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James B Wood, Lauren S Jones, Nicole R Soper, Meng Xu, Victor J Torres, C Buddy Creech, Isaac P Thomsen
Background: Staphylococcus aureus is among the most commonly identified causes of invasive bacterial infection in children; however, reliable results from cultures of sterile-site samples often cannot be obtained, which necessitates prescription of a broad empiric antimicrobial agent(s). Children with invasive S aureus infection rapidly generate high antibody titers to the cytotoxin LukAB; therefore, the aim of this study was to assess the diagnostic utility of an anti-LukAB antibody assay for children with musculoskeletal infection (MSKI)...
March 10, 2018: Journal of the Pediatric Infectious Diseases Society
James B Wood, Lauren S Jones, Nicole R Soper, Meera Nagarsheth, C Buddy Creech, Isaac P Thomsen
The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB...
November 2017: Antimicrobial Agents and Chemotherapy
Adriana Badarau, Nikolina Trstenjak, Eszter Nagy
Staphylococcus aureus can produce up to five different bi-component cytotoxins: two gamma-hemolysins HlgAB and HlgCB, and leukocidins SF-PV (Panton Valentine leukocidin), ED (LukED) and GH (LukGH, also called LukAB). Their major function in S. aureus pathogenesis is to evade innate immunity by attacking phagocytic cells and to support bacterial growth by lysing red blood cells. The five cytotoxins display different levels of amino acid sequence conservation (30-82%), but all form a remarkably similar beta-barrel type pore structure (greatly resembling the mono-component toxin alpha-hemolysin) that inserts into the target cell membrane leading to necrotic cell death...
April 29, 2017: Advances in Experimental Medicine and Biology
Philipp Janesch, Harald Rouha, Susanne Weber, Stefan Malafa, Karin Gross, Barbara Maierhofer, Adriana Badarau, Zehra C Visram, Lukas Stulik, Eszter Nagy
OBJECTIVES: Staphylococcus aureus produces up to five bi-component leukocidins - LukSF-PV, gamma-hemolysins AB and CB, LukGH (LukAB) and LukED - to evade innate immunity by lysing phagocytic cells. Species specificity of these leukocidins limits the relevance of animal models, therefore we assessed their individual contribution using human neutrophils. METHODS: Human polymorphonuclear leukocytes (PMNs) were activated with stimuli relevant during bacterial infections and sensitivity to recombinant leukocidins was measured in cell-viability assays...
May 2017: Journal of Infection
Isaac P Thomsen, Gopal Sapparapu, David B A James, James E Cassat, Meera Nagarsheth, Nurgun Kose, Nicole Putnam, Kristina M Boguslawski, Lauren S Jones, James B Wood, Clarence B Creech, Victor J Torres, James E Crowe
The 2-component leukotoxin LukAB is critical for Staphylococcus aureus targeting and killing of human neutrophils ex vivo and is produced in the setting of human infection. We report 3 LukAB-specific human monoclonal antibodies (mAbs) with distinct mechanisms of toxin neutralization and in vivo efficacy. Three hybridomas secreting mAbs with anti-LukAB activity (designated SA-13, -15, and -17) were generated from B cells obtained from a 12-year-old boy with S. aureus osteomyelitis. Each of the 3 mAbs neutralized LukAB-mediated neutrophil toxicity, exhibited differing levels of potency, recognized different antigenic sites on the toxin, and displayed at least 2 distinct mechanisms for cytotoxic inhibition...
April 1, 2017: Journal of Infectious Diseases
Manouk Vrieling, Eveline M Boerhout, Glenn F van Wigcheren, Kirsten J Koymans, Tanja G Mols-Vorstermans, Carla J C de Haas, Piet C Aerts, Ineke J J M Daemen, Kok P M van Kessel, Ad P Koets, Victor P M G Rutten, Piet J M Nuijten, Jos A G van Strijp, Lindert Benedictus
Staphylococcus aureus is a major human and animal pathogen and a common cause of mastitis in cattle. S. aureus secretes several leukocidins that target bovine neutrophils, crucial effector cells in the defence against bacterial pathogens. In this study, we investigated the role of staphylococcal leukocidins in the pathogenesis of bovine S. aureus disease. We show that LukAB, in contrast to the γ-hemolysins, LukED, and LukMF', was unable to kill bovine neutrophils, and identified CXCR2 as a bovine receptor for HlgAB and LukED...
November 25, 2016: Scientific Reports
Alice Prince, Hui Wang, Kipyegon Kitur, Dane Parker
Staphylococcus aureus is a highly successful human pathogen that has evolved in response to human immune pressure. The common USA300 methicillin-resistant S. aureus (MRSA) strains express a number of toxins, such as Panton-Valentine leukocidin and LukAB, that have specificity for human receptors. Using nonobese diabetic (NOD)-scid IL2Rγnull (NSG) mice reconstituted with a human hematopoietic system, we were able to discriminate the roles of these toxins in the pathogenesis of pneumonia. We demonstrate that expression of human immune cells confers increased severity of USA300 infection...
May 1, 2017: Journal of Infectious Diseases
Adriana Badarau, Harald Rouha, Stefan Malafa, Michael B Battles, Laura Walker, Nels Nielson, Ivana Dolezilkova, Astrid Teubenbacher, Srijib Banerjee, Barbara Maierhofer, Susanne Weber, Lukas Stulik, Derek T Logan, Martin Welin, Irina Mirkina, Clara Pleban, Gerhild Zauner, Karin Gross, Michaela Jägerhofer, Zoltán Magyarics, Eszter Nagy
LukGH (LukAB) is a potent leukocidin of Staphylococcus aureus that lyses human phagocytic cells and is thought to contribute to immune evasion. Unlike the other bi-component leukocidins of S. aureus, LukGH forms a heterodimer before binding to its receptor, CD11b expressed on professional phagocytic cells, and displays significant sequence variation. We employed a high diversity human IgG1 library presented on yeast cells to discover monoclonal antibodies (mAbs) neutralizing the cytolytic activity of LukGH...
October 2016: MAbs
Ashley D Chadha, Isaac P Thomsen, Natalia Jimenez-Truque, Nicole R Soper, Lauren S Jones, Andrew G Sokolow, Victor J Torres, C Buddy Creech
BACKGROUND: Staphylococcus aureus is one of the earliest bacterial pathogens to colonize the lungs of children with cystic fibrosis and is an important contributor to pulmonary exacerbations. The adaptive host response to S. aureus in cystic fibrosis remains inadequately defined and has important implications for pathogenesis and potential interventions. The objectives of this study were to determine the functional antibody response to select staphylococcal exotoxins (LukAB, alpha-hemolysin, and PVL) in children with cystic fibrosis and to evaluate the relationship of this response with pulmonary exacerbations...
September 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Rajan P Adhikari, Thomas Kort, Sergey Shulenin, Tulasikumari Kanipakala, Nader Ganjbaksh, Mary-Claire Roghmann, Frederick W Holtsberg, M Javad Aman
S. aureus vaccine development has proven particularly difficult. The conventional approach to achieve sterile immunity through opsonophagocytic killing has been largely unsuccessful. S. aureus is highly toxigenic and a great body of evidence suggests that a successful future vaccine for this organism should target extracellular toxins which are responsible for host tissue destruction and immunosuppression. Major staphylococcal toxins are alpha toxin (a single subunit hemolysin) along with a group of bicomponent pore-forming toxins (BCPFT), namely Panton-Valentine leukocidin (PVL), gamma hemolysins (HlgCB and AB), LukAB and LukED...
2015: PloS One
Tyler D Scherr, Mark L Hanke, Ouwen Huang, David B A James, Alexander R Horswill, Kenneth W Bayles, Paul D Fey, Victor J Torres, Tammy Kielian
UNLABELLED: The macrophage response to planktonic Staphylococcus aureus involves the induction of proinflammatory microbicidal activity. However, S. aureus biofilms can interfere with these responses in part by polarizing macrophages toward an anti-inflammatory profibrotic phenotype. Here we demonstrate that conditioned medium from mature S. aureus biofilms inhibited macrophage phagocytosis and induced cytotoxicity, suggesting the involvement of a secreted factor(s). Iterative testing found the active factor(s) to be proteinaceous and partially agr-dependent...
2015: MBio
Jason H Melehani, David B A James, Ashley L DuMont, Victor J Torres, Joseph A Duncan
Staphylococcus aureus infections are a growing health burden worldwide, and paramount to this bacterium's pathogenesis is the production of virulence factors, including pore-forming leukotoxins. Leukocidin A/B (LukAB) is a recently discovered toxin that kills primary human phagocytes, though the underlying mechanism of cell death is not understood. We demonstrate here that LukAB is a major contributor to the death of human monocytes. Using a variety of in vitro and ex vivo intoxication and infection models, we found that LukAB activates Caspase 1, promotes IL-1β secretion and induces necrosis in human monocytes...
June 2015: PLoS Pathogens
Kipyegon Kitur, Dane Parker, Pamela Nieto, Danielle S Ahn, Taylor S Cohen, Samuel Chung, Sarah Wachtel, Susan Bueno, Alice Prince
Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells...
April 2015: PLoS Pathogens
Adeline Dozois, Isaac Thomsen, Natalia Jimenez-Truque, Nicole Soper, Alexis Pearson, Pheona Mohamed-Rambaran, Kristen B Dettorre, C Buddy Creech, Seth W Wright
OBJECTIVE: The characteristics of staphylococcal skin and soft tissue infections (SSTIs) are poorly understood in northern South America and the Caribbean. The objectives of this study were to determine the frequency of methicillin resistance among Staphylococcus aureus isolates in an emergency department (ED) in Guyana and to identify specific molecular characteristics of these methicillin-resistant Staphylococcus aureus (MRSA) strains. METHODS: This was a cross-sectional study conducted at the main teaching hospital in Georgetown, Guyana...
October 2015: Emergency Medicine Journal: EMJ
Caralyn E Flack, Oliwia W Zurek, Delisha D Meishery, Kyler B Pallister, Cheryl L Malone, Alexander R Horswill, Jovanka M Voyich
Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the histidine kinase SaeS recognizes specific host stimuli is unknown. After mutagenizing the predicted extracellular loop of SaeS, we discovered one methionine residue (M31) was essential for the ability of S...
May 13, 2014: Proceedings of the National Academy of Sciences of the United States of America
Machi Yanai, Miguel A Rocha, Anthony Z Matolek, Archana Chintalacharuvu, Yasuhiko Taira, Koteswara Chintalacharuvu, David O Beenhouwer
Staphylococcus aureus is a major human pathogen that elaborates several exotoxins. Among these are the bicomponent leukotoxins (BCLs), which include γ-hemolysin, Panton-Valentine leukocidin (PVL), and LukDE. The toxin components are classified as either F or S proteins, which are secreted individually and assemble on cell surfaces to form hetero-oligomeric pores resulting in lysis of PMNs and/or erythrocytes. F and S proteins of γ-hemolysin, PVL and LukDE have ∼ 70% sequence homology within the same class and several heterologous combinations of F and S members from these three bicomponent toxin groups are functional...
2014: PloS One
Ashley L DuMont, Pauline Yoong, Xiang Liu, Christopher J Day, Nicole M Chumbler, David B A James, Francis Alonzo, Nadine J Bode, D Borden Lacy, Michael P Jennings, Victor J Torres
The bicomponent leukotoxins produced by Staphylococcus aureus kill host immune cells through osmotic lysis by forming β-barrel pores in the host plasma membrane. The current model for bicomponent pore formation proposes that octameric pores, comprised of two separate secreted polypeptides (S and F subunits), are assembled from water-soluble monomers in the extracellular milieu and multimerize on target cell membranes. However, it has yet to be determined if all staphylococcal bicomponent leukotoxin family members exhibit these properties...
March 2014: Infection and Immunity
Isaac P Thomsen, Ashley L Dumont, David B A James, Pauline Yoong, Benjamin R Saville, Nicole Soper, Victor J Torres, C Buddy Creech
Despite the importance of Staphylococcus aureus as a common invasive bacterial pathogen, the humoral response to infection remains inadequately defined, particularly in children. The purpose of this study was to assess the humoral response to extracellular staphylococcal virulence factors, including the bicomponent leukotoxins, which are critical for the cytotoxicity of S. aureus toward human neutrophils. Children with culture-proven S. aureus infection were prospectively enrolled and stratified by disease type...
March 2014: Infection and Immunity
Natalia Malachowa, Scott D Kobayashi, Brett Freedman, David W Dorward, Frank R DeLeo
Staphylococcus aureus secretes numerous virulence factors that facilitate evasion of the host immune system. Among these molecules are pore-forming cytolytic toxins, including Panton-Valentine leukocidin (PVL), leukotoxin GH (LukGH; also known as LukAB), leukotoxin DE, and γ-hemolysin. PVL and LukGH have potent cytolytic activity in vitro, and both toxins are proinflammatory in vivo. Although progress has been made toward elucidating the role of these toxins in S. aureus virulence, our understanding of the mechanisms that underlie the proinflammatory capacity of these toxins, as well as the associated host response toward them, is incomplete...
December 15, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Ashley L DuMont, Pauline Yoong, Christopher J Day, Francis Alonzo, W Hayes McDonald, Michael P Jennings, Victor J Torres
Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and cell-type specificities...
June 25, 2013: Proceedings of the National Academy of Sciences of the United States of America
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