Bradley G Stiles

U.S. Army Medical Research Institute of Infectious Diseases, Фредерик, Maryland, United States

Are you Bradley G Stiles?

Claim your profile

Publications (79)252.6 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Some pathogenic spore-forming bacilli employ a binary protein mechanism for intoxicating the intestinal tracts of insects, animals, and humans. These Gram-positive bacteria and their toxins include Clostridium botulinum (C2 toxin), Clostridium difficile (C. difficile toxin or CDT), Clostridium perfringens (ι-toxin and binary enterotoxin, or BEC), Clostridium spiroforme (C. spiroforme toxin or CST), as well as Bacillus cereus (vegetative insecticidal protein or VIP). These gut-acting proteins form an AB complex composed of ADP-ribosyl transferase (A) and cell-binding (B) components that intoxicate cells via receptor-mediated endocytosis and endosomal trafficking. Once inside the cytosol, the A components inhibit normal cell functions by mono-ADP-ribosylation of globular actin, which induces cytoskeletal disarray and death. Important aspects of each bacterium and binary enterotoxin will be highlighted in this review, with particular focus upon the disease process involving the biochemistry and modes of action for each toxin.
    Toxins 09/2014; 6(9):2626-2656. DOI:10.3390/toxins6092626 · 2.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that Clostridium perfringens iota toxin binds to CD44 and lipolysis stimulated lipoprotein receptor (LSR) cell-surface proteins. We recently demonstrated that LSR expression correlates with estrogen receptor positive breast cancers and that LSR signaling directs aggressive, tumor-initiating cell behaviors. Herein, we identify the mechanisms of iota toxin cytotoxicity in a tissue-specific, breast cancer model with the ultimate goal of laying the foundation for using iota toxin as a targeted breast cancer therapy.
    Molecular Cancer 07/2014; 13(1):163. DOI:10.1186/1476-4598-13-163 · 5.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Infectious diseases are a significant cause of morbidity and mortality worldwide, accounting for approximately 50% of all deaths in tropical countries and as much as 20% of deaths in the USA. The emergence of multi-drug resistant (MDR) strains makes the risk of these infections even more threatening and an important public health problem thereby increasing need of new agents for fighting pathogens. In this review, the remarkable antibacterial properties possessed by various snake venoms (Crotalide, Elapidae, and Viperidae families) were discussed and in particular phospholipase A2s (PLA2s) that have emerged from various studies as potential in the last few years. Group IIA PLA2s are the most potent among the snake venom (sv)PLA2s against various types of bacteria. Further, antibacterial derivatives from PLA2s, e.g. peptides derived from the C-terminal sequence of Lys49-PLA2s (amino acids 115-129), kill bacteria and cause severe membrane-damaging effects. Mechanisms of binding to the bacterial surface and subsequent killing by peptides are based on positive charge, hydrophobicity, and length. These peptide candidates are easy to design and synthesize in pure form (~95% purity). Such peptides may be potentially useful in the clinic as new antimicrobials for combating infections due to antibiotic-resistant bacteria that include methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus in the near future.
    Mini-Reviews in Organic Chemistry 05/2014; 11(1). DOI:10.2174/1570193X1101140402100131 · 0.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Basic phospholipase A2 was identified from the venom of the eastern diamondback rattlesnake. The Crotalus adamanteus toxin-II (CaTx-II) induced bactericidal effects (7.8 µg/ml) on Staphylococcus aureus, while on Burkholderia pseudomallei (KHW), and Enterobacter aerogenes were killed at 15.6 µg/ml. CaTx-II caused pore formation and membrane damaging effects on the bacterial cell wall. CaTx-II was not cytotoxic on lung (MRC-5), skin fibroblast (HEPK) cells and in mice. CaTx-II-treated mice showed significant wound closure and complete healing by 16 days as compared to untreated controls (**P<0.01). Histological examination revealed enhanced collagen synthesis and neovascularization after treatment with CaTx-II versus 2% Fusidic Acid ointment (FAO) treated controls. Measurement of tissue cytokines revealed that interleukin-1 beta (IL-1β) expression in CaTx-II treated mice was significantly suppressed versus untreated controls. In contrast, cytokines involved in wound healing and cell migration i.e., monocyte chemotactic protein-1 (MCP-1), fibroblast growth factor-basic (FGF-b), chemokine (KC), granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly enhanced in CaTx-II treated mice, but not in the controls. CaTx-II also modulated nuclear factor-kappa B (NF-κB) activation during skin wound healing. The CaTx-II protein highlights distinct snake proteins as a potential source of novel antimicrobial agents with significant therapeutic application for bacterial skin infections.
    PLoS ONE 02/2014; 9(2):e80199. DOI:10.1371/journal.pone.0080199 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clostridium perfringens is a prolific, toxin-producing anaerobe causing multiple diseases in humans and animals. One of these toxins is epsilon, a 33 kDa protein produced by Clostridium perfringens (types B and D) that induces fatal enteric disease of goats, sheep and cattle. Epsilon toxin (Etx) belongs to the aerolysin-like toxin family. It contains three distinct domains, is proteolytically-activated and forms oligomeric pores on cell surfaces via a lipid raft-associated protein(s). Vaccination controls Etx-induced disease in the field. However, therapeutic measures are currently lacking. This review initially introduces C. perfringens toxins, subsequently focusing upon the Etx and its biochemistry, disease characteristics in various animals that include laboratory models (in vitro and in vivo), and finally control mechanisms (vaccines and therapeutics).
    Toxins 11/2013; 5(11):2138-2160. DOI:10.3390/toxins5112138 · 2.48 Impact Factor
  • Source
    Teresa Krakauer, Bradley G Stiles
    [Show abstract] [Hide abstract]
    ABSTRACT: Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s.
    Virulence 04/2013; 4(7). DOI:10.4161/viru.23905 · 3.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Snake venom contains a number of different, pharmacologically-active proteins and peptides. Most of the haemorrhagic proteins of snake venoms are metalloproteinases. Agkistrodon halys metalloproteinase (AHM) was isolated from the snake venom of Pallas (Mol wt. 23145). In vitro toxicological effects of AHM (0.1-2 mM) on human macrophages (THP-1 and U-937), lung fibroblasts (MRC-5) and murine lung epithelial (LA4) cells were evaluated by (2,3-bis- (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-hydroxide) assay and light microscopy. AHM strongly inhibited cell proliferation and adhesion to extracellular matrix, as well as induced morphological changes in a dose-dependent manner. Apoptosis was evaluated using propidium iodide (PI) staining and a terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay for DNA fragmentation. PI staining indicated an accumulation of cells at the sub-G1-phase following AHM treatment, and there was also DNA fragmentation as shown by TUNEL staining. Besides cell-based assays, an in vivo assessment of AHM (1.56-300 mg/kg, body weight) in mice was also done. Histopathology of muscle fibers revealed massive necrotic aggregations after AHM exposure. There were translucent vacuoles in the purkinje cells, which may cause substantial damage to kidney tubular epithelium. There were also clear areas in the cerebellum due to cell death, deposition of fibrinogen or fibrin on the intestinal epithelium, and skin necrosis following an AHM dose of 300 mg/kg. We also observed marked erythrocyte accumulation in lung alveolar walls that resulted in infarction, along with a consequent reduction of the alveolar space and necrosis linked to neutrophil infiltration. These results cumulatively suggest that AHM induces lethality at high doses, inhibits cell proliferation, and induces morphological changes in various cell types.
    Current Chemical Biology 01/2013; 7(3). DOI:10.2174/2212796807999131128125719
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the most common cancer among women. To date, improvements in hormonal and cytotoxic therapies have not yet led to a sustained remission or cure. In the present study, we investigated the in vitro and in vivo antitumor activities of a novel Calotropis procera protein (CP-P) isolated from root bark. CP-P protein inhibited the proliferation and induced apoptosis of breast cancer cells through the suppression of nuclear factor kappaB (NF-kB) activation. CP-P, when administered individually or in combination with cyclophosphamide (CYC, 0.2 mg/kg) to rats with 7, 12-dimethyl benz(a)anthracene (DMBA)-induced breast cancer decreased tumor volume significantly without affecting the body weight. To elucidate the anticancer mechanism of CP-P, antioxidant activities such as superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and non-enzymatic antioxidant - reduced glutathione (GSH), vitamin E and C generation in the breast were analyzed by various assays. SOD, CAT, GST, GSH, vitamin E and C levels were high in combination-treated groups (CP-P+CYC) versus the CYC alone-treated groups. Also, the combination was more effective in down-regulating the expression of NF-kB-regulated gene products (cyclin D1 and Bcl-2) in breast tumor tissues. Our findings indicate that CP-P possesses significant antitumor activity comparable to a commonly used anticancer drug, cyclophosphamide, and may form the basis of a novel therapy for breast cancer.
    PLoS ONE 12/2012; 7(12):e48514. DOI:10.1371/journal.pone.0048514 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Various pathogenic clostridia produce binary protein toxins associated with enteric diseases of humans and animals. Separate binding/translocation (B) components bind to a protein receptor on the cell surface, assemble with enzymatic (A) component(s), and mediate endocytosis of the toxin complex. Ultimately there is translocation of A component(s) from acidified endosomes into the cytosol, leading to destruction of the actin cytoskeleton. Our results revealed that CD44, a multifunctional surface protein of mammalian cells, facilitates intoxication by the iota family of clostridial binary toxins. Specific antibody against CD44 inhibited cytotoxicity of the prototypical Clostridium perfringens iota toxin. Versus CD44(+) melanoma cells, those lacking CD44 bound less toxin and were dose-dependently resistant to C. perfringens iota, as well as Clostridium difficile and Clostridium spiroforme iota-like, toxins. Purified CD44 specifically interacted in vitro with iota and iota-like, but not related Clostridium botulinum C2, toxins. Furthermore, CD44 knockout mice were resistant to iota toxin lethality. Collective data reveal an important role for CD44 during intoxication by a family of clostridial binary toxins.
    PLoS ONE 12/2012; 7(12):e51356. DOI:10.1371/journal.pone.0051356 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The majority of snake venom phospholipases A2 (svPLA2s) are toxic and induce a wide spectrum of biological effects. They are cysteine-rich proteins that contain 119-134 amino acids and share similar structures and functions. About 50% of the residues are incorporated into α-helices, whereas only 10% are in β -sheets. Fourteen conserved cysteines form a network of seven disulfide bridges that stabilize the tertiary structure. They show a high degree of sequence and structural similarity, and are believed to have a common calcium-dependent catalytic mechanism. Additionally, svPLA2s display an array of biological actions that are either dependent or independent of catalysis. The PLA2s of mammalian origin also exert potent bactericidal activity by binding to anionic surfaces and enzymatic degradation of phospholipids in the target membranes, preferentially of Gram-positive species. The bactericidal activity against Gram-negatives by svPLA2 requires a synergistic action with bactericidal/permeability-increasing protein (BPI), but is equally dependent on enzymatic-based membrane degradation. Several hypotheses account for the bactericidal properties of svPLA2s, which include fatal depolarization of the bacterial membrane, creation of physical holes in the membrane, scrambling of normal distribution of lipids between the bilayer leaflets, and damage of critical intracellular targets after internalization of the peptide. The present review discusses several svPLA2s and derived peptides that exhibit strong bactericidal activity. The reports demonstrate that svPLA2 -derived peptides have the potential to counteract microbial infections. In fact, the C-terminal cationic/hydrophobic segment (residues 115-129) of svPLA2s is bactericidal. Thus identification of the bactericidal sites in svPLA2s has potential for developing novel antimicrobials.
    Current Medicinal Chemistry 09/2012; DOI:10.2174/092986712804485791 · 3.85 Impact Factor
  • Source
    Scott A Weinstein, Bradley G Stiles
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycoplasma genitalium is a globally important sexually transmitted pathogen. Men infected with M. genitalium frequently present with dysuria, while women may present with or without urogenital symptoms. In some populations, M. genitalium is significantly associated with HIV-1 infection, and is also an etiological agent in pelvic inflammatory disease. However, there is insufficient evidence to establish a causative role of the organism in obstetric complications, including tubal factor infertility. Although several nucleic acid amplification tests offer rapid, sensitive methods for detecting M. genitalium, there is no standardized assay. Available evidence supports treatment of M. genitalium infections with an extended regimen of azithromycin and resistant strains respond to moxifloxacin. Accumulating evidence indicates growing fluoroquinolone resistance, including against moxifloxacin, emphasizing the need for new therapeutic strategies to treat M. genitalium infections.
    Expert Review of Anticancer Therapy 04/2012; 10(4):487-99. DOI:10.1586/eri.12.20 · 3.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There are many pathogenic Clostridium species with diverse virulence factors that include protein toxins. Some of these bacteria, such as C. botulinum, C. difficile, C. perfringens, and C. spiroforme, cause enteric problems in animals as well as humans. These often fatal diseases can partly be attributed to binary protein toxins that follow a classic AB paradigm. Within a targeted cell, all clostridial binary toxins destroy filamentous actin via mono-ADP-ribosylation of globular actin by the A component. However, much less is known about B component binding to cell-surface receptors. These toxins share sequence homology amongst themselves and with those produced by another Gram-positive, spore-forming bacterium also commonly associated with soil and disease: Bacillus anthracis. This review focuses upon the iota and C2 families of clostridial binary toxins and includes: (1) basics of the bacterial source; (2) toxin biochemistry; (3) sophisticated cellular uptake machinery; and (4) host-cell responses following toxin-mediated disruption of the cytoskeleton. In summary, these protein toxins aid diverse enteric species within the genus Clostridium.
    Frontiers in Cellular and Infection Microbiology 12/2011; 1:11. DOI:10.3389/fcimb.2011.00011 · 2.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Potential bioweapons are biological agents (bacteria, viruses, and toxins) at risk of intentional dissemination. Biodefense, defined as development of therapeutics and vaccines against these agents, has seen an increase, particularly in the US following the 2001 anthrax attack. This review focuses on recombinant antibodies and polyclonal antibodies for biodefense that have been accepted for clinical use. These antibodies aim to protect against primary potential bioweapons, or category A agents as defined by the Centers for Disease Control and Prevention (Bacillus anthracis, Yersinia pestis, Francisella tularensis, botulinum neurotoxins, smallpox virus, and certain others causing viral hemorrhagic fevers) and certain category B agents. Potential for prophylactic use is presented, as well as frequent use of oligoclonal antibodies or synergistic effect with other molecules. Capacities and limitations of antibodies for use in biodefense are discussed, and are generally applicable to the field of infectious diseases.
    mAbs 11/2011; 3(6):517-27. DOI:10.4161/mabs.3.6.17621 · 4.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The innate immune system is the first line of defense against microbial diseases. Antimicrobial proteins produced by snake venoms have recently attracted significant attention due to their relevance to bacterial infection and potential development into new therapeutic agents. Staphylococcus aureus is one of the major human pathogens causing a variety of infections involving pneumonia, toxic shock syndrome, and skin lesions. With the recent emergence of methicillin (MRSA) and vancomycin (VRSA) resistance, S. aureus infection is a serious clinical problem that will have a grave socio-economic impact in the near future. Although S. aureus susceptibility to innate antimicrobial peptides has been reported recently, the protective effect of snake venom phospholipase A₂ (svPLA₂) proteins on the skin from S. aureus infection has been understudied. This review details the protective function of svPLA₂s derived from venoms against skin infections caused by S. aureus. We have demonstrated in vivo that local application of svPLA₂ provides complete clearance of S. aureus within 2 weeks after treatment compared to fusidic acid ointment (FAO). In vitro experiments also demonstrate that svPLA₂ proteins have inhibitory (bacteriostatic) and killing (bactericidal) effects on S. aureus in a dose-dependant manner. The mechanism of bacterial membrane damage and perturbation was clearly evidenced by electron microscopic studies. In summary, svPLA₂s from Viperidae and Elapidae snakes are novel molecules that can activate important mechanisms of innate immunity in animals to endow them with protection against skin infection caused by S. aureus.
    Current Medicinal Chemistry 10/2011; 18(33):5104-13. DOI:10.2174/092986711797636108 · 3.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The CaTx-I (PLA2) toxin of Crotalus adamanteus venom is responsible for most of the symptoms observed during envenomation. Synthetic peptides were designed and screened for venom (0.8 μg/ml) and CaTx-I (0.1 μM) inhibition at varying doses of the peptide (10000- 0.0001 μM) using a Cayman chemical human secretory phospholipase A2 (sPLA2, Type II) assay kit. Further, in vitro neutralization studies were evaluated by a fixed dose of peptide (1 μM) against venom (0.8 μg/ml) and toxin (0.1 μM). Among the linear peptides (PIP-18, cyclic C and PIP59-67) that showed potent neutralizing effects against the venom/toxin of C. adamanteus. PIP-18 [IC50, 1.23 μM] and cyclic C [IC50, 1.27 μM] peptides possessed the strongest inhibitory effect against CaTx-I. A fixed dose of CaTx-I (75 μg/kg) was administered intraperitoneally (i.p.) into mice followed by an i.p. injection of peptides PIP-18 and cyclic C at (6 μg/mouse), venom (150 μg/kg) and toxin CaTx-I alone served as references. Mice treated with PIP-18 and cyclic C showed a very strong neutralizing effect and markedly reduced mortality compared to the control after 24 h. The CA venom and CaTx-I injected mice showed severe toxicity after 24 h. Peptides PIP-18 and cyclic C were non-hemolytic at 100 μM. They produced a significant decrease in lipid peroxidase (LPx) and enhancement of superoxide dismutase (SOD), catalase (CAT) and Glutathione-s-transferase (GST) levels indicating their antioxidant property against venom-induced changes in mice. This study confirmed the potent snake venom neutralizing properties of peptides.
    Current topics in medicinal chemistry 06/2011; 11(20):2540-55. DOI:10.2174/156802611797633384 · 3.45 Impact Factor
  • Source
    Scott A Weinstein, Bradley G Stiles
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycoplasma genitalium is attracting increasing recognition as an important sexually transmitted pathogen. Presented is a review of the epidemiology, detection, presentation and management of M. genitalium infection. Accumulating evidence suggests that M. genitalium is an important cause of non-gonococcal, non-chlamydial urethritis and cervicitis, and is linked with pelvic inflammatory disease and, possibly, obstetric complications. Although there is no standard detection assay, several nucleic acid amplification tests have >95% sensitivity and specificity for M. genitalium. To date, there is a general lack of established protocols for screening in public health clinics. Patients with urethritis or cervicitis should be screened for M. genitalium and some asymptomatic sub-groups should be screened depending on individual factors and local prevalence. Investigations estimating M. genitalium geographic prevalence document generally low incidence, but some communities exhibit infection frequencies comparable to that of Chlamydia trachomatis. Accumulating evidence supports an extended regimen of azithromycin for treatment of M. genitalium infection, as data suggest that stat 1 g azithromycin may be less effective. Although data are limited, azithromycin-resistant cases documented to date respond to an appropriate fluoroquinolone (e.g. moxifloxacin). Inconsistent clinical recognition of M. genitalium may result in treatment failure and subsequent persistence due to ineffective antibiotics. The contrasting nature of existing literature regarding risks of M. genitalium infection emphasises the need for further carefully controlled studies of this emerging pathogen.
    Sexual Health 06/2011; 8(2):143-58. DOI:10.1071/SH10065 · 1.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clostridium difficile is a major enteropathogen of humans. It produces two main virulence factors, toxins A and B. A third, less well known toxin, C. difficile toxin (CDT), is a binary toxin composed of distinct enzymatic (CdtA) and cell binding/translocation (CdtB) proteins. We used a novel enzyme linked immunoassay (EIA) to detect CdtB protein in feces and culture fluids. Additionally, PCR was used to assay C. difficile isolates from fecal samples for the CDT locus (CdtLoc). Although the results from 80 isolates suggest no relationship between toxin concentrations in situ and in vitro, there is a good correlation between PCR detection of the cdtB gene and EIA detection of CdtB protein in vitro. Possible implications of the detection of CDT in patients are discussed.
    Anaerobe 03/2011; 17(4):161-5. DOI:10.1016/j.anaerobe.2011.02.005 · 2.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clostridial binary toxins, such as Clostridium perfringens Iota and Clostridium botulinum C2, are composed of a binding protein (Ib and C2II respectively) that recognizes distinct membrane receptors and mediates internalization of a catalytic protein (Ia and C2-I respectively) with ADP-ribosyltransferase activity that disrupts the actin cytoskeleton. We show here that the endocytic pathway followed by these toxins is independent of clathrin but requires the activity of dynamin and is regulated by Rho-GDI. This endocytic pathway is similar to a recently characterized clathrin-independent pathway followed by the interleukin-2 (IL2) receptor. We found indeed that Ib and C2II colocalized intracellularly with the IL2 receptor but not the transferrin receptor after different times of endocytosis. Accordingly, the intracellular effects of Iota and C2 on the cytoskeleton were inhibited by inactivation of dynamin or by Rho-GDI whereas inhibitors of clathrin-dependent endocytosis had no protective effect.
    Cellular Microbiology 01/2011; 13(1):154-70. DOI:10.1111/j.1462-5822.2010.01527.x · 4.82 Impact Factor
  • Source
    Eileen A Larkin, Bradley G Stiles, Robert G Ulrich
    [Show abstract] [Hide abstract]
    ABSTRACT: Staphylococcus aureus is implicated in many opportunistic bacterial infections around the world. Rising antibiotic resistance and few alternative methods of treatment are just two looming problems associated with clinical management of S. aureus. Among numerous virulence factors produced by S. aureus, staphylococcal enterotoxin (SE) B is a secreted protein that binds T-cell receptor and major histocompatibility complex class II, potentially causing toxic shock mediated by pathological activation of T cells. Recombinant monoclonal antibodies that target SEB and block receptor interactions can be of therapeutic value. The inhibitory and biophysical properties of ten human monoclonal antibodies, isolated from a recombinant library by panning against SEB vaccine (STEBVax), were examined as bivalent Fabs and native full-length IgG (Mab). The best performing Fabs had binding affinities equal to polyclonal IgG, low nanomolar IC(50)s against SEB in cell culture assays, and protected mice from SEB-induced toxic shock. The orthologous staphylococcal proteins, SEC1 and SEC2, as well as streptococcal pyrogenic exotoxin C were recognized by several Fabs. Four Fabs against SEB, with the lowest IC(50)s, were converted into native full-length Mabs. Although SEB-binding kinetics were identical between each Fab and respective Mab, a 250-fold greater inhibition of SEB-induced T-cell activation was observed with two Mabs. Results suggest that these human monoclonal antibodies possess high affinity, target specificity, and toxin neutralization qualities essential for any therapeutic agent.
    PLoS ONE 10/2010; 5(10):e13253. DOI:10.1371/journal.pone.0013253 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Staphylococcus aureus and Streptococcus pyogenes are gram-positive bacteria that possess great pathogenic potential in humans, causing numerous maladies such as arthritis, cutaneous infections, endocarditis, enterocolitis, food poisoning, pharyngitis, pneumonia, rheumatic fever, surgical site infections, and toxic shock. These prevalent pathogens produce various virulence factors that include the staphylococcal enterotoxins (SEs), toxic shock syndrome toxin-1 (TSST-1), and streptococcal pyrogenic exotoxins (SPEs). Minute (picomolar) amounts of these structurally-similar "superantigens" (SAgs) elicit high levels of proinflammatory cytokines and chemokines that can induce fever, hypotension, and lethal shock. In vitro and in vivo models have provided important tools for studying the biological effects of, and potential vaccines plus therapeutics against, these related protein toxins. This review will delve into the known physical and biological properties of the SEs, TSST-1, and SPEs. The reader will hopefully derive a general appreciation of these wonderfully-complex, structurally-similar toxins produced by S. aureus and S. pyogenes.
    The Open Toxinology Journal 03/2010; 3(2). DOI:10.2174/1875414701003020069

Publication Stats

2k Citations
252.60 Total Impact Points

Institutions

  • 1991–2014
    • U.S. Army Medical Research Institute of Infectious Diseases
      Фредерик, Maryland, United States
  • 2010–2013
    • Wilson College
      Chambersburg, Pennsylvania, United States
  • 2009
    • Universität Ulm
      • Institute of Pharmacology and Toxicology
      Ulm, Baden-Wuerttemberg, Germany
  • 1991–2009
    • United States Army Medical Research Institute for Infectious Diseases
      Maryland, United States
  • 1999
    • Shippensburg University
      Shippensburg, Pennsylvania, United States
  • 1997
    • Bernhard Nocht Institute for Tropical Medicine
      Hamburg, Hamburg, Germany
  • 1996
    • University of Havana
      La Habana, La Habana, Cuba
    • Karolinska Institutet
      • Department of Medical Biochemistry and Biophysics
      Solna, Stockholm, Sweden
  • 1989
    • Jefferson College
      Хиллсборо, Missouri, United States
  • 1986
    • Virginia Polytechnic Institute and State University
      Блэксбург, Virginia, United States