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Staphylococcus aureus Infects Osteoclasts and Replicates Intracellularly.
Krauss JL, Roper PM, Ballard A, Shih CC, Fitzpatrick JAJ, Cassat JE, Ng PY, Pavlos NJ, Veis DJ
(2019) mBio 10:
MeSH Terms: Animals, Bacterial Proteins, Cell Differentiation, Cells, Cultured, Female, Macrophages, Male, Mice, Osteoblasts, Osteoclasts, Osteomyelitis, Phagosomes, RANK Ligand, Staphylococcus aureus
Show Abstract · Added March 25, 2020
Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by , and even with proper treatment, OM has a high rate of recurrence and chronicity. While has been shown to infect osteoblasts, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. Here, we demonstrate the ability of to intracellularly infect and divide within OCs. OCs were differentiated from bone marrow macrophages (BMMs) by exposure to receptor activator of nuclear factor kappa-B ligand (RANKL). By utilizing an intracellular survival assay and flow cytometry, we found that at 18 h postinfection the intracellular burden of increased dramatically in cells with at least 2 days of RANKL exposure, while the bacterial burden decreased in BMMs. To further explore the signals downstream of RANKL, we manipulated factors controlling OC differentiation, NFATc1 and alternative NF-κB, and found that intracellular bacterial growth correlates with NFATc1 levels in RANKL-treated cells. Confocal and time-lapse microscopy in mature OCs showed a range of intracellular infection that correlated inversely with -phagolysosome colocalization. The propensity of OCs to become infected, paired with their diminished bactericidal capacity compared to BMMs, could promote OM progression by allowing to evade initial immune regulation and proliferate at the periphery of lesions where OCs are most abundant. The inflammation of bone tissue is called osteomyelitis, and most cases are caused by an infection with the bacterium To date, the bone-building cells, osteoblasts, have been implicated in the progression of these infections, but not much is known about how the bone-resorbing cells, osteoclasts, participate. In this study, we show that can infect osteoclasts and proliferate inside these cells, whereas bone-residing macrophages, immune cells related to osteoclasts, destroy the bacteria. These findings elucidate a unique role for osteoclasts to harbor bacteria during infection, providing a possible mechanism by which bacteria could evade destruction by the immune system.
Copyright © 2019 Krauss et al.
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14 MeSH Terms
A Clinical Review of Diabetic Foot Infections.
Chastain CA, Klopfenstein N, Serezani CH, Aronoff DM
(2019) Clin Podiatr Med Surg 36: 381-395
MeSH Terms: Anti-Bacterial Agents, Debridement, Diabetic Foot, Drug Resistance, Microbial, Humans, Infectious Disease Medicine, Osteomyelitis, Risk Factors, Wound Healing
Show Abstract · Added March 18, 2020
"Diabetic foot infections (DFIs) are a common cause of morbidity and mortality. This article summarizes current knowledge regarding DFI epidemiology, disease pathogenesis, and the impact of antimicrobial resistance among DFI. An evidence-based approach to clinical assessment, diagnosing osteomyelitis, as well as medical and surgical treatment is discussed, including a review of empiric and directed antibiotic treatment recommendations. The current state and needs of the clinical literature are identified throughout, with a discussion of the supporting role of infectious diseases specialists as well as future directions of the field."
Copyright © 2019 Elsevier Inc. All rights reserved.
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MyD88 and IL-1R signaling drive antibacterial immunity and osteoclast-driven bone loss during Staphylococcus aureus osteomyelitis.
Putnam NE, Fulbright LE, Curry JM, Ford CA, Petronglo JR, Hendrix AS, Cassat JE
(2019) PLoS Pathog 15: e1007744
MeSH Terms: Animals, Bone Resorption, Cell Differentiation, Cells, Cultured, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Osteoclasts, Osteomyelitis, Receptors, Interleukin-1 Type I, Signal Transduction, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added April 15, 2019
Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. We previously established that S. aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this study was to identify host immune pathways that contribute to antibacterial immunity during S. aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL-1R) and downstream adapter protein MyD88 given the prominent role of this signaling pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered that while IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demonstrate that S. aureus enhances osteoclastogenesis of myeloid precursors in vitro, and increases the abundance of osteoclasts residing on bone surfaces in vivo. This enhanced osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define IL-1R signaling as a critical component of the host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption.
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16 MeSH Terms
Advances in the local and targeted delivery of anti-infective agents for management of osteomyelitis.
Ford CA, Cassat JE
(2017) Expert Rev Anti Infect Ther 15: 851-860
MeSH Terms: Absorbable Implants, Anti-Infective Agents, Copper, Debridement, Disease Management, Drug Delivery Systems, Humans, Microspheres, Osteomyelitis, Polyurethanes, Silver, Staphylococcal Infections, Staphylococcus aureus, Tissue Scaffolds
Show Abstract · Added April 3, 2018
INTRODUCTION - Osteomyelitis, a common and debilitating invasive infection of bone, is a frequent complication following orthopedic surgery and causes pathologic destruction of skeletal tissues. Bone destruction during osteomyelitis results in necrotic tissue, which is poorly penetrated by antibiotics and can serve as a nidus for relapsing infection. Osteomyelitis therefore frequently necessitates surgical debridement procedures, which provide a unique opportunity for targeted delivery of antimicrobial and adjunctive therapies. Areas covered: Following surgical debridement, tissue voids require implanted materials to facilitate the healing process. Antibiotic-loaded, non-biodegradable implants have been the standard of care. However, a new generation of biodegradable, osteoconductive materials are being developed. Additionally, in the face of widespread antimicrobial resistance, alternative therapies to traditional antibiotic regimens are being investigated, including bone targeting compounds, antimicrobial surface modifications of orthopedic implants, and anti-virulence strategies. Expert commentary: Recent advances in biodegradable drug delivery scaffolds make this technology an attractive alternative to traditional techniques for orthopedic infection that require secondary operations for removal. Advances in novel treatment methods are expanding the arsenal of viable antimicrobial treatment strategies in the face of widespread drug resistance. Despite a need for large scale clinical investigations, these strategies offer hope for future treatment of this difficult invasive disease.
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14 MeSH Terms
Staphylococcus aureus protein A enhances osteoclastogenesis via TNFR1 and EGFR signaling.
Mendoza Bertelli A, Delpino MV, Lattar S, Giai C, Llana MN, Sanjuan N, Cassat JE, Sordelli D, Gómez MI
(2016) Biochim Biophys Acta 1862: 1975-83
MeSH Terms: Animals, Cell Differentiation, ErbB Receptors, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Osteoclasts, Osteomyelitis, RANK Ligand, Receptors, Tumor Necrosis Factor, Type I, Staphylococcal Infections, Staphylococcal Protein A, Staphylococcus aureus, Tumor Necrosis Factor-alpha
Added April 3, 2018
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15 MeSH Terms
Impact of sarA and Phenol-Soluble Modulins on the Pathogenesis of Osteomyelitis in Diverse Clinical Isolates of Staphylococcus aureus.
Loughran AJ, Gaddy D, Beenken KE, Meeker DG, Morello R, Zhao H, Byrum SD, Tackett AJ, Cassat JE, Smeltzer MS
(2016) Infect Immun 84: 2586-94
MeSH Terms: Animals, Bacterial Proteins, Gene Expression Regulation, Bacterial, Mice, Mice, Inbred C57BL, Mutation, Operon, Osteoblasts, Osteoclasts, Osteomyelitis, Proteomics, Staphylococcal Infections, Staphylococcus aureus, Virulence, Virulence Factors
Show Abstract · Added April 3, 2018
We used a murine model of acute, posttraumatic osteomyelitis to evaluate the virulence of two divergent Staphylococcus aureus clinical isolates (the USA300 strain LAC and the USA200 strain UAMS-1) and their isogenic sarA mutants. The results confirmed that both strains caused comparable degrees of osteolysis and reactive new bone formation in the acute phase of osteomyelitis. Conditioned medium (CM) from stationary-phase cultures of both strains was cytotoxic to cells of established cell lines (MC3TC-E1 and RAW 264.7 cells), primary murine calvarial osteoblasts, and bone marrow-derived osteoclasts. Both the cytotoxicity of CM and the reactive changes in bone were significantly reduced in the isogenic sarA mutants. These results confirm that sarA is required for the production and/or accumulation of extracellular virulence factors that limit osteoblast and osteoclast viability and that thereby promote bone destruction and reactive bone formation during the acute phase of S. aureus osteomyelitis. Proteomic analysis confirmed the reduced accumulation of multiple extracellular proteins in the LAC and UAMS-1 sarA mutants. Included among these were the alpha class of phenol-soluble modulins (PSMs), which were previously implicated as important determinants of osteoblast cytotoxicity and bone destruction and repair processes in osteomyelitis. Mutation of the corresponding operon reduced the cytotoxicity of CM from both UAMS-1 and LAC cultures for osteoblasts and osteoclasts. It also significantly reduced both reactive bone formation and cortical bone destruction by CM from LAC cultures. However, this was not true for CM from cultures of a UAMS-1 psmα mutant, thereby suggesting the involvement of additional virulence factors in such strains that remain to be identified.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis.
Hendrix AS, Spoonmore TJ, Wilde AD, Putnam NE, Hammer ND, Snyder DJ, Guelcher SA, Skaar EP, Cassat JE
(2016) Antimicrob Agents Chemother 60: 5322-30
MeSH Terms: Animals, Anti-Bacterial Agents, Anti-Inflammatory Agents, Non-Steroidal, Bacterial Proteins, Bone Density Conservation Agents, Cell Survival, Delayed-Action Preparations, Diflunisal, Drug Repositioning, Female, Gene Expression, Humans, Mice, Mice, Inbred C57BL, Osteoblasts, Osteomyelitis, Primary Cell Culture, Staphylococcal Infections, Staphylococcus aureus, Trans-Activators, Treatment Outcome
Show Abstract · Added April 8, 2017
Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms
Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection.
Wilde AD, Snyder DJ, Putnam NE, Valentino MD, Hammer ND, Lonergan ZR, Hinger SA, Aysanoa EE, Blanchard C, Dunman PM, Wasserman GA, Chen J, Shopsin B, Gilmore MS, Skaar EP, Cassat JE
(2015) PLoS Pathog 11: e1005341
MeSH Terms: Animals, Cell Hypoxia, Cell Line, DNA Transposable Elements, Disease Models, Animal, Female, Gene Expression Regulation, Bacterial, Genes, Viral, Host-Pathogen Interactions, Humans, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Osteomyelitis, Quorum Sensing, Reverse Transcriptase Polymerase Chain Reaction, Staphylococcal Infections, Staphylococcus aureus, Virulence, Virulence Factors
Show Abstract · Added February 8, 2016
Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survival during invasive infection, we performed a transposon sequencing (TnSeq) analysis of S. aureus during experimental osteomyelitis. TnSeq identified 65 genes essential for staphylococcal survival in infected bone and an additional 148 mutants with compromised fitness in vivo. Among the loci essential for in vivo survival was SrrAB, a staphylococcal two-component system previously reported to coordinate hypoxic and nitrosative stress responses in vitro. Healthy bone is intrinsically hypoxic, and intravital oxygen monitoring revealed further decreases in skeletal oxygen concentrations upon S. aureus infection. The fitness of an srrAB mutant during osteomyelitis was significantly increased by depletion of neutrophils, suggesting that neutrophils impose hypoxic and/or nitrosative stresses on invading bacteria. To more globally evaluate staphylococcal responses to changing oxygenation, we examined quorum sensing and virulence factor production in staphylococci grown under aerobic or hypoxic conditions. Hypoxic growth resulted in a profound increase in quorum sensing-dependent toxin production, and a concomitant increase in cytotoxicity toward mammalian cells. Moreover, aerobic growth limited quorum sensing and cytotoxicity in an SrrAB-dependent manner, suggesting a mechanism by which S. aureus modulates quorum sensing and toxin production in response to environmental oxygenation. Collectively, our results demonstrate that bacterial hypoxic responses are key determinants of the staphylococcal-host interaction.
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20 MeSH Terms
Inter- and intraspecies metabolite exchange promotes virulence of antibiotic-resistant Staphylococcus aureus.
Hammer ND, Cassat JE, Noto MJ, Lojek LJ, Chadha AD, Schmitz JE, Creech CB, Skaar EP
(2014) Cell Host Microbe 16: 531-7
MeSH Terms: Animals, Coinfection, Disease Models, Animal, Drug Resistance, Bacterial, Humans, Mice, Inbred C57BL, Microbial Interactions, Mutation, Osteomyelitis, Staphylococcal Infections, Staphylococcus aureus, Virulence
Show Abstract · Added January 20, 2015
Adaptations that enable antimicrobial resistance often pose a fitness cost to the microorganism. Resistant pathogens must therefore overcome such fitness decreases to persist within their hosts. Here we demonstrate that the reduced fitness associated with one resistance-conferring mutation can be offset by community interactions with microorganisms harboring alternative mutations or via interactions with the human microbiota. Mutations that confer antibiotic resistance in the human pathogen Staphylococcus aureus led to decreased fitness, whereas coculture or coinfection of two distinct mutants resulted in collective recovery of fitness comparable to that of wild-type. Such fitness enhancements result from the exchange of metabolites between distinct mutants, leading to enhanced growth, virulence factor production, and pathogenicity. Interspecies fitness enhancements were also identified, as members of the human microbiota can promote growth of antibiotic-resistant S. aureus. Thus, inter- and intraspecies community interactions offset fitness costs and enable S. aureus to develop antibiotic resistance without loss of virulence.
Copyright © 2014 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Recent advances in experimental models of osteomyelitis.
Cassat JE, Skaar EP
(2013) Expert Rev Anti Infect Ther 11: 1263-5
MeSH Terms: Adult, Animals, Anti-Bacterial Agents, Biofilms, Bone and Bones, Child, Disease Models, Animal, Drug Delivery Systems, Drug Resistance, Multiple, Bacterial, Humans, Osteomyelitis, Rabbits, Rats, Staphylococcal Infections, Staphylococcus aureus
Added January 20, 2015
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15 MeSH Terms