scholarly journals Characterization and functional analysis of cathelicidin-MH, a novel frog-derived peptide with anti-septicemic properties

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jinwei Chai ◽  
Xin Chen ◽  
Tiaofei Ye ◽  
Baishuang Zeng ◽  
Qingye Zeng ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Cecal Ligation ◽  
Helical Structure ◽  
Mapk Signaling ◽  
Vital Role ◽  
Innate Immune ◽  
Gram Negative Bacteria ◽  
Membrane Mimetic ◽  
Form Part ◽  
Tissue Plasminogen

Antimicrobial peptides form part of the innate immune response and play a vital role in host defense against pathogens. Here we report a new antimicrobial peptide belonging to the cathelicidin family, cathelicidin-MH (cath-MH), from the skin of Microhyla heymonsivogt frog. Cath-MH has a single α-helical structure in membrane-mimetic environments and is antimicrobial against fungi and bacteria, especially Gram-negative bacteria. In contrast to other cathelicidins, cath-MH suppresses coagulation by affecting the enzymatic activities of tissue plasminogen activator, plasmin, β-tryptase, elastase, thrombin, and chymase. Cath-MH protects against lipopolysaccharide (LPS)- and cecal ligation and puncture-induced sepsis, effectively ameliorating multiorgan pathology and inflammatory cytokine through its antimicrobial, LPS-neutralizing, coagulation suppressing effects as well as suppression of MAPK signaling. Taken together, these data suggest that cath-MH is an attractive candidate therapeutic agent for the treatment of septic shock.

scholarly journals Immune Responses to Gram-Negative Bacteria in Hemolymph of the Chinese Horseshoe Crab, Tachypleus tridentatus

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei-Feng Wang ◽  
Xiao-Yong Xie ◽  
Kang Chen ◽  
Xiu-Li Chen ◽  
Wei-Lin Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
Horseshoe Crab ◽  
Mapk Signaling ◽  
Innate Immune ◽  
Coagulation Cascade ◽  
Gram Negative Bacteria ◽  
Fossil Species ◽  
Living Fossil ◽  
Gram Negative ◽  
Tachypleus Tridentatus

Chinese horseshoe crab, Tachypleus tridentatus, is an ancient marine arthropod with a long evolutionary history. As a kind of living fossil species, the pathogen defenses of horseshoe crabs entirely depend on the innate immune system. Although, there are abundant immune molecules found in the horseshoe crab hemolymph, the biological mechanisms underlying their abilities of distinguishing and defending against invading microbes are still unclear. In this study, we used high-throughput sequencing at mRNA and protein levels and bioinformatics analysis methods to systematically analyze the innate immune response to Gram-negative bacteria in hemolymph of Chinese horseshoe crab. These results showed that many genes in the complement and coagulation cascades, Toll, NF-κB, C-type lectin receptor, JAK-STAT, and MAPK signaling pathways, and antimicrobial substances were activated at 12 and 24 h post-infection, suggesting that Gram-negative bacteria could activate the hemolymph coagulation cascade and antibacterial substances release via the above pathways. In addition, we conjectured that Toll and NF-κB signaling pathway were most likely to participate in the immune response to Gram-negative bacteria in hemolymph of horseshoe crab through an integral signal cascade. These findings will provide a useful reference for exploring the ancient original innate immune mechanism.

scholarly journals High Cell Selectivity and Bactericidal Mechanism of Symmetric Peptides Centered on d-Pro–Gly Pairs

2020 ◽  
Vol 21 (3) ◽  
pp. 1140
Author(s):  
Boyan Jia ◽  
Yiming Wang ◽  
Ying Zhang ◽  
Zi Wang ◽  
Xue Wang ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Geometric Mean ◽  
Therapeutic Index ◽  
Helical Structure ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Membrane Mimetic ◽  
High Therapeutic Index ◽  
Low Toxicity ◽  
Conventional Antibiotics

Antimicrobial peptides (AMPs) have a unique action mechanism that can help to solve global problems in antibiotic resistance. However, their low therapeutic index and poor stability seriously hamper their development as therapeutic agents. In order to overcome these problems, we designed peptides based on the sequence template XXRXXRRzzRRXXRXX-NH2, where X represents a hydrophobic amino acid like Phe (F), Ile (I), and Leu (L), while zz represents Gly–Gly (GG) or d-Pro–Gly (pG). Showing effective antimicrobial activity against Gram-negative bacteria and low toxicity, designed peptides had a tendency to form an α-helical structure in membrane-mimetic environments. Among them, peptide LRpG (X: L, zz: pG) showed the highest geometric mean average treatment index (GMTI = 73.1), better salt, temperature and pH stability, and an additive effect with conventional antibiotics. Peptide LRpG played the role of anti-Gram-negative bacteria through destroying the cell membrane. In addition, peptide LRpG also exhibited an anti-inflammatory activity by effectively neutralizing endotoxin. Briefly, peptide LRpG has the potential to serve as a therapeutic agent to reduce antibiotic resistance owing to its high therapeutic index and great stability.

scholarly journals Glycoconjugates of Gram-negative bacteria and parasitic protozoa – are they similar in orchestrating the innate immune response?

2019 ◽  
Vol 25 (1) ◽  
pp. 73-96 ◽  
Author(s):  
Magdalena A Karaś ◽  
Anna Turska-Szewczuk ◽  
Monika Janczarek ◽  
Agnieszka Szuster-Ciesielska
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Innate Immune ◽  
Gram Negative Bacteria ◽  
Parasitic Protozoa ◽  
Gram Negative ◽  
Immune Balance

Innate immunity is an evolutionarily ancient form of host defense that serves to limit infection. The invading microorganisms are detected by the innate immune system through germline-encoded PRRs. Different classes of PRRs, including TLRs and cytoplasmic receptors, recognize distinct microbial components known collectively as PAMPs. Ligation of PAMPs with receptors triggers intracellular signaling cascades, activating defense mechanisms. Despite the fact that Gram-negative bacteria and parasitic protozoa are phylogenetically distant organisms, they express glycoconjugates, namely bacterial LPS and protozoan GPI-anchored glycolipids, which share many structural and functional similarities. By activating/deactivating MAPK signaling and NF-κB, these ligands trigger general pro-/anti-inflammatory responses depending on the related patterns. They also use conservative strategies to subvert cell-autonomous defense systems of specialized immune cells. Signals triggered by Gram-negative bacteria and parasitic protozoa can interfere with host homeostasis and, depending on the type of microorganism, lead to hypersensitivity or silencing of the immune response. Activation of professional immune cells, through a ligand which triggers the opposite effect (antagonist versus agonist) appears to be a promising solution to restoring the immune balance.

Bovine mammary epithelial cells, initiators of innate immune responses to mastitis

2005 ◽  
Vol 45 (8) ◽  
pp. 757 ◽  
Author(s):  
C. Gray ◽  
Y. Strandberg ◽  
L. Donaldson ◽  
R. L. Tellam
Keyword(s):  
Immune Response ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Vital Role ◽  
Mammary Epithelial ◽  
Innate Immune ◽  
Mammary Tissue ◽  
Effector Cells ◽  
Bovine Mammary Epithelial Cells

Innate immunity plays a vital role in the protection of the bovine mammary gland against mastitis. Until recently, the migration of effector cells such as neutrophils and monocytes into the mammary gland was thought to provide the only defence against invading pathogens. However, mammary epithelial cells may also play an important role in the immune response, contributing to the innate defence of the mammary tissue through secretion of antimicrobial peptides and attraction of circulating immune effector cells. This paper reviews the innate immune pathways in mammary epithelial cells and examines their role in the initiation of an innate immune response to Gram-positive and Gram-negative bacteria.

scholarly journals Towards an Understanding of Ligand Induced Functional Conformational Changes of MexB Efflux Transporter

2021 ◽  
Author(s):  
Khondaker Miraz Rahman ◽  
Shirin Jamshidi ◽  
J Mark Sutton ◽  
Sara Jambarsang
Keyword(s):  
Conformational Changes ◽  
Efflux Pump ◽  
Vital Role ◽  
Gram Negative Bacteria ◽  
Efflux Transporter ◽  
Structural Rearrangements ◽  
Protonation State ◽  
New Information ◽  
Cytotoxic Molecules ◽  
Efflux Pump Inhibitors

<p>MexB, an RND-superfamily efflux pump, plays a vital role in conferring resistance to cytotoxic molecules, including antibiotics, upon Gram-negative bacteria. Although the principal mechanistic elements of switching between the access, binding and extrusion conformers of the protomers of tripartite efflux transporters have been described previously, details surrounding the further mechanism that ends in either substrate extrusion or pump inhibition are limited to observations based on the type of ligand bound to the transporter. A central but missing link in the structure/mechanism relationship is a description of how ligand-induced conformational changes in the presence of a membrane and changing transporter protonation state lead to either substrate extrusion or inhibition of the pump. Here, we report that differences in conformational changes are governed by ligand binding to the transporter. The current study describes important new information about ligand-induced structural rearrangements and conformational changes of MexB in relation to the protonation state of critical acidic residues. We used tetracycline (TET) as a model substrate of MexB and phenylalanine-arginine beta-naphthylamide (PAβN) as a model inhibitor of MexB to study the aforementioned conformational changes. This new information will contribute to the design of new, effective and selective efflux pump inhibitors that could play key roles in reversing antimicrobial resistance.</p>

Select Gram-negative Aerobic Bacteria

2012 ◽  
pp. 90-101
Author(s):  
David R. McNamara ◽  
Franklin R. Cockerill
Keyword(s):  
Cell Wall ◽  
Sepsis Syndrome ◽  
Vital Role ◽  
Klebsiella Pneumonia ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Neisseria Meningitides ◽  
A Cell ◽  
Normal Human ◽  
Specific Species

Gram-negative bacteria may be rod-shaped (bacilli), spherical (cocci), oval, helical, or filamentous. Cytoplasmic membrane is surrounded by a cell wall consisting of a peptidoglycan layer and an outer cell membrane. Gram-negative bacteria are widely distributed in the natural environment. They are commensals with many animals and play a vital role in normal human physiology as intestinal commensals. Gram-negative bacteria are the cause of various human illnesses. The gram-negative bacterial cell wall contains various lipopolysaccharide endotoxins. Endotoxins trigger intense inflammation and the sepsis syndrome during infection. Specific species of gram-negative bacteria such as Neisseria meningitides, Moraxella catarrhalis, Acinetobacter, Vibrio, Klebsiella pneumonia, Salmonella, Pseudomonas aeruginosa, and Haemophilus influenza are reviewed.

scholarly journals Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

2019 ◽  
Vol 131 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Wenling Jian ◽  
Lili Gu ◽  
Brittney Williams ◽  
Yan Feng ◽  
Wei Chao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Innate Immune ◽  
Organ Injury ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Wild Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. Methods Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. Results The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. Conclusions Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

scholarly journals Metabolome and Transcriptome Analysis of Hexaploid Solidago canadensis Roots Reveals its Invasive Capacity Related to Polyploidy

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 187 ◽  
Author(s):  
Miao Wu ◽  
Yimeng Ge ◽  
Chanchan Xu ◽  
Jianbo Wang
Keyword(s):  
Gene Expression ◽  
Transcriptome Analysis ◽  
Gene Expression Regulation ◽  
Mapk Signaling ◽  
Vital Role ◽  
Solidago Canadensis ◽  
Metabolome Analysis ◽  
Regulation Of Expression ◽  
Invasive Capacity ◽  
Metabolite Synthesis

Polyploid plants are more often invasive species than their diploid counterparts. As the invasiveness of a species is often linked to its production of allelopathic compounds, we hypothesize that differences in invasive ability between cytotypes may be due to their different ability to synthesize allelopathic metabolites. We test this using two cytotypes of Solidago canadensis as the model and use integrated metabolome and transcriptome data to resolve the question. Metabolome analysis identified 122 metabolites about flavonoids, phenylpropanoids and terpenoids, of which 57 were differentially accumulated between the two cytotypes. Transcriptome analysis showed that many differentially expressed genes (DEGs) were enriched in ‘biosynthesis of secondary metabolites’, ‘plant hormone signal transduction’, and ‘MAPK signaling’, covering most steps of plant allelopathic metabolite synthesis. Importantly, the differentially accumulated flavonoids, phenylpropanoids and terpenoids were closely correlated with related DEGs. Furthermore, 30 miRNAs were found to be negatively associated with putative targets, and they were thought to be involved in target gene expression regulation. These miRNAs probably play a vital role in the regulation of metabolite synthesis in hexaploid S. canadensis. The two cytotypes of S. canadensis differ in the allelopathic metabolite synthesis and this difference is associated with regulation of expression of a range of genes. These results suggest that changes in gene expression may underlying the increased invasive potential of the polyploidy.

scholarly journals Peptidoglycan O-Acetylation as a Virulence Factor: Its Effect on Lysozyme in the Innate Immune System

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 94 ◽  
Author(s):  
Ashley S. Brott ◽  
Anthony J. Clarke
Keyword(s):  
Immune System ◽  
Virulence Factor ◽  
Innate Immune System ◽  
Innate Immune ◽  
Host Immune System ◽  
Gram Negative Bacteria ◽  
First Line ◽  
Structural Support ◽  
Important Virulence Factor ◽  
Novel Target

The peptidoglycan sacculus of both Gram-positive and Gram-negative bacteria acts as a protective mesh and provides structural support around the entirety of the cell. The integrity of this structure is of utmost importance for cell viability and so naturally is the first target for attack by the host immune system during bacterial infection. Lysozyme, a muramidase and the first line of defense of the innate immune system, targets the peptidoglycan sacculus hydrolyzing the β-(1→4) linkage between repeating glycan units, causing lysis and the death of the invading bacterium. The O-acetylation of N-acetylmuramoyl residues within peptidoglycan precludes the productive binding of lysozyme, and in doing so renders it inactive. This modification has been shown to be an important virulence factor in pathogens such as Staphylococcus aureus and Neisseria gonorrhoeae and is currently being investigated as a novel target for anti-virulence therapies. This article reviews interactions made between peptidoglycan and the host immune system, specifically with respect to lysozyme, and how the O-acetylation of the peptidoglycan interrupts these interactions, leading to increased pathogenicity.

scholarly journals The role of type 1 interferons in Gram-negative bacteria-induced coagulation

Blood ◽  
2020 ◽  
Author(s):  
Xinyu Yang ◽  
Xiaoye Cheng ◽  
Yiting Tang ◽  
Xianhui Qiu ◽  
Zhongtai Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Infection ◽  
Innate Immune ◽  
Coagulation Cascade ◽  
Outer Cell ◽  
Gram Negative Bacteria ◽  
Innate Immune Responses ◽  
Gram Negative ◽  
Type 1 Interferons

Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC through amplifying the release of high mobility box group box 1 (HMGB1) into the blood stream. Inhibition of the expression of type 1 IFNs, disruption of their receptor IFN-α/βR or downstream effector (e.g., HMGB1) uniformly decreased Gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the pro-coagulant activity of tissue factor (TF) by promoting the externalization of phosphatidylserine (PS) to the outer cell surface, where PS assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

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