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1
Plano, Lisa R. W., Delia M. Gutman, Markus Woischnik, and Carleen M. Collins. "Recombinant Staphylococcus aureusExfoliative Toxins Are Not Bacterial Superantigens." Infection and Immunity 68, no. 5 (May 1, 2000): 3048–52. http://dx.doi.org/10.1128/iai.68.5.3048-3052.2000.
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ABSTRACT Staphylococcal scalded-skin syndrome is an exfoliative dermatitis characterized by the separation of the epidermis at the stratum granulosum. This disruption is mediated by one of twoStaphylococcus aureus exotoxins, exfoliative toxins A and B (ETA and ETB). Both ETA and ETB have been reported to be bacterial superantigens. A controversy exists, however, as other data indicate that these exotoxins are not superantigens. Here we demonstrate that recombinant exfoliative toxins produced in Escherichia colido not act as T-cell mitogens and thus are not bacterial superantigens. These data fit the clinical profile of the disease, which is not associated with the classic symptoms of a superantigen-mediated syndrome.
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Mishra, Arun K., Pragya Yadav, and Amrita Mishra. "A Systemic Review on Staphylococcal Scalded Skin Syndrome (SSSS): A Rare and Critical Disease of Neonates." Open Microbiology Journal 10, no. 1 (August 31, 2016): 150–59. http://dx.doi.org/10.2174/1874285801610010150.
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The symptoms of Staphylococcal scalded skin syndrome (SSSS) include blistering of skin on superficial layers due to the exfoliative toxins released fromStaphylococcus aureus. After the acute exfoliation of skin surface, erythematous cellulitis occurs. The SSSS may be confined to few blisters localized to the infection site and spread to severe exfoliation affecting complete body. The specific antibodies to exotoxins and increased clearence of exotoxins decrease the frequency of SSSS in adults. Immediate medication with parenteral anti-staphylococcal antibiotics is mandatory. Mostly, SSSS are resistant to penicillin. Penicillinase resistant synthetic penicillins such as Nafcillin or Oxacillin are prescribed as emergency treatment medicine. If Methicillin-resistantStaphylococcus aureus(MRSA) is suspected), antibiotics with MRSA coverage (e.g., Vancomycin or Linezolid) are indicated. Clindamycin is considered as drug of choice to stop the production of exotoxin from bacteria ribosome. The use of Ringer solution to to balance the fluid loss, followed by maintainence therapy with an objective to maintain the fluid loss from exfoliation of skin, application of Cotrimoxazole on topical surface are greatlly considered to treat the SSSS. The drugs that reduce renal function are avoided. Through this article, an attempt has been made to focus the source, etiology, mechanism, outbreaks, mechanism, clinical manisfestation, treatment and other detail of SSSS.
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Su, Min-Gang, Chien-Hsun Huang, Tzong-Yi Lee, Yu-Ju Chen, and Hsin-Yi Wu. "Incorporating Amino Acids Composition and Functional Domains for Identifying Bacterial Toxin Proteins." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/972692.
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Aside from pathogenesis, bacterial toxins also have been used for medical purpose such as drugs for cancer and immune diseases. Correctly identifying bacterial toxins and their types (endotoxins and exotoxins) has great impact on the cell biology study and therapy development. However, experimental methods for bacterial toxins identification are time-consuming and labor-intensive, implying an urgent need for computational prediction. Thus, we are motivated to develop a method for computational identification of bacterial toxins based on amino acid sequences and functional domain information. In this study, a nonredundant dataset of 167 bacterial toxins including 77 exotoxins and 90 endotoxins is adopted to learn the predictive model by using support vector machines (SVMs). The cross-validation evaluation shows that the SVM models trained with amino acids and dipeptides composition could yield an accuracy of 96.07% and 92.50%, respectively. For discriminating endotoxins from exotoxins, the SVM models trained with amino acids and dipeptides composition have achieved an accuracy of 95.71% and 92.86%, respectively. After incorporating functional domain information, the predictive performance is further improved. The proposed method has been demonstrated to be able to more effectively identify and classify bacterial toxins than the other two features on independent dataset, which may aid in bacterial biomedical development.
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Duport, Alpha-Bazin, and Armengaud. "Advanced Proteomics as a Powerful Tool for Studying Toxins of Human Bacterial Pathogens." Toxins 11, no. 10 (October 4, 2019): 576. http://dx.doi.org/10.3390/toxins11100576.
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Exotoxins contribute to the infectious processes of many bacterial pathogens, mainly by causing host tissue damages. The production of exotoxins varies according to the bacterial species. Recent advances in proteomics revealed that pathogenic bacteria are capable of simultaneously producing more than a dozen exotoxins. Interestingly, these toxins may be subject to post-transcriptional modifications in response to environmental conditions. In this review, we give an outline of different bacterial exotoxins and their mechanism of action. We also report how proteomics contributed to immense progress in the study of toxinogenic potential of pathogenic bacteria over the last two decades.
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Kotb, M. "Bacterial pyrogenic exotoxins as superantigens." Clinical Microbiology Reviews 8, no. 3 (July 1995): 411–26. http://dx.doi.org/10.1128/cmr.8.3.411.
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The recent discovery of the mode of interaction between a group of microbial proteins known as superantigens and the immune system has opened a wide area of investigation into the possible role of these molecules in human diseases. Superantigens produced by certain viruses and bacteria, including Mycoplasma species, are either secreted or membrane-bound proteins. A unique feature of these proteins is that they can interact simultaneously with distinct receptors on different types of cells, resulting in enhanced cell-cell interaction and triggering a series of biochemical reactions that can lead to excessive cell proliferation and the release of inflammatory cytokines. However, although superantigens share many features, they can have very different biological effects that are potentiated by host genetic and environmental factors. This review focuses on a group of secreted pyrogenic toxins that belong to the superantigen family and highlights some of their structural-functional features and their roles in diseases such as toxic shock and autoimmunity. Deciphering the biological activities of the various superantigens and understanding their role in the pathogenesis of microbial infections and their sequelae will enable us to devise means by which we can intervene with their activity and/or manipulate them to our advantage.
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Suttorp, N., M. Fuhrmann, S. Tannert-Otto, F. Grimminger, and S. Bhadki. "Pore-forming bacterial toxins potently induce release of nitric oxide in porcine endothelial cells." Journal of Experimental Medicine 178, no. 1 (July 1, 1993): 337–41. http://dx.doi.org/10.1084/jem.178.1.337.
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Nitric oxide (NO) is believed to play an important role in sepsis-related hypotension. We examined the effects of two pore-forming bacterial exotoxins, Escherichia coli hemolysin and Staphylococcus aureus alpha-toxin, on NO formation in cultured porcine pulmonary artery endothelial cells. NO was quantified using a difference-spectrophotometric method based on the rapid and stoichiometric reaction of NO with oxyhemoglobin. Endothelial cyclic guanosine monophosphate levels were also monitored. Both exotoxins increased NO synthesis in endothelial cells in a time- and dose-dependent manner to an extent exceeding that observed with the ionophore A23187 or thrombin. The capacity of exotoxins to induce NO formation may be relevant in patients with severe local or systemic bacterial infections.
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Frey, Joachim. "RTX Toxins of Animal Pathogens and Their Role as Antigens in Vaccines and Diagnostics." Toxins 11, no. 12 (December 10, 2019): 719. http://dx.doi.org/10.3390/toxins11120719.
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Exotoxins play a central role in the pathologies caused by most major bacterial animal pathogens. The large variety of vertebrate and invertebrate hosts in the animal kingdom is reflected by a large variety of bacterial pathogens and toxins. The group of repeats in the structural toxin (RTX) toxins is particularly abundant among bacterial pathogens of animals. Many of these toxins are described as hemolysins due to their capacity to lyse erythrocytes in vitro. Hemolysis by RTX toxins is due to the formation of cation-selective pores in the cell membrane and serves as an important marker for virulence in bacterial diagnostics. However, their physiologic relevant targets are leukocytes expressing β2 integrins, which act as specific receptors for RTX toxins. For various RTX toxins, the binding to the CD18 moiety of β2 integrins has been shown to be host specific, reflecting the molecular basis of the host range of RTX toxins expressed by bacterial pathogens. Due to the key role of RTX toxins in the pathogenesis of many bacteria, antibodies directed against specific RTX toxins protect against disease, hence, making RTX toxins valuable targets in vaccine research and development. Due to their specificity, several structural genes encoding for RTX toxins have proven to be essential in modern diagnostic applications in veterinary medicine.
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Lainhart, William, Gino Stolfa, and Gerald B. Koudelka. "Shiga Toxin as a Bacterial Defense against a Eukaryotic Predator, Tetrahymena thermophila." Journal of Bacteriology 191, no. 16 (June 5, 2009): 5116–22. http://dx.doi.org/10.1128/jb.00508-09.
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ABSTRACT Bacterially derived exotoxins kill eukaryotic cells by inactivating factors and/or pathways that are universally conserved among eukaryotic organisms. The genes that encode these exotoxins are commonly found in bacterial viruses (bacteriophages). In the context of mammals, these toxins cause diseases ranging from cholera to diphtheria to enterohemorrhagic diarrhea. Phage-carried exotoxin genes are widespread in the environment and are found with unexpectedly high frequency in regions lacking the presumed mammalian “targets,” suggesting that mammals are not the primary targets of these exotoxins. We suggest that such exotoxins may have evolved for the purpose of bacterial antipredator defense. We show here that Tetrahymena thermophila, a bacterivorous predator, is killed when cocultured with bacteria bearing a Shiga toxin (Stx)-encoding temperate bacteriophage. In cocultures with Tetrahymena, the Stx-encoding bacteria display a growth advantage over those that do not produce Stx. Tetrahymena is also killed by purified Stx. Disruption of the gene encoding the StxB subunit or addition of an excess of the nontoxic StxB subunit substantially reduced Stx holotoxin toxicity, suggesting that this subunit mediates intake and/or trafficking of Stx by Tetrahymena. Bacterially mediated Tetrahymena killing was blocked by mutations that prevented the bacterial SOS response (recA mutations) or by enzymes that breakdown H2O2 (catalase), suggesting that the production of H2O2 by Tetrahymena signals its presence to the bacteria, leading to bacteriophage induction and production of Stx.
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Kim, Byoung Sik. "Spatiotemporal Regulation of Vibrio Exotoxins by HlyU and Other Transcriptional Regulators." Toxins 12, no. 9 (August 22, 2020): 544. http://dx.doi.org/10.3390/toxins12090544.
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After invading a host, bacterial pathogens secrete diverse protein toxins to disrupt host defense systems. To ensure successful infection, however, pathogens must precisely regulate the expression of those exotoxins because uncontrolled toxin production squanders energy. Furthermore, inappropriate toxin secretion can trigger host immune responses that are detrimental to the invading pathogens. Therefore, bacterial pathogens use diverse transcriptional regulators to accurately regulate multiple exotoxin genes based on spatiotemporal conditions. This review covers three major exotoxins in pathogenic Vibrio species and their transcriptional regulation systems. When Vibrio encounters a host, genes encoding cytolysin/hemolysin, multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin, and secreted phospholipases are coordinately regulated by the transcriptional regulator HlyU. At the same time, however, they are distinctly controlled by a variety of other transcriptional regulators. How this coordinated but distinct regulation of exotoxins makes Vibrio species successful pathogens? In addition, anti-virulence strategies that target the coordinating master regulator HlyU and related future research directions are discussed.
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Moss, David, Ajit Basak, and Claire Naylor. "The most poisonous substances known: What makes some bacterial toxins so dangerous?" Biochemist 32, no. 4 (August 1, 2010): 4–8. http://dx.doi.org/10.1042/bio03204004.
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We are used to thinking of proteins as beneficial, so it is surprising to realize that the most toxic substances known to man are also protein molecules. These are the bacterial exotoxins, proteins secreted by pathogenic bacteria. Toxicity is measured by the median lethal dose (LD50). An LD50 value is defined as the mass of toxin per kg of body weight required to wipe out half of an animal population. Whereas classic poisons, such as potassium cyanide or arsenic trioxide, have LD50 values in the range 5–15 mg/ kg, the causative agent of botulism, botulinum toxin, has an LD50 in the range 1–3 ng/kg, a million times more toxic!
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Huerta-Uribe, Alejandro, and Andrew J. Roe. "Disarming the enemy: targeting bacterial toxins with small molecules." Emerging Topics in Life Sciences 1, no. 1 (April 21, 2017): 31–39. http://dx.doi.org/10.1042/etls20160013.
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The rapid emergence of antibiotic-resistant bacterial strains has prompted efforts to find new and more efficacious treatment strategies. Targeting virulence factors produced by pathogenic bacteria has gained particular attention in the last few years. One of the inherent advantages of this approach is that it provides less selective pressure for the development of resistance mechanisms. In addition, antivirulence drugs could potentially be the answer for diseases in which the use of conventional antibiotics is counterproductive. That is the case for bacterial toxin-mediated diseases, in which the severity of the symptoms is a consequence of the exotoxins produced by the pathogen. Examples of these are haemolytic-uraemic syndrome produced by Shiga toxins, the profuse and dangerous dehydration caused by Cholera toxin or the life-threatening colitis occasioned by clostridial toxins. This review focuses on the recent advances on the development of small molecules with antitoxin activity against Enterohaemorrhagic Escherichia coli, Vibrio cholerae and Clostridium difficile given their epidemiological importance. The present work includes studies of small molecules with antitoxin properties that act directly on the toxin (direct inhibitors) or that act by preventing expression of the toxin (indirect inhibitors).
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Yordanova, Rozalina, and Katya Kichukova. "MODERN AND RAPID METHODS FOR TOXICOLOGICAL ANALYSIS OF FOODSTUFFS WITH BACTERIAL CONTAMINATION." Applied Researches in Technics, Technologies and Education 6, no. 1 (2018): 69–78. http://dx.doi.org/10.15547/artte.2018.01.011.
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Foodborne illnesses are a widespread problem throughout the world. Food poisoning due to bacterial toxins can be caused by the ingestion of exotoxins which are preformed in the food, or by the ingestion of food containing large numbers of bacterial cells which then release endotoxins in the gastrointestinal tract. Early methods for the assay of bacteria toxins were based on in vivo or in vitro tests. Later, immunological tests were developed based on techniques such as gel diffusion. Different types of methods have been developed for the detection of toxin genes and their toxic products. These methods include the detection of toxin genes by amplification methods and hybridization probing. There are now a number of rapid test kits available which give results within hours and are much simpler to perform and interpret than bioassays.
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Visvanathan, Kumar, Alain Charles, Jason Bannan, Pavel Pugach, Khosrow Kashfi, and John B. Zabriskie. "Inhibition of Bacterial Superantigens by Peptides and Antibodies." Infection and Immunity 69, no. 2 (February 1, 2001): 875–84. http://dx.doi.org/10.1128/iai.69.2.875-884.2001.
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ABSTRACT The pyrogenic exotoxins of group A streptococci and staphylococcal enterotoxins are a family of structurally related superantigens with similar biological activity. Two distinct areas have been identified which have a highly conserved amino acid homology in all of the toxin families. A number of peptides were constructed from these regions, some of which were concatenated and polymerized to enhance their immunogenicity in animals. Antibodies prepared against these polymerized peptides were used to serologically identify the majority of the superantigen toxins, block the biological activities of the superantigens, and protect an experimental animal model against shock. In addition certain peptides were able per se to block up to 90% of the proliferative responses induced by the toxins. The peptide also proved protective in a septic shock model in mice. Binding experiments indicate that the peptide binds tightly to the major histocompatibility complex class II molecule, thus preventing binding and hence activation of the superantigen. The selective and rapid binding of the peptide to the major histocompatibility complex class II molecule may lead to a novel therapeutic modality in treatment of superantigen-mediated diseases.
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Song, Nan, Lihong Chen, Zhemin Zhou, Xingmei Ren, Bo Liu, Siyu Zhou, Caihong Wang, et al. "Genome-wide dissection reveals diverse pathogenic roles of bacterial Tc toxins." PLOS Pathogens 17, no. 2 (February 4, 2021): e1009102. http://dx.doi.org/10.1371/journal.ppat.1009102.
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Tc toxins were originally identified in entomopathogenic bacteria, which are important as biological pest control agents. Tc toxins are heteromeric exotoxins composed of three subunit types, TcA, TcB, and TcC. The C-terminal portion of the TcC protein encodes the actual toxic domain, which is translocated into host cells by an injectosome nanomachine comprising the other subunits. Currently the pathogenic roles and distribution of Tc toxins among different bacterial genera remain unclear. Here we have performed a comprehensive genome-wide analysis, and established a database that includes 1,608 identified Tc loci containing 2,528 TcC proteins in 1,421 Gram-negative and positive bacterial genomes. Our findings indicate that TcCs conform to the architecture of typical polymorphic toxins, with C-terminal hypervariable regions (HVR) encoding more than 100 different classes of putative toxic domains, most of which have not been previously recognized. Based on further analysis of Tc loci in the genomes of all Salmonella and Yersinia strains in EnteroBase, a “two-level” evolutionary dynamics scenario is proposed for TcC homologues. This scenario implies that the conserved TcC RHS core domain plays a critical role in the taxonomical specific distribution of TcC HVRs. This study provides an extensive resource for the future development of Tc toxins as valuable agrochemical tools. It furthermore implies that Tc proteins, which are encoded by a wide range of pathogens, represent an important versatile toxin superfamily with diverse pathogenic mechanisms.
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Sonnen, Andreas F. P., and Philipp Henneke. "Role of Pore-Forming Toxins in Neonatal Sepsis." Clinical and Developmental Immunology 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/608456.
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Protein toxins are important virulence factors contributing to neonatal sepsis. The major pathogens of neonatal sepsis, group B Streptococci,Escherichia coli,Listeria monocytogenes, andStaphylococcus aureus, secrete toxins of different molecular nature, which are key for defining the disease. Amongst these toxins are pore-forming exotoxins that are expressed as soluble monomers prior to engagement of the target cell membrane with subsequent formation of an aqueous membrane pore. Membrane pore formation is not only a means for immediate lysis of the targeted cell but also a general mechanism that contributes to penetration of epithelial barriers and evasion of the immune system, thus creating survival niches for the pathogens. Pore-forming toxins, however, can also contribute to the induction of inflammation and hence to the manifestation of sepsis. Clearly, pore-forming toxins are not the sole factors that drive sepsis progression, but they often act in concert with other bacterial effectors, especially in the initial stages of neonatal sepsis manifestation.
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Braga, Andréa A., Fabiana C. P. Valera, Francesca M. Faria, Maria Rossato, Adriana A. B. Murashima, Marina Z. Fantucci, Davi C. Aragon, Danielle L. C. Queiroz, Wilma T. Anselmo-Lima, and Edwin Tamashiro. "An Experimental Model of Eosinophilic Chronic Rhinosinusitis Induced by Bacterial Toxins in Rabbits." American Journal of Rhinology & Allergy 33, no. 6 (July 25, 2019): 737–50. http://dx.doi.org/10.1177/1945892419865642.
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Background The pathophysiology of chronic rhinosinusitis (CRS) is still not well known due to the multifactorial etiologies involved. Bacteria play a role in the pathogenesis of CRS by various means, including biofilm adhesion, intracellular persistence, or inducing inflammation secondary to toxins. Endotoxins and exotoxins, especially Staphylococcus aureus superantigens, can produce significant immune responses in the host and are implicated in patients with CRS. The majority of animal models described for CRS revalidates the pathophysiology of acute sinusitis, ostium occlusion, or foreign body associated infection. Objectives To evaluate an experimental model of eosinophilic CRS using prolonged exposure to bacterial toxins. The histological changes in rabbits exposed to S. aureus enterotoxin B (SEB), lipopolysaccharide (LPS), or lipoteichoic acid (LTA) were compared. Methods After induction with ovalbumin (OVA) sensitization with subcutaneous injection for 2 weeks, rabbits underwent surgery to insert an indwelling catheter into the maxillary sinus. The sinus was irrigated with OVA 3 times weekly for 2 weeks, followed by sinus irrigation with bacterial toxin (SEB: 1 µg/mL, LPS: 100 ng/mL, or LTA: 100 ng/mL) 3 times weekly for 4 weeks. The histological changes in the treated sinus were compared with control rabbits. Results Sinuses exposed to bacterial toxins (SEB, LPS, and LTA) produced significant mucosal thickening with infiltration of inflammatory cells, notably eosinophils. SEB was the only toxin that promoted a mixed pattern of inflammation, including eosinophilic and neutrophilic infiltration. Conclusion Our experimental model of eosinophilic CRS in rabbits produced significant mucosal thickening and inflammation in the sinuses exposed to bacterial toxins, with histological changes analogous to what is observed in patients with CRS with nasal polyps. This model may serve as a basis for future investigation of the pathogenesis of eosinophilic CRS in relation to bacterial toxins or as a model for testing new therapeutic modalities for this disease.
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Wu, Xinyi, Yichen Li, Faisal Raza, Xuerui Wang, Shulei Zhang, Ruonan Rong, Mingfeng Qiu, and Jing Su. "Red Blood Cell Membrane-Camouflaged Tedizolid Phosphate-Loaded PLGA Nanoparticles for Bacterial-Infection Therapy." Pharmaceutics 13, no. 1 (January 14, 2021): 99. http://dx.doi.org/10.3390/pharmaceutics13010099.
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Multiple drug resistance (MDR) in bacterial infections is developed with the abuse of antibiotics, posing a severe threat to global health. Tedizolid phosphate (TR-701) is an efficient prodrug of tedizolid (TR-700) against gram-positive bacteria, including methicillin-sensitive staphylococcus aureus (MSSA) and methicillin-resistant staphylococcus aureus (MRSA). Herein, a novel drug delivery system: Red blood cell membrane (RBCM) coated TR-701-loaded polylactic acid-glycolic acid copolymer (PLGA) nanoparticles (RBCM-PLGA-TR-701NPs, RPTR-701Ns) was proposed. The RPTR-701Ns possessed a double-layer core-shell structure with 192.50 ± 5.85 nm in size, an average encapsulation efficiency of 36.63% and a 48 h-sustained release in vitro. Superior bio-compatibility was confirmed with red blood cells (RBCs) and HEK 293 cells. Due to the RBCM coating, RPTR-701Ns on one hand significantly reduced phagocytosis by RAW 264.7 cells as compared to PTR-701Ns, showing an immune escape effect. On the other hand, RPTR-701Ns had an advanced exotoxins neutralization ability, which helped reduce the damage of MRSA exotoxins to RBCs by 17.13%. Furthermore, excellent in vivo bacteria elimination and promoted wound healing were observed of RPTR-701Ns with a MRSA-infected mice model without causing toxicity. In summary, the novel delivery system provides a synergistic antibacterial treatment of both sustained release and bacterial toxins absorption, facilitating the incorporation of TR-701 into modern nanotechnology.
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Kim, Byoung. "The Modes of Action of MARTX Toxin Effector Domains." Toxins 10, no. 12 (December 2, 2018): 507. http://dx.doi.org/10.3390/toxins10120507.
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Many Gram-negative bacterial pathogens directly deliver numerous effector proteins from the bacterium to the host cell, thereby altering the target cell physiology. The already well-characterized effector delivery systems are type III, type IV, and type VI secretion systems. Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are another effector delivery platform employed by some genera of Gram-negative bacteria. These single polypeptide exotoxins possess up to five effector domains in a modular fashion in their central regions. Upon binding to the host cell plasma membrane, MARTX toxins form a pore using amino- and carboxyl-terminal repeat-containing arms and translocate the effector domains into the cells. Consequently, MARTX toxins affect the integrity of the host cells and often induce cell death. Thus, they have been characterized as crucial virulence factors of certain human pathogens. This review covers how each of the MARTX toxin effector domains exhibits cytopathic and/or cytotoxic activities in cells, with their structural features revealed recently. In addition, future directions for the comprehensive understanding of MARTX toxin-mediated pathogenesis are discussed.
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Nocadello, S., G. Minasov, L. Shuvalova, I. Dubrovska, E. Sabini, F. Bagnoli, G. Grandi, and W. F. Anderson. "Crystal structures of the components of theStaphylococcus aureusleukotoxin ED." Acta Crystallographica Section D Structural Biology 72, no. 1 (January 1, 2016): 113–20. http://dx.doi.org/10.1107/s2059798315023207.
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Staphylococcal leukotoxins are a family of β-barrel, bicomponent, pore-forming toxins with membrane-damaging functions. These bacterial exotoxins share sequence and structural homology and target several host-cell types. Leukotoxin ED (LukED) is one of these bicomponent pore-forming toxins thatStaphylococcus aureusproduces in order to suppress the ability of the host to contain the infection. The recent delineation of the important role that LukED plays inS. aureuspathogenesis and the identification of its protein receptors, combined with its presence inS. aureusmethicillin-resistant epidemic strains, establish this leukocidin as a possible target for the development of novel therapeutics. Here, the crystal structures of the water-soluble LukE and LukD components of LukED have been determined. The two structures illustrate the tertiary-structural variability with respect to the other leukotoxins while retaining the conservation of the residues involved in the interaction of the protomers in the bipartite leukotoxin in the pore complex.
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Huntley, James S., Venugopal Sathyamoorthy, Robert H. Hall, and Andrew C. Hall. "Membrane attack induced by HlyA, a pore-forming toxin of Vibrio cholerae." Human & Experimental Toxicology 16, no. 2 (February 1997): 101–5. http://dx.doi.org/10.1177/096032719701600205.
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Determining the activity of purified toxins has generally provided the basis for establishing their role in the host- pathogen relationship. The bacterial genus Vibrio pro duces a number of exotoxins in addition to cholera toxin, including haemolysin A (HIyA; Vibrio cholerae) and thermostable direct haemolysin (TDH; Vibrio parahae molyticus) , both of which possess membrane-targeting cytolytic activity. The action of HlyA has been analyzed using protocols previously applied to TDH: lysis and flux experiments on human erythrocytes showed that HlyA similarly causes lysis after cell swelling (by colloid osmosis) due to an elevation of cation permeability. However, kinetic measurements of flux, haemolysis and cation selectivity showed that HlyA and TDH form pores with distinct and characteristic features.
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Shettigar, Kavitha, and Thokur Sreepathy Murali. "Virulence factors and clonal diversity of Staphylococcus aureus in colonization and wound infection with emphasis on diabetic foot infection." European Journal of Clinical Microbiology & Infectious Diseases 39, no. 12 (July 18, 2020): 2235–46. http://dx.doi.org/10.1007/s10096-020-03984-8.
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AbstractFoot ulcer is a common complication in diabetic subjects and infection of these wounds contributes to increased rates of morbidity and mortality. Diabetic foot infections are caused by a multitude of microbes and Staphylococcus aureus, a major nosocomial and community-associated pathogen, significantly contributes to wound infections as well. Staphylococcus aureus is also the primary pathogen commonly associated with diabetic foot osteomyelitis and can cause chronic and recurrent bone infections. The virulence capability of the pathogen and host immune factors can determine the occurrence and progression of S. aureus infection. Pathogen-related factors include complexity of bacterial structure and functional characteristics that provide metabolic and adhesive properties to overcome host immune response. Even though, virulence markers and toxins of S. aureus are broadly similar in different wound models, certain distinguishing features can be observed in diabetic foot infection. Specific clonal lineages and virulence factors such as TSST-1, leukocidins, enterotoxins, and exfoliatins play a significant role in determining wound outcomes. In this review, we describe the role of specific virulence determinants and clonal lineages of S. aureus that influence wound colonization and infection with special reference to diabetic foot infections.
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Franke, Gefion C., Alexandra Böckenholt, Motoyuki Sugai, Holger Rohde, and Martin Aepfelbacher. "Epidemiology, variable genetic organization and regulation of the EDIN-B toxin in Staphylococcus aureus from bacteraemic patients." Microbiology 156, no. 3 (March 1, 2010): 860–72. http://dx.doi.org/10.1099/mic.0.030304-0.
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EDIN-B (epidermal cell differentiation inhibitor-B; also termed C3Stau) is an exotoxin of Staphylococcus aureus which ADP-ribosylates and inactivates Rho GTP binding proteins. The EDIN-B gene (edin-B) and the gene for exfoliative toxin D (etd) make up the central part of a recently described pathogenicity island. Here we evaluated the prevalence and genetic organization of the edin-B/etd pathogenicity island in invasive S. aureus isolates, and characterized edin-B transcription and EDIN-B production using artificial constructs transduced in S. aureus strains RN6390 and Newman. We found that eight out of121 (7 %) S. aureus blood culture isolates harbour edin-B, which is organized in three novel variants of the original edin-B/etd pathogenicity island. In the serum of patients infected with edin-B-positive S. aureus, significant titres of anti-EDIN-B antibodies could be detected. Regulation of edin-B transcription depended on the sarA but not on the agr regulatory system. Furthermore, retrieval of EDIN-B protein secreted by S. aureus RN6390 required the presence of α2-macroglobulin to inhibit the activity of extracellular proteases. These data suggest that the EDIN-B toxin is produced during human infection, is part of a highly variable pathogenicity island and can be controlled by the sarA gene regulon and secreted bacterial proteases.
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Leung, D. Y., M. Gately, A. Trumble, B. Ferguson-Darnell, P. M. Schlievert, and L. J. Picker. "Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production." Journal of Experimental Medicine 181, no. 2 (February 1, 1995): 747–53. http://dx.doi.org/10.1084/jem.181.2.747.
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T lymphocyte infiltration is a prominent feature of the skin inflammation associated with infections by toxin (superantigen)-secreting Staphylococcus aureus or Streptococcus bacteria. The cutaneous lymphocyte-associated antigen (CLA) has been hypothesized to be a homing receptor (HR) involved in selective migration of memory/effector T cells to the skin. Since the expression of this putative skin-selective HR is known to be under strict microenvironmental control, we sought to determine the effect of staphylococcal and streptococcal toxins on T cell expression of CLA. After in vitro stimulation of peripheral blood mononuclear cells with staphylococcal enterotoxin B, toxic shock syndrome toxin-1, and streptococcal pyrogenic exotoxins A and C, there was a significant increase in the numbers of CLA+ T cell blasts (p < 0.01), but not blasts bearing the mucosa-associated adhesion molecule alpha e beta 7-integrin, compared with T cells stimulated with phytohemaglutinin (PHA) or anti-CD3. Bacterial toxins were also found to specifically induce interleukin (IL) 12 production. More importantly, induction of toxin-induced CLA expression was blocked by anti-IL-12, and the addition of IL-12 to PHA-stimulated T cells induced CLA, but not alpha e beta 7-integrin, expression. These data suggest that bacterial toxins induce the expansion of skin-homing CLA+ T cells in an IL-12-dependent manner, and thus may contribute to the development of skin rashes in superantigen-mediated diseases.
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Shulga, Nikolay, Natalia Trush, Lyudmila Bugaeva, and Irina Sayapina. "Pathogenic properties of enterobacteria isolated from calves in the Far Eastern Federal District." E3S Web of Conferences 203 (2020): 01004. http://dx.doi.org/10.1051/e3sconf/202020301004.
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Methods of modern control of infectious animal diseases have led to a change in the etiological structure of infectious agents. Irrational use of antibiotic therapy may be the cause of bacterial variability and involvement in the infectious process of opportunistic bacteria that are present in the normal microflora of the animal body. Opportunistic bacteria are the cause of many animal diseases. Infections caused by them have a prolonged character, the pathogenetic basis of which is the persistence of the pathogen in the host body. Bacterial exotoxins damage the plasma membrane of cells. Pore-forming toxins and enzymes disrupt the selective entry and exit of ions through the plasma membrane. This group of toxins includes cytolysins, hemolysins of gram-negative opportunistic enterobacteria, leukotoxins, metalloproteases, and lipases. When pores are formed under the action of hemolysin, secondary processes are triggered that cause the development of pathological consequences. The vaccines and serums produced by biofactories lag behind the practical needs in terms of antigenicity and do not provide protection for newborn calves in the system of anti-epizootic measures. Of particular importance in the etiopathogenesis of acute intestinal disorders is a decrease in colonization resistance of the gastrointestinal mucosa, resulting in an expansion of the spectrum of pathogenic and opportunistic microorganisms that lead to the development of diarrhea.
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Kelly, C. P., C. Pothoulakis, F. Vavva, I. Castagliuolo, E. F. Bostwick, J. C. O'Keane, S. Keates, and J. T. LaMont. "Anti-Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins." Antimicrobial Agents and Chemotherapy 40, no. 2 (February 1996): 373–79. http://dx.doi.org/10.1128/aac.40.2.373.
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Clostridium difficile diarrhea and colitis result from the actions of bacterial exotoxins on the colonic mucosa. This study examined the ability of hyperimmune bovine colostral antibodies to neutralize the biological effects of these toxins. Anti-C. difficile bovine immunoglobulin concentrate was prepared from the colostral milk of Holstein cows previously immunized with C. difficile toxoids. The anti-C. difficile bovine immunoglobulin concentrate contained high levels of bovine immunoglobulin G specific for C. difficile toxins A and B, as evaluated by enzyme-linked immunosorbent assay. Anti-C. difficile bovine immunoglobulin concentrate neutralized the cytotoxic effects of purified toxin A and toxin B on cultured human fibroblasts, whereas control bovine immunoglobulin concentrate had little toxin-neutralizing activity. Anti-C. difficile bovine immunoglobulin concentrate also blocked the binding of toxin A to its enterocyte receptor and inhibited the enterotoxic effects of C. difficile toxins on the rat ileum, as measured by an increased rat ileal loop weight/length ratio (63% inhibition; P < 0.01), increased mannitol permeability (92% inhibition; P < 0.01), and histologic grading of enteritis (P < 0.01 versus nonimmune bovine immunoglobulin concentrate). Thus, anti-C. difficile bovine immunoglobulin concentrate neutralizes the cytotoxic effects of C. difficile toxins in vitro and inhibits their enterotoxic effects in vivo. This agent may be clinically useful in the prevention and treatment of C. difficile diarrhea and colitis.
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Menge, Christian. "Molecular Biology of Escherichia coli Shiga Toxins’ Effects on Mammalian Cells." Toxins 12, no. 5 (May 23, 2020): 345. http://dx.doi.org/10.3390/toxins12050345.
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Shiga toxins (Stxs), syn. Vero(cyto)toxins, are potent bacterial exotoxins and the principal virulence factor of enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC). EHEC strains, e.g., strains of serovars O157:H7 and O104:H4, may cause individual cases as well as large outbreaks of life-threatening diseases in humans. Stxs primarily exert a ribotoxic activity in the eukaryotic target cells of the mammalian host resulting in rapid protein synthesis inhibition and cell death. Damage of endothelial cells in the kidneys and the central nervous system by Stxs is central in the pathogenesis of hemolytic uremic syndrome (HUS) in humans and edema disease in pigs. Probably even more important, the toxins also are capable of modulating a plethora of essential cellular functions, which eventually disturb intercellular communication. The review aims at providing a comprehensive overview of the current knowledge of the time course and the consecutive steps of Stx/cell interactions at the molecular level. Intervention measures deduced from an in-depth understanding of this molecular interplay may foster our basic understanding of cellular biology and microbial pathogenesis and pave the way to the creation of host-directed active compounds to mitigate the pathological conditions of STEC infections in the mammalian body.
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Patel, Vineet I., J. Leland Booth, Mikhail Dozmorov, Brent R. Brown, and Jordan P. Metcalf. "Anthrax Edema and Lethal Toxins Differentially Target Human Lung and Blood Phagocytes." Toxins 12, no. 7 (July 20, 2020): 464. http://dx.doi.org/10.3390/toxins12070464.
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Bacillus anthracis, the causative agent of inhalation anthrax, is a serious concern as a bioterrorism weapon. The vegetative form produces two exotoxins: Lethal toxin (LT) and edema toxin (ET). We recently characterized and compared six human airway and alveolar-resident phagocyte (AARP) subsets at the transcriptional and functional levels. In this study, we examined the effects of LT and ET on these subsets and human leukocytes. AARPs and leukocytes do not express high levels of the toxin receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). Less than 20% expressed surface TEM8, while less than 15% expressed CMG2. All cell types bound or internalized protective antigen, the common component of the two toxins, in a dose-dependent manner. Most protective antigen was likely internalized via macropinocytosis. Cells were not sensitive to LT-induced apoptosis or necrosis at concentrations up to 1000 ng/mL. However, toxin exposure inhibited B. anthracis spore internalization. This inhibition was driven primarily by ET in AARPs and LT in leukocytes. These results support a model of inhalation anthrax in which spores germinate and produce toxins. ET inhibits pathogen phagocytosis by AARPs, allowing alveolar escape. In late-stage disease, LT inhibits phagocytosis by leukocytes, allowing bacterial replication in the bloodstream.
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Bouillot, Stéphanie, Ina Attrée, and Philippe Huber. "Pharmacological Activation of Rap1 Antagonizes the Endothelial Barrier Disruption Induced by Exotoxins ExoS and ExoT of Pseudomonas aeruginosa." Infection and Immunity 83, no. 5 (February 17, 2015): 1820–29. http://dx.doi.org/10.1128/iai.00010-15.
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Most clinical strains ofPseudomonas aeruginosa, a leading agent of nosocomial infections, are multiresistant to antibiotherapy. Because of the paucity of new available antibiotics, the investigation of strategies aimed at limiting the action of its major virulence factors has gained much interest. The type 3 secretion system ofP. aeruginosaand its effectors are known to be major determinants of toxicity and are required for bacterial dissemination in the host. Bacterial transmigration across the vascular wall is considered to be an important step in the infectious process. Using human endothelial primary cells, we demonstrate that forskolin (FSK), a drug inducing cyclic AMP (cAMP) elevation in eukaryotic cells, strikingly reduced the cell retraction provoked by two type 3 toxins, ExoS and ExoT, found in the majority of clinical strains. Conversely, cytotoxicity of a strain carrying the type 3 effector ExoU was unaffected by FSK. In addition, FSK altered the capacity of two ExoS/ExoT strains to transmigrate across cell monolayers. In agreement with these findings, other drugs and a cytokine inducing the increase of cAMP intracellular levels have also protected cells from retraction. cAMP is an activator of both protein kinase A and EPAC, a GTPase exchange factor of Rap1. Using activators or inhibitors of either pathway, we show that the beneficial effect of FSK is exerted by the activation of the EPAC/Rap1 axis, suggesting that its protective effect is mediated by reinforcing cell-cell and cell-substrate adhesion.
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Grutsch, Alyssa A., Pierre S. Nimmer, Rachel H. Pittsley, Katherine G. Kornilow, and John L. McKillip. "Molecular Pathogenesis of Bacillus spp., with Emphasis on the Dairy Industry." Fine Focus 4, no. 2 (December 21, 2018): 203–22. http://dx.doi.org/10.33043/ff.4.2.203-222.
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The bacterial species Bacillus cereus accounts for 1.4-12% of foodborne illness outbreaks worldwide, a statistic that is certainly an underestimate. This bacterial genus is capable of contaminating a wide range of food products, including rice, chicken, vegetables, spices, and dairy products. B. cereus endospores are partially resistant to pasteurization, dehydration, gamma radiation, and other physical stresses used in food processing, and their adhesive characteristics promote biofilm-forming capability on a variety of substrates in dairy operations. B. cereus and other closely-related species produce several types of exotoxins, including at least four hemolysins, three phospholipases, a heat/acid stable emetic toxin called cereulide, and three well-studied heat-labile enterotoxins that all cause gastroenteritis following ingestion. While a great deal of information on virulence gene presence and expression is known in B. cereus, very little has been done to explore the virulence potential of thermoduric spore-formers that may be found in ultrahigh temperature (UHT) pasteurized milk, and their ability to produce biofilms. Biofilm production is understood to be under similar regulation as toxins and other extracellular virulence determinants. This chapter describes the current status of knowledge with Bacillus spp. relevant to the dairy industry, virulence potential, and biofilm production from the perspective of food safety.
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Munson, Sibyl H., Mary T. Tremaine, Marsha J. Betley, and Rodney A. Welch. "Identification and Characterization of Staphylococcal Enterotoxin Types G and I fromStaphylococcus aureus." Infection and Immunity 66, no. 7 (July 1, 1998): 3337–48. http://dx.doi.org/10.1128/iai.66.7.3337-3348.1998.
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ABSTRACT Staphylococcal enterotoxins are exotoxins produced byStaphylococcus aureus that possess emetic and superantigenic properties. Prior to this research there were six characterized enterotoxins, staphylococcal enterotoxin types A to E and H (referred to as SEA to SEE and SEH). Two new staphylococcal enterotoxin genes have been identified and designated segand sei (staphylococcal enterotoxin types G and I, respectively). seg and sei consist of 777 and 729 nucleotides, respectively, encoding precursor proteins of 258 (SEG) and 242 (SEI) deduced amino acids. SEG and SEI have typical bacterial signal sequences that are cleaved to form toxins with 233 (SEG) and 218 (SEI, predicted) amino acids, corresponding to mature proteins of 27,043 Da (SEG) and 24,928 Da (SEI). Biological activities for SEG and SEI were determined with recombinant S. aureus strains. SEG and SEI elicited emetic responses in rhesus monkeys upon nasogastric administration and stimulated murine T-cell proliferation with the concomitant production of interleukin 2 (IL-2) and gamma interferon (IFN-γ), as measured by cytokine enzyme-linked immunoassays. SEG and SEI are related to other enterotoxins of S. aureus and to streptococcal pyrogenic exotoxin A (SpeA) and streptococcal superantigen (SSA) of Streptococcus pyogenes. Phylogenetic analysis and comparisons of amino acid and nucleotide sequence identities were performed on related staphylococcal and streptococcal protein toxins to group SEG and SEI among the characterized toxins. SEG is most similar to SpeA, SEB, SEC, and SSA (38 to 42% amino acid identity), while SEI is most similar to SEA, SEE, and SED (26 to 28% amino acid identity). Polyclonal antiserum was generated against purified histidine-tagged SEG and SEI (HisSEG and HisSEI). Immunoblot analysis of the enterotoxins, toxic-shock syndrome toxin 1, and SpeA with antiserum prepared against HisSEG and HisSEI revealed that SEG shares some epitopes with SEC1 while SEI does not.
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Roy, Chad J., Kelly L. Warfield, Brent C. Welcher, Raoul F. Gonzales, Tom Larsen, Julie Hanson, Chella S. David, Theresa Krakauer, and Sina Bavari. "Human Leukocyte Antigen-DQ8 Transgenic Mice: a Model To Examine the Toxicity of Aerosolized Staphylococcal Enterotoxin B." Infection and Immunity 73, no. 4 (April 2005): 2452–60. http://dx.doi.org/10.1128/iai.73.4.2452-2460.2005.
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ABSTRACT Staphylococcal enterotoxins (SEs) belong to a large group of bacterial exotoxins that cause severe immunopathologies, especially when delivered as an aerosol. SEs elicit the release of lethal amounts of cytokines by binding to major histocompatibility complex (MHC) class II and cross-linking susceptible T-cell receptors. Efforts to develop effective therapeutic strategies to protect against SEs delivered as an aerosol have been hampered by the lack of small animal models that consistently emulate human responses to these toxins. Here, we report that human leukocyte antigen-DQ8 (HLA-DQ8) transgenic (Tg) mice, but not littermate controls, succumbed to lethal shock induced by SEB aerosols without potentiation. Substantial amounts of perivascular edema and inflammatory infiltrates were noted in the lungs of Tg mice, similar to the pathology observed in nonhuman primates exposed by aerosol to SEB. Furthermore, the observed pathologies and lethal shock correlated with an upsurge in proinflammatory cytokine mRNA gene expression in the lungs and spleens, as well as with marked increases in the levels of proinflammatory circulating cytokines in the Tg mice. Unlike the case for littermate controls, telemetric evaluation showed significant hypothermia in Tg mice exposed to lethal doses of SEB. Taken together, these results show that this murine model will allow for the examination of therapeutics and vaccines developed specifically against SEB aerosol exposure and possibly other bacterial superantigens in the context of human MHC class II receptors.
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Marcato, Paola, George Mulvey, and Glen D. Armstrong. "Cloned Shiga Toxin 2 B Subunit Induces Apoptosis in Ramos Burkitt's Lymphoma B Cells." Infection and Immunity 70, no. 3 (March 2002): 1279–86. http://dx.doi.org/10.1128/iai.70.3.1279-1286.2002.
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ABSTRACT The Shiga toxins (Stx1 and Stx2), produced by Shigella dysenteriae type 1 and enterohemorrhagic Escherichia coli, consist of one A subunit and five B subunits. The Stx1 and Stx2 B subunits form a pentameric structure that binds to globotriaosylceramide (Gb3-Cer) receptors on eukaryotic cells and promotes endocytosis. The A subunit then inhibits protein biosynthesis, which triggers apoptosis in the affected cell. In addition to its Gb3-Cer binding activity, the data in the following report demonstrate that the Stx2 B pentamer induces apoptosis in Ramos Burkitt's lymphoma B cells independently of A subunit activity. Apoptosis was not observed in A subunit-free preparations of the Stx1 B pentamer which competitively inhibited Stx2 B pentamer-mediated apoptosis. The pancaspase inhibitor, Z-VAD-fmk, prevented apoptosis in Ramos cells exposed to the Stx2 B subunit, Stx1 or Stx2. Brefeldin A, an inhibitor of the Golgi transport system, also prevented Stx2 B subunit-mediated apoptosis. These observations suggest that the Stx2 B subunit must be internalized, via Gb3-Cer receptors, to induce Ramos cell apoptosis. Moreover, unlike the two holotoxins, Stx2 B subunit-mediated apoptosis does not involve inhibition of protein biosynthesis. This study provides further insight into the pathogenic potential of this family of potent bacterial exotoxins.
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Giannasca, Paul J., Zhen-xi Zhang, Wen-de Lei, James A. Boden, Mary Ann Giel, Thomas P. Monath, and William D. Thomas. "Serum Antitoxin Antibodies Mediate Systemic and Mucosal Protection from Clostridium difficileDisease in Hamsters." Infection and Immunity 67, no. 2 (February 1, 1999): 527–38. http://dx.doi.org/10.1128/iai.67.2.527-538.1999.
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ABSTRACT Clostridium difficile is the bacterial pathogen identified as the cause of pseudomembranous colitis and is principally responsible for nosocomial antibiotic-associated diarrhea and colitis. The pathologic findings associated with this infection are believed to be caused by two large (∼300-kDa) exotoxins, toxins A and B. Because of the mucosal nature of this infection, vaccination strategies aimed at providing prophylactic or therapeutic immune protection have included immunization by mucosal routes. Using the hamster model ofC. difficile infection, we examined the protective efficacy of inactivated toxin (toxoid) vaccine formulations prepared as either culture filtrate or partially purified toxoid. We compared combination parenteral and mucosal vaccination regimens involving intranasal, intragastric, or rectal routes of immunization and found that rectal immunization in conjunction with intramuscular (i.m.) vaccination provided full protection of hamsters from death and diarrhea while the other mucosal routes did not. Protection was associated with high levels of toxin-neutralizing antibodies in serum. The requirement for adjuvants for protection was assessed by using sequential i.m. and rectal or i.m. vaccination regimens. Unexpectedly, i.m. immunization without adjuvant conferred the highest protection from death and diarrhea; this regimen elicited the highest serum anti-toxin B titers as well as toxin B neutralizing titers. Passive transfer of mouse antitoxin antibodies protected hamsters in a dose-dependent manner, demonstrating the principal role of circulating antitoxin antibodies in immunity from this toxin-mediated mucosal disease. These results suggest that prophylactic parenteral vaccination or intravenous immunotherapy could provide protection from C. difficiledisease in humans.
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Skeen, M. J., and H. K. Ziegler. "Induction of murine peritoneal gamma/delta T cells and their role in resistance to bacterial infection." Journal of Experimental Medicine 178, no. 3 (September 1, 1993): 971–84. http://dx.doi.org/10.1084/jem.178.3.971.
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Previous studies have reported an association of gamma/delta T cells with microbial infection in both human lesions and murine infectious disease models. In this study we provide a comprehensive analysis of the conditions under which the induction of gamma/delta T cells occurs at a site of infection. We found a site-specific induction of gamma/delta T cells after the injection of Listeria monocytogenes in the peritoneal cavity of C3H mice. No changes were seen in the splenic or lymph node populations after these injections. Both the proportion and the absolute number of gamma/delta T cells increased in the peritoneal cavity. Additionally, when peritoneal T cells from Listeria-immune mice were restimulated in vitro, the induced gamma/delta T cells exhibited a greater expansion potential than the alpha/beta T cells. Neither the induced gamma/delta T cells nor those from normal mice expressed CD4 or CD8 on the cell surface. Thy-1 was expressed on only 29% of normal peritoneal gamma/delta T cells, but after intraperitoneal Listeria injection 65% of induced gamma/delta T cells expressed. Thy-1, Pgp-1 and CD45R expression on both normal and induced gamma/delta T cells was consistent with an activation phenotype. Significant increases in peritoneal gamma/delta T cells were not seen until 5-7 d after Listeria injection. The proportion of the CD3+ population expressing the gamma/delta T cell receptor remained elevated for 6-7 wk, while the absolute numbers of peritoneal gamma/delta T cells declined gradually over this time period, reflecting a decrease in both the number of lymphocytes and the percentage of these that were CD3+. Peak numbers of gamma/delta T cells were seen at day 10 with live microbes such as Listeria. A variety of microbes, toxins, mitogens, antigens, cytokines, and nonspecific inflammatory agents were evaluated for their ability to induce gamma/delta T cells in the peritoneal cavity. Both Gram-positive and Gram-negative bacteria as well as Mycobacteria were able to induce gamma/delta T cells that showed increased in vitro expansion potential. An exotoxin from a Gram-positive organism, listeriolysin-o, and the lipopolysaccharide (LPS) endotoxin from a Gram-negative organism were also effective. gamma/delta T cell responses to LPS were under lps gene control. Peak numbers of gamma/delta T cells were observed at day 3 after injection with exotoxins and endotoxins. Modifications that abrogated the virulence of a bacterial strain also eliminated the inductive effect for gamma/delta T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Bryant, Amy, Eva Katahira, David Huang, and Dennis Stevens. "Effects of Iclaprim and Trimethoprim on Exotoxin Production by Methicillin-resistant Staphylococcus aureus." Open Forum Infectious Diseases 4, suppl_1 (2017): S372—S373. http://dx.doi.org/10.1093/ofid/ofx163.915.
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Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) causes serious, often life-threatening, infections. Exotoxins such as alpha-hemolysin (AH), Panton Valentine leukocidin (PVL), and Toxic shock syndrome toxin 1 (TSST-1) mediate pathogenesis and inhibition of toxin production is an important consideration in choosing appropriate treatments. Vancomycin is recommended for severe MRSA infections; however, increasing vancomycin resistance, poor clinical outcomes and nephrotoxicity are serious concerns. Thus newer agents are needed, including those that block bacterial toxin production. In the current study, we compared the effects of sub-inhibitory doses (sub-MIC) of two folic acid inhibitor antibiotics (iclaprim, trimethoprim) with cell wall-active agents (nafcillin, vancomycin) on transcription and translation of AH, PVL and TSST-1 in two clinical MRSA isolates. Methods Community-acquired MRSA strains 1560 (a USA400 strain; AH+, TSST-1+, PVL-) and 04014 (CDC strain 368–04; AH+, TSST-1-, PVL+) were studied. MICs were determined by standard microbroth dilution. Gene expression was studied by northern blotting and/or qRT-PCR; toxins were quantitated by ELISA (PVL and TSST-1) and rabbit erythrocyte lysate assay (AH). Results In agreement with our previous findings, nafcillin increased production of AH, TSST-1, and PVL compared with untreated control cultures. In both MRSA strains, iclaprim and trimethoprim delayed the onset of mRNA production and shifted its peak production to later time points. Both iclaprim and trimethoprim suppressed AH production in both strains of MRSA and delayed, but did not reduce, maximal TSST-1 production in MRSA1560. Trimethoprim significantly increased maximal PVL production over both untreated and iclaprim-treated cultures. Conclusion The folic acid antagonist antibiotics, iclaprim and trimethoprim, altered both mRNA synthesis dynamics and protein toxin production in MRSA at concentrations below those that inhibit bacterial growth. These results, plus the fact that iclaprim is 15-fold more active than trimethoprim (MICs = 0.13 and 2.0 ug/ml, respectively), provide additional rationale for the use of iclaprim to treat complicated MRSA infections. Disclosures A. Bryant, Motif Biosciences: Grant Investigator, Research grant; D. Huang, Motif Bio: Employee, Salary; D. Stevens, Motif Biosciences: Grant Investigator, Research grant
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Orrell, Kathleen E., and Roman A. Melnyk. "Large Clostridial Toxins: Mechanisms and Roles in Disease." Microbiology and Molecular Biology Reviews 85, no. 3 (August 18, 2021). http://dx.doi.org/10.1128/mmbr.00064-21.
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Large clostridial toxins (LCTs) are a family of bacterial exotoxins that infiltrate and destroy target cells. Members of the LCT family include Clostridioides difficile toxins TcdA and TcdB, Paeniclostridium sordellii toxins TcsL and TcsH, Clostridium novyi toxin TcnA, and Clostridium perfringens toxin TpeL.
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Besançon, Hervé, Viktoriia Babiychuk, Yu Larpin, René Köffel, Dominik Schittny, Lara Brockhus, Lucy J. Hathaway, Parham Sendi, Annette Draeger, and Eduard Babiychuk. "Tailored liposomal nanotraps for the treatment of Streptococcal infections." Journal of Nanobiotechnology 19, no. 1 (February 15, 2021). http://dx.doi.org/10.1186/s12951-021-00775-x.
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Abstract Background Streptococcal infections are associated with life-threatening pneumonia and sepsis. The rise in antibiotic resistance calls for novel approaches to treat bacterial diseases. Anti-virulence strategies promote a natural way of pathogen clearance by eliminating the advantage provided to bacteria by their virulence factors. In contrast to antibiotics, anti-virulence agents are less likely to exert selective evolutionary pressure, which is a prerequisite for the development of drug resistance. As part of their virulence mechanism, many bacterial pathogens secrete cytolytic exotoxins (hemolysins) that destroy the host cell by destabilizing their plasma membrane. Liposomal nanotraps, mimicking plasmalemmal structures of host cells that are specifically targeted by bacterial toxins are being developed in order to neutralize-by competitive sequestration-numerous exotoxins. Results In this study, the liposomal nanotrap technology is further developed to simultaneously neutralize the whole palette of cytolysins produced by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis-pathogens that can cause life-threatening streptococcal toxic shock syndrome. We show that the mixture of liposomes containing high amounts of cholesterol and liposomes composed exclusively of choline-containing phospholipids is fully protective against the combined action of exotoxins secreted by these pathogens. Conclusions Unravelling the universal mechanisms that define targeting of host cells by streptococcal cytolysins paves the way for a broad-spectrum anti-toxin therapy that can be applied without a diagnostic delay for the treatment of bacterial infections including those caused by antibiotic-resistant pathogens.
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Carter, Glen P., Anjana Chakravorty, Tu Anh Pham Nguyen, Steven Mileto, Fernanda Schreiber, Lucy Li, Pauline Howarth, et al. "Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections." mBio 6, no. 3 (June 2, 2015). http://dx.doi.org/10.1128/mbio.00551-15.
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ABSTRACTClostridium difficileis a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA+TcdB−mutants are attenuated in virulence in comparison to the wild-type (TcdA+TcdB+) strain, whereas TcdA−TcdB+mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication ofC. difficileinfection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing thein vivohost innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor ofC. difficileand provide new insights into the host response toC. difficileduring infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms.IMPORTANCEClostridium difficileis a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms ofC. difficileinfections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response toC. difficileduring infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.