cyclic-gmp and Bacterial-Infections

RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons (IFN). After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutations in DDX41 gene are identified from myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML) patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survival at all stages throughout the life cycle of the fly.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Bacterial Infections; Cyclic GMP; DEAD-box RNA Helicases; Drosophila melanogaster; Drosophila Proteins; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Nuclear Proteins; Protein-Tyrosine Kinases; Virus Diseases

First discovered in prokaryotes and more recently in eukaryotes, cyclic dinucleotides (CDNs) constitute a unique branch of second messenger signaling systems. Within prokaryotes CDNs regulate a wide array of different biological processes, whereas in the vertebrate system CDN signaling is largely dedicated to activation of the innate immune system. In this book chapter we summarize the occurrence and signaling pathways of these small-molecule second messengers, most importantly in the scope of the mammalian immune system. In this regard, our main focus is the role of the cGAS-STING axis in the context of microbial infection and sterile inflammation and its implications for therapeutic applications.

Topics: Adjuvants, Immunologic; Animals; Bacterial Infections; Cyclic AMP; Cyclic GMP; Evolution, Molecular; Humans; Immune System; Immunity, Innate; Inflammation; Membrane Proteins; Molecular Structure; Second Messenger Systems

Microorganisms growing in a biofilm state are very resilient in the face of treatment by many antimicrobial agents. Biofilm infections are a significant problem in chronic and long-term infections, including those colonizing medical devices and implants. Anti-biofilm peptides represent a very promising approach to treat biofilm-related infections and have an extraordinary ability to interfere with various stages of the biofilm growth mode. Anti-biofilm peptides possess promising broad-spectrum activity in killing both Gram-positive and Gram-negative bacteria in biofilms, show strong synergy with conventional antibiotics, and act by targeting a universal stringent stress response. Understanding downstream processes at the molecular level will help to develop and design peptides with increased activity. Anti-biofilm peptides represent a novel, exciting approach to treating recalcitrant bacterial infections.

Topics: Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Infections; Biofilms; Cyclic GMP; Drug Synergism; Escherichia coli; Microbial Sensitivity Tests; Prostheses and Implants; Prosthesis-Related Infections; Quorum Sensing; Staphylococcus aureus

Biofilm formation of microorganisms causes persistent tissue and foreign body infections resistant to treatment with antimicrobial agents. Up to 80% of human bacterial infections are biofilm associated; such infections are most frequently caused by Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus and Enterobacteria such as Escherichia coli. The accurate diagnosis of biofilm infections is often difficult, which prevents the appropriate choice of treatment. As biofilm infections significantly contribute to patient morbidity and substantial healthcare costs, novel strategies to treat these infections are urgently required. Nucleotide second messengers, c-di-GMP, (p)ppGpp and potentially c-di-AMP, are major regulators of biofilm formation and associated antibiotic tolerance. Consequently, different components of these signalling networks might be appropriate targets for antibiofilm therapy in combination with antibiotic treatment strategies. In addition, cyclic di-nucleotides are microbial-associated molecular patterns with an almost universal presence. Their conserved structures sensed by the eukaryotic host have a widespread effect on the immune system. Thus, cyclic di-nucleotides are also potential immunotherapeutic agents to treat antibiotic-resistant bacterial infections.

Topics: Anti-Bacterial Agents; Bacterial Infections; Bacterial Physiological Phenomena; Biofilms; Cyclic GMP; Drug Resistance, Bacterial; Escherichia coli; Humans; Pseudomonas aeruginosa; Second Messenger Systems; Staphylococcus; Therapies, Investigational

Small molecules that can attenuate bacterial toxin production or biofilm formation have the potential to solve the bacteria resistance problem. Although several molecules, which inhibit bacterial cell-to-cell communication (quorum sensing), biofilm formation and toxin production, have been discovered, there is a paucity of US FDA-approved drugs that target these processes. Here, we review the current understanding of quorum sensing in important pathogens such as Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus and provide examples of experimental molecules that can inhibit both known and unknown targets in bacterial virulence factor production and biofilm formation. Structural data for protein targets that are involved in both quorum sensing and cyclic diguanylic acid signaling are needed to aid the development of molecules with drug-like properties in order to target bacterial virulence factors production and biofilm formation.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Biofilms; Cyclic GMP; Drug Discovery; Humans; Quorum Sensing; Signal Transduction; Small Molecule Libraries

Topics: Animals; Bacteria; Bacterial Infections; Bacterial Proteins; Cyclic GMP; Gene Expression Regulation, Bacterial; Plant Diseases; Signal Transduction; Virulence

Cellular microbiology is a new discipline that is emerging at the interface between cell biology and microbiology. The application of molecular techniques to the study of bacterial pathogenesis has made possible discoveries that are changing the way scientists view the bacterium-host interaction. Today, research on the molecular basis of the pathogenesis of infective diarrheal diseases of necessity transcends established boundaries between cell biology, bacteriology, intestinal pathophysiology, and immunology. The use of microbial pathogens to address questions in cell physiology is just now yielding promising applications and striking results.

Topics: Amino Acid Sequence; Animals; Bacterial Infections; Calcium; Cells; Cyclic GMP; Diarrhea; Gastrointestinal Hormones; Humans; Intestinal Mucosa; Models, Biological; Molecular Sequence Data; Natriuretic Peptides; Peptides; Sequence Alignment; Signal Transduction

The understanding of passive transfer of cell mediated-immune responses with transfer factor and other cell free materials has progressed to the point that investigators are seeking the chemical identity of the molecule(s) that are responsible for these effects and are working on their mechanisms of action. In addition, clinical trials are underway that should clarify the potential for use of transfer factor in treatment of infections, neoplastic and autoimmune diseases. This chapter will critically review the past and current data concerning the components of transfer factor and their effects on immunologic and inflammatory reactions. Some of the recently developed animal models will be described and evaluated, and the clinical studies that have provided conclusive data regarding efficacy will be reviewed.

Topics: Animals; Antibody Formation; Antineoplastic Agents; Bacterial Infections; Cattle; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Cytotoxicity, Immunologic; Dermatitis, Contact; Dogs; Guinea Pigs; Haplorhini; Humans; Hypersensitivity, Delayed; Immune System Diseases; Immunoglobulins; Lymphatic System; Lymphocyte Activation; Lymphokines; Macrophages; Mice; Mice, Inbred Strains; Mycoses; Neoplasms; Organ Size; Parasitic Diseases; Rosette Formation; Transfer Factor; Virus Diseases

Topics: Antibody Formation; Autoimmune Diseases; Bacterial Infections; Carrier State; Communicable Diseases; Cyclic AMP; Cyclic GMP; Enzymes; Haptens; Humans; Immune Tolerance; Immunity, Cellular; Immunoglobulin A, Secretory

We talk about a hypersensitive bronchial system, when under certain endogen prepositions or exogen influences, upon which a healthy persons reacts hardly or not at all, it comes to a significant raise of the airway resistances. Probably this is the prestadium of a chronic obstructive airway disease, which often occurs with patients suffering from an existant bronchial disease. Therefore it is important for actual clinical practice to discuss those problems, which interfere with the raise of sensitivity of the bronchial airways. The discussion should be based on the actual state of science, because several therapeutic problems and consequences ensue.

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Airway Obstruction; Allergens; Asthma; Bacterial Infections; Bronchi; Bronchial Provocation Tests; Cyclic AMP; Cyclic GMP; Parasympatholytics; Pulmonary Embolism; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Virus Diseases

Topics: Adhesins, Bacterial; Bacteria; Bacterial Infections; Bacterial Proteins; Cyclic GMP; Gene Expression Regulation, Bacterial; Riboswitch

Cyclic-di-GMP and cyclic-di-AMP are second messengers produced by bacteria and influence bacterial cell survival, differentiation, colonization, biofilm formation, virulence, and bacteria-host interactions. In this study, we show that in both RAW264.7 macrophage cells and primary bone marrow-derived macrophages, the production of IFN-β and IL-6, but not TNF, in response to cyclic-di-AMP and cyclic-di-GMP requires MPYS (also known as STING, MITA, and TMEM173). Furthermore, expression of MPYS was required for IFN response factor 3 but not NF-κB activation in response to these bacterial metabolites. We also confirm that MPYS is required for type I IFN production by cultured macrophages infected with the intracellular pathogens Listeria monocytogenes and Francisella tularensis. However, during systemic infection with either pathogen, MPYS deficiency did not impact bacterial burdens in infected spleens. Serum IFN-β and IL-6 concentrations in the infected control and MPYS(-/-) mice were also similar at 24 h postinfection, suggesting that these pathogens stimulate MPYS-independent cytokine production during in vivo infection. Our findings indicate that bifurcating MPYS-dependent and -independent pathways mediate sensing of cytosolic bacterial infections.

Topics: Animals; Bacterial Infections; Cell Line; Cyclic AMP; Cyclic GMP; Cytokines; Enzyme-Linked Immunosorbent Assay; Interferon Regulatory Factor-3; Interferon Type I; Macrophages; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phagocytes; Reverse Transcriptase Polymerase Chain Reaction

A commonly observed coupling of sensory domains to GGDEF-class diguanylate cyclases and EAL-class phosphodiesterases has long suggested that c-di-GMP synthesizing and degrading enzymes sense environmental signals. Nevertheless, relatively few signal ligands have been identified for these sensors, and even fewer instances of in vitro switching by ligand have been demonstrated. Here we describe an Escherichia coli two-gene operon, dosCP, for control of c-di-GMP by oxygen. In this operon, the gene encoding the oxygen-sensing c-di-GMP phosphodiesterase Ec Dos (here renamed Ec DosP) follows and is translationally coupled to a gene encoding a diguanylate cyclase, here designated DosC. We present the first characterizations of DosC and a detailed study of the ligand-dose response of DosP. Our results show that DosC is a globin-coupled sensor with an apolar but accessible heme pocket that binds oxygen with a K(d) of 20 microM. The response of DosP activation to increasing oxygen concentration is a complex function of its ligand saturation such that over 80% of the activation occurs in solutions that exceed 30% of air saturation (oxygen >75 microM). Finally, we find that DosP and DosC associate into a functional complex. We conclude that the dosCP operon encodes two oxygen sensors that cooperate in the controlled production and removal of c-di-GMP.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; Bordetella pertussis; Cyclic GMP; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Enzymologic; Homeostasis; Humans; Hydrogen-Ion Concentration; Models, Molecular; Operon; Oxygen; Phosphoric Diester Hydrolases; Phosphorus-Oxygen Lyases; Protein Binding

Our purpose was to compare amniotic fluid nitric oxide metabolites and cyclic guanosine 3',5'-monophosphate in pregnant women with and without intraamniotic infection.. Amniocentesis was performed on 72 pregnant women with preterm contractions, labor, or rupture of membranes. Fourteen patients had intraamniotic infection and 58 did not. Intraamniotic infection was defined as the presence of a positive amniotic fluid culture. Amniotic fluid Gram stain, glucose, leukocyte counts, leukocyte esterase activity, creatinine, pH, and specific gravity were performed. Endogenous nitrite was determined using Griess reagent. Amniotic fluid nitric oxide metabolites (nitrite and nitrate) were measured after reduction of nitrate to nitrite with Aspergillus nitrate reductase. Tests for amniotic fluid cyclic guanosine monophosphate levels were determined by enzyme immunoassay. Two-tailed t test, contingency table methods, linear regression, and correlation were used for statistical analyses.. Amniotic fluid levels of nitric oxide metabolites, endogenous nitrite, nitrate, and cyclic guanosine monophosphate were significantly higher in pregnant women with intraamniotic infection than in those without intraamniotic infection (2.66 +/- 0.49 vs 1.77 +/- 0.07 mumol/mg creatinine, p = 0.002; 0.69 +/- 0.15 vs 0.38 +/- 0.03 mumol/mg creatinine, p = 0.003; 1.99 +/- 0.41 vs 1.38 +/- 0.07 mumol/mg creatinine, p = 0.02; and 1.47 +/- 0.22 vs 0.90 +/- 0.08 nmol/mg creatinine, p = 0.004, respectively). Both amniotic fluid nitric oxide metabolites and cyclic guanosine monophosphate were positively correlated with amniotic fluid leukocyte counts and leukocyte esterase activity and negatively correlated with amniotic fluid glucose concentrations.. Our data indicate that amniotic fluid nitric oxide and cyclic guanosine monophosphate may play important roles in the pathogenesis of intraamniotic infection. Measurements of amniotic fluid nitric oxide metabolites and cyclic guanosine monophosphate may be part of a panel of tests that can be used to detect intraamniotic infection.

Topics: Adult; Amniotic Fluid; Bacterial Infections; Carboxylic Ester Hydrolases; Cyclic GMP; Female; Humans; Leukocyte Count; Nitrates; Nitric Oxide; Nitrites; Pregnancy; Pregnancy Complications, Infectious; Uterine Diseases

The modulation of vascular function by guanosine 3',5'-cyclic monophosphate (cGMP) in sepsis was examined in isolated rat aortas. Basal cGMP content was similar in aortas from sham-operated [3.6 +/- 0.8 (SE) pmol cGMP/mg protein] and from septic (3.2 +/- 1.0) rats. Acetylcholine-induced increases in cGMP content were significantly greater in aortas from sham (109.7 +/- 31.1) than aortas from septic rats (42.1 +/- 10.6). Maximal contractile performance by aortas from septic rats was impaired whether contractions were induced by the alpha 1-receptor agonist norepinephrine (497 +/- 49 mg tension/mg tissue vs. sham 749 +/- 43) or by KCl depolarization (265 +/- 31 vs. sham 613 +/- 79). Aortas from septic rats also exhibited a rightward-shifted dose response to norepinephrine. Inhibition of endogenous cGMP production by myoglobin or methylene blue treatment disproportionally improved responses by aortas from septic rats to both norepinephrine and KCl. In contrast, exposure of aortas to exogenous 8-bromo-cGMP engaged exaggerated vasodilatory responses in tissue from septic animals. Aortas from sham and septic rats contracted equally to stimulation by phorbol 12,13-dibutyrate. These findings indicate that reduced vascular contraction in sepsis is not mediated by altered cGMP levels, but rather that enhanced sensitivity to effects of cGMP may contribute to the disorder.

Topics: Animals; Aorta; Bacterial Infections; Biological Products; Cyclic GMP; In Vitro Techniques; Male; Methylene Blue; Myoglobin; Nitric Oxide; Norepinephrine; Potassium Chloride; Rats; Rats, Inbred Strains; Vasoconstriction

Topics: Acute Disease; Bacterial Infections; Catecholamines; Chronic Disease; Cyclic AMP; Cyclic GMP; Humans

Polymorphonuclear leukocytes of 18 patients during 19 episodes of active bacterial infection produced increased chemiluminescence (mean +/- standard error [SE], 56.3 +/- 4.4 X 10(3) cpm) when the production was compared to that of 29 uninfected controls (35.3 +/- 2.4 X 10(3) cpm; P less than 0.01). Chemiluminescence production remained increased with persistent infection but fell to the levels of controls with appropriate therapy. Phagocytic uptake as determined with radiolabeled bacteria was increased, and chemotactic responsiveness was markedly enhanced in the patients (mean index +/- SE, 260 +/- 51) when these responses were compared with those of controls (77 +/- 18). Chemiluminescence and chemotactic activity correlated in the patients with bacterial infection (r = 0.76), but one function did not appear to depend upon the intactness of the other. The ratio of cyclic guanosine 3',5'-phosphate to cyclic adenosine 3',5'-hosphate in the polymorphonuclear leukocytes of patients with infections (mean +/- SE, 0.102 +/- 0.0008) was also significantly higher than in controls (0.067 +/- 0.007). These data indicate that the polymorphonuclear leukocytes of the majority of patients with active bacterial infection are in an activated state both functionally and metabolically.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Chemotaxis; Cyclic AMP; Cyclic GMP; Humans; Luminescent Measurements; Middle Aged; Neutrophils; Phagocytosis

Topics: Bacterial Infections; Blood Bactericidal Activity; Cell Membrane; Cell Movement; Chemotaxis, Leukocyte; Child; Cyclic GMP; Female; Humans; Leukocytes; Microtubules; Neutrophils; Recurrence; Rosette Formation; Staphylococcus aureus