECOMP results in largely unambiguous assignments of the aliphatic side chain groups. Furthermore, DIADECOMP applied to a 15N-HSQC-NOESY-15N-HSQC provides all expected short distances between amide groups (defined as all HN-HN distances <3.5Å in a reference structure). It is worth noting that short HN-HN distances unambiguously define α-helices, the alignment of ß-strands in sheets, as well as the presence of ß-bulges. This approach of using a minimal amount of NMR data, namely four projection experiments recorded in â¼2.5days, resulted for the human defensin ß6 in complete assignments and a backbone fold with a RMSD of the non-flexible structure of 0.6Å. Uniqueness of decompositions specifically from TOCSY- and NOESY-type 4D experiments is discussed.
ABSTRACT
The gut epithelium is critically involved in maintaining intestinal immune homeostasis. Acting as a physical barrier, it separates the intestinal microflora from cells of the immune system. In addition to its barrier function, the intestinal epithelium expresses defensins, natural, endogenous antimicrobial peptides. In humans, specialized epithelial cells, termed Paneth cells, located primarily in the small intestine express two defensins, Human Defensin-5 (HD-5) and Human Defensin-6 (HD-6). Previously, we have shown that HD-5 potently kills bacteria and induces secretion of interleukin-8 by intestinal epithelial cells. We show that HD-6 specifically and synergistically enhances the HD-5-induced IL-8 secretion, but does not alter its anti-bacterial activity. Further, we find that HD-5 decreases the trans-epithelial electrical resistance of intestinal epithelial cells and that HD-6 negates this effect of HD-5.
Subject(s)
Defensins/physiology , Humans , Interleukin-8/biosynthesis , Intestinal Mucosa/physiologyABSTRACT
Imaging mass spectrometry (IMS) was employed for the analysis of frozen skin biopsies to investigate the differences between stage IV pressure ulcers that remain stalled, stagnant, and unhealed versus those exhibiting clinical and histological signs of improvement. Our data reveal a rich diversity of proteins that are dynamically modulated, and we selectively highlight a family of calcium binding proteins (S-100 molecules) including calcyclin (S100-A6), calgranulins A (S100-A8) and B (S100-A9), and calgizzarin (S100-A11). IMS allowed us to target three discrete regions of interest: the wound bed, adjacent dermis, and hypertrophic epidermis. Plots derived using unsupervised principal component analysis of the global protein signatures within these three spatial niches indicate that these data from wound signatures have potential as a prognostic tool since they appear to delineate wounds that are favorably responding to therapeutic interventions versus those that remain stagnant or intractable in their healing status. Our discovery-based approach with IMS augments current knowledge of the molecular signatures within pressure ulcers while providing a rationale for a focused examination of the role of calcium modulators within the context of impaired wound healing.
Subject(s)
Mass Spectrometry/methods , Molecular Imaging/methods , Pressure Ulcer/metabolism , Proteome/analysis , Wound Healing/physiology , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Proteomics/methods , S100 Proteins , Young AdultABSTRACT
The intestinal mucosa squares the circle by allowing efficient nutrient absorption while generating a firm barrier toward the enteric microbiota, enteropathogenic microorganisms and high luminal concentrations of potent immunostimulatory molecules. The mucus layer together with local antimicrobial and anti-inflammatory peptides significantly contribute to this ability. Here we summarize the recent progress made to better understand the critical importance of this dynamic, complex and highly structured anti-inflammatory and antimicrobial barrier.
Subject(s)
Antimicrobial Cationic Peptides/immunology , Intestinal Mucosa/immunology , Microbiota , Animals , Bacterial Physiological Phenomena , Humans , Intestinal Mucosa/microbiologyABSTRACT
Defensins are cationic antimicrobial peptides that contribute to regulation of host cell function also. Here, we report on the regulation of cell death by Human Defensin 5, the major antimicrobial peptide of ileal Paneth cells. We find that Human Defensin 5-mediated cellular effects depend on functional expression of Tumor Necrosis Factor receptors and downstream mediators of TNF signaling. Our data indicate the involvement of interactions between Human Defensin 5 and the extra-cellular domain of Tumor Necrosis Factor receptor 1. Human Defensin-5 also induces apoptosis intrinsically by targeting the mitochondrial membrane.