The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jean C. Lee - One of the best experts on this subject based on the ideXlab platform.
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Preclinical Efficacy of Clumping Factor A in Prevention of Staphylococcus aureus Infection
mBio, 2016Co-Authors: Xiaogang Wang, Christopher D. Thompson, Saeyoung Park, Wan Beom Park, Jean C. LeeAbstract:ABSTRACT Treatment of Staphylococcus aureus Infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent Staphylococcal Infections remains a priority. To determine whether clumping factor A (ClfA) is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant Staphylococcal Infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel and mixed with Sigma Adjuvant System was more immunogenic and stimulated a more robust Th17 response than ClfA administered with alum alone. ClfA immunization induced the production of functional antibodies in rabbits and mice that blocked S. aureus binding to fibrinogen and were opsonic for S. aureus strains that produced little or no capsular polysaccharide. Mice immunized with ClfA showed a modest reduction in the bacterial burden recovered from subcutaneous abscesses provoked by S. aureus USA300 strain LAC. In addition, the ClfA vaccine reduced lethality in a sepsis model following challenge with strain Newman, but not ST80. Vaccination with ClfA did not protect against surgical wound Infection, renal abscess formation, or bacteremia. Passive immunization with antibodies to ClfA did not protect against Staphylococcal bacteremia in mice or catheter-induced endocarditis in rats. Some enhancement of bacteremia was observed by ClfA immunization or passive administration of ClfA antibodies when mice were challenged by the intraperitoneal route. Although rodent models of Staphylococcal Infection have their limitations, our data do not support the inclusion of ClfA in an S. aureus multivalent vaccine. IMPORTANCE Antibiotics are often ineffective in eradicating Staphylococcus aureus Infections, and thus, a preventative vaccine is sorely needed. Two single-component vaccines and two immunoglobulin preparations failed to meet their designated endpoints in phase III clinical trials. Importantly, recipients of an S. aureus surface protein (iron surface determinant B) vaccine who developed a Staphylococcal Infection experienced a higher rate of multiorgan failure and mortality than placebo controls, raising safety concerns. Multicomponent S. aureus vaccines have now been generated, and several include surface protein clumping factor A (ClfA). We immunized mice with ClfA and generated a robust T cell response and serum antibodies that were functional in vitro . Nonetheless, ClfA was not protective in a number of relevant animal models of S. aureus Infection, and high levels of ClfA antibodies enhanced bacteremia when mice were challenged with community-acquired methicillin-resistant S. aureus strains. Evidence supporting ClfA as a vaccine component is lacking.
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Preclinical Efficacy of Clumping Factor A in Prevention of Staphylococcus aureus Infection
American Society for Microbiology, 2016Co-Authors: Xiaogang Wang, Christopher D. Thompson, Saeyoung Park, Wan Beom Park, Jean C. LeeAbstract:Treatment of Staphylococcus aureus Infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent Staphylococcal Infections remains a priority. To determine whether clumping factor A (ClfA) is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant Staphylococcal Infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel and mixed with Sigma Adjuvant System was more immunogenic and stimulated a more robust Th17 response than ClfA administered with alum alone. ClfA immunization induced the production of functional antibodies in rabbits and mice that blocked S. aureus binding to fibrinogen and were opsonic for S. aureus strains that produced little or no capsular polysaccharide. Mice immunized with ClfA showed a modest reduction in the bacterial burden recovered from subcutaneous abscesses provoked by S. aureus USA300 strain LAC. In addition, the ClfA vaccine reduced lethality in a sepsis model following challenge with strain Newman, but not ST80. Vaccination with ClfA did not protect against surgical wound Infection, renal abscess formation, or bacteremia. Passive immunization with antibodies to ClfA did not protect against Staphylococcal bacteremia in mice or catheter-induced endocarditis in rats. Some enhancement of bacteremia was observed by ClfA immunization or passive administration of ClfA antibodies when mice were challenged by the intraperitoneal route. Although rodent models of Staphylococcal Infection have their limitations, our data do not support the inclusion of ClfA in an S. aureus multivalent vaccine
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reduced neutrophil apoptosis in diabetic mice during Staphylococcal Infection leads to prolonged tnfα production and reduced neutrophil clearance
PLOS ONE, 2011Co-Authors: Frank Hanses, Sunny Park, Jeremy N Rich, Jean C. LeeAbstract:Diabetes is a frequent underlying medical condition among individuals with Staphylococcus aureus Infections, and diabetic patients often suffer from chronic inflammation and prolonged Infections. Neutrophils are the most abundant inflammatory cells during the early stages of bacterial diseases, and previous studies have reported deficiencies in neutrophil function in diabetic hosts. We challenged age-matched hyperglycemic and normoglycemic NOD mice intraperitoneally with S. aureus and evaluated the fate of neutrophils recruited to the peritoneal cavity. Neutrophils were more abundant in the peritoneal fluids of infected diabetic mice by 48 h after bacterial inoculation, and they showed prolonged viability ex vivo compared to neutrophils from infected nondiabetic mice. These differences correlated with reduced apoptosis of neutrophils from diabetic mice and were dependent upon the presence of S. aureus and a functional neutrophil respiratory burst. Decreased apoptosis correlated with impaired clearance of neutrophils by macrophages both in vitro and in vivo and prolonged production of proinflammatory tumor necrosis factor alpha by neutrophils from diabetic mice. Our results suggest that defects in neutrophil apoptosis may contribute to the chronic inflammation and the inability to clear Staphylococcal Infections observed in diabetic patients.
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Development of antiStaphylococcal vaccines
Current Infectious Disease Reports, 2001Co-Authors: Jean C. LeeAbstract:Staphylococcus aureus is frequently isolated from both hospital-acquired and community-acquired Infections, and the emergence of antibiotic resistance among clinical isolates has made treatment of Staphylococcal Infections difficult. This scenario has sparked renewed interest in the development of a vaccine for individuals at high risk for Staphylococcal Infections. As part of the effort to develop a multicomponent vaccine against S. aureus , several vaccine candidates are currently being evaluated in animal models of Staphylococcal Infection or in human clinical trials. The most promising candidates to date include adhesins (fibronectinbinding protein, collagen-binding protein, and fibrinogenbinding protein [clumping factor]), a nontoxic alpha toxin mutant, and capsular polysaccharides type 5 and 8.
Juliane Bubeck Wardenburg - One of the best experts on this subject based on the ideXlab platform.
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α toxin induces platelet aggregation and liver injury during staphylococcus aureus sepsis
Cell Host & Microbe, 2018Co-Authors: Bas G J Surewaard, Ajitha Thanabalasuriar, Zhutian Zeng, Christine Tkaczyk, Taylor S Cohen, Bart W Bardoel, Selina K Jorch, Carsten Deppermann, Juliane Bubeck WardenburgAbstract:Summary During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus Infection, sepsis severity is linked to the bacterial α-toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute Staphylococcal Infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and help eradicate S. aureus. However, at later time points, AT causes aberrant and damaging thrombosis throughout the liver. Treatment with an AT neutralizing antibody (MEDI4893∗) prevents platelet aggregation and subsequent liver damage, without affecting the initial and beneficial platelet recruitment. Thus, AT neutralization may represent a promising approach to combat Staphylococcal-induced intravascular coagulation and organ dysfunction.
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Panton-Valentine Leukocidin Is Not a Virulence Determinant in Murine Models of Community-Associated Methicillin-Resistant Staphylococcus aureus Disease
The Journal of infectious diseases, 2008Co-Authors: Juliane Bubeck Wardenburg, Amy M. Palazzolo-ballance, Michael Otto, Olaf Schneewind, Frank R. DeleoAbstract:Increases in the incidence and severity of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) Infections have spawned efforts to define unique virulence properties among prevalent strains. Panton-Valentine leukocidin (PVL), a pore-forming cytotoxin, has garnered attention because of its epidemiologic association with CA-MRSA. Using both the clinical isolate LAC, which is representative of the epidemic USA300 strain, and its isogenic PVL-negative strain in murine models of Staphylococcal skin Infection and pneumonia, we expanded upon recent studies by assessing the contribution of PVL in the genetic background of BALB/c mice. The data presented in this report support the observation that PVL does not contribute to the pathogenesis of Staphylococcal Infection of mice.
Michael Otto - One of the best experts on this subject based on the ideXlab platform.
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phenol soluble modulins and Staphylococcal Infection
Nature Reviews Microbiology, 2013Co-Authors: Andreas Peschel, Michael OttoAbstract:Staphylococcus aureus is an important human pathogen and a leading cause of death worldwide. Phenol-soluble modulins (PSMs) have recently emerged as a novel toxin family defining the virulence potential of highly aggressive S. aureus isolates. PSMs have multiple roles in Staphylococcal pathogenesis, causing lysis of red and white blood cells, stimulating inflammatory responses and contributing to biofilm development and the dissemination of biofilm-associated Infections. Moreover, the pronounced capacity of PSMs to kill human neutrophils after phagocytosis might explain failures in the development of anti-Staphylococcal vaccines. Here, we discuss recent progress made in our understanding of the biochemical and genetic properties of PSMs and their role in S. aureus pathogenesis, and suggest potential avenues to target PSMs for the development of anti-Staphylococcal drugs.
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novel targeted immunotherapy approaches for Staphylococcal Infection
Expert Opinion on Biological Therapy, 2010Co-Authors: Michael OttoAbstract:Importance of the field: Staphylococcus aureus is a leading human pathogen in the hospital and the community. Many S. aureus strains are resistant to antibiotics, making treatment of S. aureus Infections often very complicated. In contrast to many other bacterial pathogens, a working vaccine has never been found for S. aureus despite considerable efforts in academia and pharmaceutical companies.Areas covered in this review: The latest strategies aimed at finding a working vaccine against S. aureus, including active and passive immunization efforts in pre-clinical and clinical stages, and the molecular reasons for why it may be difficult to develop a vaccine are discussed.What the reader will gain: In addition to receiving an overview of current efforts in S. aureus vaccine research, the reader will understand that vaccine development for S. aureus may be difficult owing to the facts that S. aureus is a commensal microorganism and produces toxins that lyse white blood cells, thereby undermining a vaccine's...
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Panton-Valentine Leukocidin Is Not a Virulence Determinant in Murine Models of Community-Associated Methicillin-Resistant Staphylococcus aureus Disease
The Journal of infectious diseases, 2008Co-Authors: Juliane Bubeck Wardenburg, Amy M. Palazzolo-ballance, Michael Otto, Olaf Schneewind, Frank R. DeleoAbstract:Increases in the incidence and severity of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) Infections have spawned efforts to define unique virulence properties among prevalent strains. Panton-Valentine leukocidin (PVL), a pore-forming cytotoxin, has garnered attention because of its epidemiologic association with CA-MRSA. Using both the clinical isolate LAC, which is representative of the epidemic USA300 strain, and its isogenic PVL-negative strain in murine models of Staphylococcal skin Infection and pneumonia, we expanded upon recent studies by assessing the contribution of PVL in the genetic background of BALB/c mice. The data presented in this report support the observation that PVL does not contribute to the pathogenesis of Staphylococcal Infection of mice.
Olaf Schneewind - One of the best experts on this subject based on the ideXlab platform.
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protein a neutralizing monoclonal antibody protects neonatal mice against staphylococcus aureus
Vaccine, 2015Co-Authors: Vilasack Thammavongsa, Sabine Rauch, Hwan Keun Kim, Dominique Missiakas, Olaf SchneewindAbstract:Staphylococcus aureus is a cause of sepsis and meningitis in very-low-birth-weight (VLBW) infants. Clinical trials with S. aureus specific antibodies failed to protect VLBW neonates, which may be due to the immune evasive attributes of Staphylococcal protein A (SpA). Here we show that mouse monoclonal antibody SpAKKAA-mAb 3F6, which neutralizes the immunoglobulin Fcγ-binding and B cell receptor crosslinking attributes of SpA, protects neonatal mice against S. aureus sepsis and raises protective immunity against subsequent Staphylococcal Infection. We developed a humanized SpAKKAA-mAb that protects neonatal mice against S. aureus sepsis and may therefore be subjected to clinical testing in VLBW neonates.
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Panton-Valentine Leukocidin Is Not a Virulence Determinant in Murine Models of Community-Associated Methicillin-Resistant Staphylococcus aureus Disease
The Journal of infectious diseases, 2008Co-Authors: Juliane Bubeck Wardenburg, Amy M. Palazzolo-ballance, Michael Otto, Olaf Schneewind, Frank R. DeleoAbstract:Increases in the incidence and severity of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) Infections have spawned efforts to define unique virulence properties among prevalent strains. Panton-Valentine leukocidin (PVL), a pore-forming cytotoxin, has garnered attention because of its epidemiologic association with CA-MRSA. Using both the clinical isolate LAC, which is representative of the epidemic USA300 strain, and its isogenic PVL-negative strain in murine models of Staphylococcal skin Infection and pneumonia, we expanded upon recent studies by assessing the contribution of PVL in the genetic background of BALB/c mice. The data presented in this report support the observation that PVL does not contribute to the pathogenesis of Staphylococcal Infection of mice.
James E Cassat - One of the best experts on this subject based on the ideXlab platform.
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host nutrient milieu drives an essential role for aspartate biosynthesis during invasive staphylococcus aureus Infection
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Aimee D Potter, James E Cassat, Casey E Butrico, Caleb A Ford, Jacob M Curry, Irina Trenary, Srivarun S Tummarakota, Andrew S Hendrix, Jamey D YoungAbstract:The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasive S. aureus Infection. We focused specifically on Staphylococcal Infection of bone, one of the most common sites of invasive S. aureus Infection and a unique environment characterized by dynamic substrate accessibility, Infection-induced hypoxia, and a metabolic profile skewed toward aerobic glycolysis. Using a murine model of osteomyelitis, we examined survival of S. aureus mutants deficient in central metabolic pathways, including glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid synthesis/catabolism. Despite the high glycolytic demand of skeletal cells, we discovered that S. aureus requires glycolysis for survival in bone. Furthermore, the TCA cycle is dispensable for survival during osteomyelitis, and S. aureus instead has a critical need for anaplerosis. Bacterial synthesis of aspartate in particular is absolutely essential for Staphylococcal survival in bone, despite the presence of an aspartate transporter, which we identified as GltT and confirmed biochemically. This dependence on endogenous aspartate synthesis derives from the presence of excess glutamate in infected tissue, which inhibits aspartate acquisition by S. aureus Together, these data elucidate the metabolic pathways required for Staphylococcal Infection within bone and demonstrate that the host nutrient milieu can determine essentiality of bacterial nutrient biosynthesis pathways despite the presence of dedicated transporters.
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analysis of the staphylococcus aureus abscess proteome identifies antimicrobial host proteins and bacterial stress responses at the host pathogen interface
Pathogens and Disease, 2013Co-Authors: Ahmed S Attia, James E Cassat, Sheg O Aranmolate, Lisa J Zimmerman, Kelli L Boyd, Eric P SkaarAbstract:Abscesses are a hallmark of invasive Staphylococcal Infections and the site of a dynamic struggle between pathogen and host. However, the precise host and bacterial factors that contribute to abscess formation and maintenance have not been completely described. In this work, we define the Staphylococcus aureus abscess proteome from both wild-type and neutropenic mice to elucidate the host response to Staphylococcal Infection and uncover novel S. aureus virulence factors. Among the proteins identified, the mouse protein histone H4 was enriched in the abscesses of wild-type compared with neutropenic animals. Histone H4 inhibits Staphylococcal growth in vitro demonstrating a role for this protein in the innate immune response to Staphylococcal Infection. These analyses also identified Staphylococcal proteins within the abscess, including known virulence factors and proteins with previously unrecognized roles in pathogenesis. Within the latter group was the universal stress protein Usp2, which was enriched in kidney lesions from neutropenic mice and required for the S. aureus response to stringent stress. Taken together, these data describe the S. aureus abscess proteome and lay the foundation for the identification of contributors to innate immunity and bacterial pathogenesis.