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1.
Environ Pollut ; 314: 120294, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36181932

RESUMEN

Per- and Poly-fluoroalkyl substances (PFAS) are major persistent environmental contaminants. Epidemiological studies have linked PFAS exposures to altered immunity and increased occurrence of infections in children. However, the mechanisms leading to immune susceptibility to bacterial infections remains unclear. To elucidate the mechanism, transcriptional alteration in the Caenorhabditis elegans model caused by a PFAS contaminated environmental water and two reconstituted PFAS solutions were evaluated using RNA-sequencing. PFAS affected the expression of several genes involved in C. elegans immune surveillance to Gram-positive bacteria (cpr-2, tag-38, spp-1, spp-5, clec-7, clec-172). The combined exposure to PFAS and Staphylococcus aureus significantly reduced C. elegans survival and increased intestinal membrane permeability. Furthermore, the growth of S. aureus in the presence of PFAS increased the expression of virulence genes, specifically, the virulence gene regulator saeR and α-hemolysin, hla, which resulted in increased hemolytic activity. The present study demonstrated that PFAS exposure not only increased C. elegans susceptibility to pathogens by reducing host immunity and increasing intestinal membrane permeability, but also increased bacteria virulence. This presents a broader implication for humans and other animals, where environmental contaminants simultaneously reduce host resilience, while, increasing microbial pathogenicity.


Asunto(s)
Caenorhabditis elegans , Fluorocarburos , Staphylococcus aureus , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/inmunología , Caenorhabditis elegans/microbiología , Fluorocarburos/toxicidad , Proteínas Hemolisinas , Inmunidad , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad , Virulencia/genética , Contaminantes Ambientales/toxicidad
2.
Commun Biol ; 5(1): 910, 2022 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-36065015

RESUMEN

Phenol-soluble modulin α (PSMα) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSMß which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Δpsmα, and Δpsmß). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSMα activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSMß has the ability to reduce the neutrophil activating effect of PSMα and to partly reverse the effect of PSMα on the neutrophil response to PMA. Mice infected with S. aureus lacking PSMα had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSMß strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSMα and PSMß play distinct roles in septic arthritis: PSMα aggravates systemic infection, whereas PSMß protects arthritis development.


Asunto(s)
Artritis Infecciosa , Toxinas Bacterianas , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Artritis Infecciosa/metabolismo , Toxinas Bacterianas/metabolismo , Ratones , NADP/metabolismo , Oxidorreductasas/metabolismo , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidad
3.
BMC Microbiol ; 22(1): 219, 2022 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-36115948

RESUMEN

BACKGROUND: The prevalence of Staphylococcus aureus isolates carrying the Panton-Valentine leukocidin (PVL) gene is higher in Africa (≈50%) compared to Europe (< 5%). The study aimed to measure anti-PVL-antibodies in Africans and Germans in a multi-center study and to test whether detected antibodies can neutralize the cytotoxic effect of PVL on polymorphonuclear leukocytes (PMNs). METHODS: Sera from asymptomatic Africans (n = 22, Nigeria, Gabon) and Caucasians (n = 22, Germany) were used to quantify antibody titers against PVL and α-hemolysin (in arbitrary units [AU]) by ELISA. PMNs from one African and German donor were exposed to 5 nM recombinant PVL to measure the neutralizing effect of serial dilutions of pooled sera from African and Caucasian participants, or donor sera at 0.625 and 2.5% (v/v). RESULTS: Anti-PVL-antibodies were significantly higher in Africans than in Germans (1.9 vs. 0.7 AU, p < 0.0001). The pooled sera from the study participants neutralized the cytotoxic effect of PVL on African and German PMNs in a dose dependent manner. Also, neutralization of PVL on PMNs from the African and German donors had a stronger effect with African sera (half-maximal inhibitory concentration (IC50) = 0.27 and 0.47%, respectively) compared to Caucasian sera (IC50 = 3.51 and 3.59% respectively). CONCLUSION: Africans have higher levels of neutralizing anti-PVL-antibodies. It remains unclear if or at what level these antibodies protect against PVL-related diseases.


Asunto(s)
Anticuerpos Neutralizantes/sangre , Leucocidinas , Neutrófilos , Infecciones Estafilocócicas , Staphylococcus aureus , Anticuerpos Neutralizantes/inmunología , Toxinas Bacterianas/sangre , Toxinas Bacterianas/inmunología , Exotoxinas/sangre , Exotoxinas/inmunología , Alemania/epidemiología , Proteínas Hemolisinas , Humanos , Leucocidinas/sangre , Leucocidinas/inmunología , Neutrófilos/inmunología , Nigeria/epidemiología , Infecciones Estafilocócicas/sangre , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad
4.
Proc Natl Acad Sci U S A ; 119(33): e2202661119, 2022 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-35939668

RESUMEN

In Staphylococcus aureus, virulence is under the control of a quorum sensing (QS) circuit encoded in the accessory gene regulator (agr) genomic locus. Key to this pathogenic behavior is the production and signaling activity of a secreted pheromone, the autoinducing peptide (AIP), generated following the ribosomal synthesis and posttranslational modification of a precursor polypeptide, AgrD, through two discrete cleavage steps. The integral membrane protease AgrB is known to catalyze the first processing event, generating the AIP biosynthetic intermediate, AgrD (1-32) thiolactone. However, the identity of the second protease in this biosynthetic pathway, which removes an N-terminal leader sequence, has remained ambiguous. Here, we show that membrane protease regulator of agr QS (MroQ), an integral membrane protease recently implicated in the agr response, is directly involved in AIP production. Genetic complementation and biochemical experiments reveal that MroQ proteolytic activity is required for AIP biosynthesis in agr specificity group I and group II, but not group III. Notably, as part of this effort, the biosynthesis and AIP-sensing arms of the QS circuit were reconstituted together in vitro. Our experiments also reveal the molecular features guiding MroQ cleavage activity, a critical factor in defining agr specificity group identity. Collectively, our study adds to the molecular understanding of the agr response and Staphylococcus aureus virulence.


Asunto(s)
Proteínas Bacterianas , Proteínas de la Membrana , Péptido Hidrolasas , Feromonas , Percepción de Quorum , Staphylococcus aureus , Transactivadores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/fisiología , Proteínas de la Membrana/fisiología , Péptido Hidrolasas/genética , Péptido Hidrolasas/fisiología , Feromonas/biosíntesis , Percepción de Quorum/genética , Staphylococcus aureus/patogenicidad , Transactivadores/genética , Transactivadores/metabolismo , Virulencia
5.
Proc Natl Acad Sci U S A ; 119(31): e2123017119, 2022 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-35881802

RESUMEN

Staphylococcus aureus is an opportunistic pathogen and chief among bloodstream-infecting bacteria. S. aureus produces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection with S. aureus using RNA-sequencing (RNA-Seq). We found that the overall transcriptional response to S. aureus was weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection with S. aureus resulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverse S. aureus clones but absent in blood exposed to heat-killed S. aureus or blood infected with the less virulent staphylococcal species Staphylococcus epidermidis. Notably, this signature was also present in patients with S. aureus bacteremia. We identified the master regulator S. aureus exoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. The S. aureus-mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-type S. aureus elicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lacking saeRS. Thus, S. aureus blunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.


Asunto(s)
Interacciones Huésped-Patógeno , Neutrófilos , Infecciones Estafilocócicas , Staphylococcus aureus , Bacteriemia/inmunología , Bacteriemia/microbiología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Citocinas/metabolismo , Regulación Bacteriana de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , Neutrófilos/inmunología , Neutrófilos/microbiología , Proteínas Citotóxicas Formadoras de Poros/genética , Infecciones Estafilocócicas/sangre , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Staphylococcus epidermidis/patogenicidad , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
6.
Proc Natl Acad Sci U S A ; 119(30): e2118262119, 2022 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-35858453

RESUMEN

Human infections with methicillin-resistant Staphylococcus aureus (MRSA) are commonly treated with vancomycin, and strains with decreased susceptibility, designated as vancomycin-intermediate S. aureus (VISA), are associated with treatment failure. Here, we profiled the phenotypic, mutational, and transcriptional landscape of 10 VISA strains adapted by laboratory evolution from one common MRSA ancestor, the USA300 strain JE2. Using functional and independent component analysis, we found that: 1) despite the common genetic background and environmental conditions, the mutational landscape diverged between evolved strains and included mutations previously associated with vancomycin resistance (in vraT, graS, vraFG, walKR, and rpoBCD) as well as novel adaptive mutations (SAUSA300_RS04225, ssaA, pitAR, and sagB); 2) the first wave of mutations affected transcriptional regulators and the second affected genes involved in membrane biosynthesis; 3) expression profiles were predominantly strain-specific except for sceD and lukG, which were the only two genes significantly differentially expressed in all clones; 4) three independent virulence systems (φSa3, SaeR, and T7SS) featured as the most transcriptionally perturbed gene sets across clones; 5) there was a striking variation in oxacillin susceptibility across the evolved lineages (from a 10-fold increase to a 63-fold decrease) that also arose in clinical MRSA isolates exposed to vancomycin and correlated with susceptibility to teichoic acid inhibitors; and 6) constitutive expression of the VraR regulon explained cross-susceptibility, while mutations in walK were associated with cross-resistance. Our results show that adaptation to vancomycin involves a surprising breadth of mutational and transcriptional pathways that affect antibiotic susceptibility and possibly the clinical outcome of infections.


Asunto(s)
Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Staphylococcus aureus , Resistencia a la Vancomicina , Vancomicina , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Evolución Molecular , Humanos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Pruebas de Sensibilidad Microbiana , Oxacilina/química , Oxacilina/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Vancomicina/química , Vancomicina/farmacología , Vancomicina/uso terapéutico , Resistencia a la Vancomicina/genética , Virulencia/genética
7.
Biomed Res Int ; 2022: 8221622, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35586806

RESUMEN

Staphylococcus aureus is a major human bacterial pathogen that carries a large number of virulence factors. Many virulence factors of S. aureus are regulated by the accessory gene regulator (agr) quorum-sensing system. Phenol-soluble modulins (PSMs) are one of the agr-mediated virulence determinants known to play a significant role in S. aureus pathogenesis. In the present study, the efficacy of thymol to inhibit PSM production including δ-toxin in S. aureus was explored. We employed liquid chromatography-mass spectrometry (LC-MS) to quantify the PSMsα1-PSMα4, PSMß1 and PSMß2, and δ-toxin production from culture supernatants. We found that thymol at 0.5 MIC (128 µg/mL) significantly reduced the PSMα and δ-toxin production in S. aureus WKZ-1, WKZ-2, LAC USA300, and ATCC29213. Downregulation in transcription by quantitative real-time (qRT) PCR analysis of response regulator agrA and receptor histidine kinase agrC upon 0.5 MIC thymol treatment affirmed the results of LC-MS quantification of PSMs. In silico molecular docking analysis demonstrated the binding affinity of thymol with receptors AgrA and AgrC. Transmission electron microscopy images revealed no ultrastructural alterations (cell wall and membrane) in thymol-treated WKZ-1 and WKZ-2 S. aureus strains. Here, we demonstrated that thymol reduces various PSM production in S. aureus clinical isolates and reference strains with mass spectrometry.


Asunto(s)
Toxinas Bacterianas , Staphylococcus aureus , Timol , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Percepción de Quorum , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidad , Timol/farmacología , Factores de Virulencia/genética , Factores de Virulencia/metabolismo
8.
J Mol Biol ; 434(12): 167623, 2022 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-35533763

RESUMEN

Pathogenic Staphylococcus aureus actively acquires iron from human hemoglobin (Hb) using the IsdH surface receptor. Heme extraction is mediated by a tri-domain unit within the receptor that contains its second (N2) and third (N3) NEAT domains joined by a helical linker domain. Extraction occurs within a dynamic complex, in which receptors engage each globin chain; the N2 domain tightly binds to Hb, while substantial inter-domain motions within the receptor enable its N3 domain to transiently distort the globin's heme pocket. Using molecular simulations coupled with Markov modeling, along with stopped-flow experiments to quantitatively measure heme transfer kinetics, we show that directed inter-domain motions within the receptor play a critical role in the extraction process. The directionality of N3 domain motion and the rate of heme extraction is controlled by amino acids within a short, flexible inter-domain tether that connects the N2 and linker domains. In the wild-type receptor directed motions originating from the tether enable the N3 domain to populate configurations capable of distorting Hb's pocket, whereas mutant receptors containing altered tethers are less able to adopt these conformers and capture heme slowly via indirect processes in which Hb first releases heme into the solvent. Thus, our results show inter-domain motions within the IsdH receptor play a critical role in its ability to extract heme from Hb and highlight the importance of directed motions by the short, unstructured, amino acid sequence connecting the domains in controlling the directionality and magnitude of these functionally important motions.


Asunto(s)
Antígenos Bacterianos , Hemo , Hemoglobinas , Receptores de Superficie Celular , Infecciones Estafilocócicas , Staphylococcus aureus , Antígenos Bacterianos/química , Antígenos Bacterianos/genética , Hemo/química , Hemoglobinas/química , Humanos , Simulación de Dinámica Molecular , Movimiento (Física) , Dominios Proteicos , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/patogenicidad
9.
Int J Mol Sci ; 23(3)2022 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-35163165

RESUMEN

Recently, the drawbacks arising from the overuse of antibiotics have drawn growing public attention. Among them, drug-resistance (DR) and even multidrug-resistance (MDR) pose significant challenges in clinical practice. As a representative of a DR or MDR pathogen, Staphylococcus aureus can cause diversity of infections related to different organs, and can survive or adapt to the diverse hostile environments by switching into other phenotypes, including biofilm and small colony variants (SCVs), with altered physiologic or metabolic characteristics. In this review, we briefly describe the development of the DR/MDR as well as the classical mechanisms (accumulation of the resistant genes). Moreover, we use multidimensional scaling analysis to evaluate the MDR relevant hotspots in the recent published reports. Furthermore, we mainly focus on the possible non-classical resistance mechanisms triggered by the two important alternative phenotypes of the S. aureus, biofilm and SCVs, which are fundamentally caused by the different global regulation of the S. aureus population, such as the main quorum-sensing (QS) and agr system and its coordinated regulated factors, such as the SarA family proteins and the alternative sigma factor σB (SigB). Both the biofilm and the SCVs are able to escape from the host immune response, and resist the therapeutic effects of antibiotics through the physical or the biological barriers, and become less sensitive to some antibiotics by the dormant state with the limited metabolisms.


Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Biopelículas/crecimiento & desarrollo , Farmacorresistencia Bacteriana/genética , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Animales , Proteínas Bacterianas/genética , Biopelículas/efectos de los fármacos , Regulación Bacteriana de la Expresión Génica , Humanos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad
10.
J Immunol ; 208(5): 1170-1179, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35140134

RESUMEN

Mucosa-associated invariant T (MAIT) cells recognize bacterial riboflavin metabolite Ags presented by MHC class Ib-related protein (MR1) and play important roles in immune control of microbes that synthesize riboflavin. This includes the pathobiont Staphylococcus aureus, which can also express a range of virulence factors, including the secreted toxin leukocidin ED (LukED). In this study, we found that human MAIT cells are hypersensitive to LukED-mediated lysis and lost on exposure to the toxin, leaving a T cell population devoid of MAIT cells. The cytolytic effect of LukED on MAIT cells was rapid and occurred at toxin concentrations lower than those required for toxicity against conventional T cells. Furthermore, this coincided with high MAIT cell expression of CCR5, and loss of these cells was efficiently inhibited by the CCR5 inhibitor maraviroc. Interestingly, exposure and preactivation of MAIT cells with IL-12 and IL-18, or activation via TCR triggering, partially protected from LukED toxicity. Furthermore, analysis of NK cells indicated that LukED targeted the mature cytotoxic CD57+ NK cell subset in a CCR5-independent manner. Overall, these results indicate that LukED efficiently eliminates immune cells that can respond rapidly to S. aureus in an innate fashion without the need for clonal expansion, and that MAIT cells are exceptionally vulnerable to this toxin. Thus, the findings support a model where LukED secretion may allow S. aureus to avoid recognition by the rapid cell-mediated responses mediated by MAIT cells and NK cells.


Asunto(s)
Evasión Inmune/inmunología , Células Asesinas Naturales/inmunología , Leucocidinas/metabolismo , Células T Invariantes Asociadas a Mucosa/patología , Receptores CCR5/metabolismo , Staphylococcus aureus/patogenicidad , Antagonistas de los Receptores CCR5/farmacología , Línea Celular , Humanos , Subunidad p35 de la Interleucina-12/metabolismo , Interleucina-18/metabolismo , Activación de Linfocitos/inmunología , Maraviroc/farmacología , Células T Invariantes Asociadas a Mucosa/inmunología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/inmunología , Células THP-1 , Factores de Virulencia/metabolismo
11.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35165181

RESUMEN

Staphylococcus aureus is a foremost bacterial pathogen responsible for a vast array of human diseases. Staphylococcal superantigens (SAgs) constitute a family of exotoxins from S. aureus that bind directly to major histocompatibility complex (MHC) class II and T cell receptors to drive extensive T cell activation and cytokine release. Although these toxins have been implicated in serious disease, including toxic shock syndrome, the specific pathological mechanisms remain unclear. Herein, we aimed to elucidate how SAgs contribute to pathogenesis during bloodstream infections and utilized transgenic mice encoding human MHC class II to render mice susceptible to SAg activity. We demonstrate that SAgs contribute to S. aureus bacteremia by massively increasing bacterial burden in the liver, and this was mediated by CD4+ T cells that produced interferon gamma (IFN-γ) to high levels in a SAg-dependent manner. Bacterial burdens were reduced by blocking IFN-γ, phenocopying SAg-deletion mutant strains, and inhibiting a proinflammatory response. Infection kinetics and flow cytometry analyses suggested that this was a macrophage-driven mechanism, which was confirmed through macrophage-depletion experiments. Experiments in human cells demonstrated that excessive IFN-γ allowed S. aureus to replicate efficiently within macrophages. This indicates that SAgs promote bacterial survival by manipulating the immune response to inhibit effective clearing of S. aureus Altogether, this work implicates SAg toxins as critical therapeutic targets for preventing persistent or severe S. aureus disease.


Asunto(s)
Interferón gamma/inmunología , Infecciones Estafilocócicas/inmunología , Superantígenos/inmunología , Animales , Bacteriemia , Enterotoxinas/inmunología , Exotoxinas/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/inmunología , Staphylococcus aureus/patogenicidad , Linfocitos T/inmunología , Factores de Virulencia/inmunología
12.
PLoS One ; 17(2): e0263847, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35180238

RESUMEN

BACKGROUND: The interaction between pathogenic bacteria and cholesterol crystals (CCs) has not been investigated. However, CCs are found extensively in atherosclerotic plaques and sclerotic cardiac valves. Interactions between pathogenic bacteria and CCs could provide insights into destabilization of atherosclerotic plaques and bacterial adhesion to cardiac valves. METHODS: Staphylococcus aureus and Pseudomonas aeruginosa were used to assess in vitro bacterial adhesion to CCs and proliferation in the presence of CCs compared to plastic microspheres and glass shards as controls. Ex vivo studies evaluated bacterial adhesion to atherosclerotic rabbit arteries compared to normal arteries and human atherosclerotic carotid plaques compared to normal carotid arteries. Scanning electron microscopy (SEM) was used to visualize bacterial adhesion to CCs and confocal microscopy was used to detect cholesterol binding to bacteria grown in the presence or absence of CCs. RESULTS: In vitro, S. aureus and P. aeruginosa displayed significantly greater adhesion, 36% (p<0.0001) and 89% (p<0.0001), respectively, and growth upon exposure to CCs compared to microspheres or glass shards. Rabbit and human atherosclerotic arteries contained significantly greater bacterial burdens compared to controls (4× (p<0.0004); 3× (p<0.019), respectively. SEM demonstrated that bacteria adhered and appeared to degrade CCs. Consistent with this, confocal microscopy indicated increased cholesterol bound to the bacterial cells. CONCLUSIONS: This study is the first to demonstrate an interaction between bacteria and CCs showing that bacteria dissolve and bind to CCs. This interaction helps to elucidate adhesion of bacteria to sclerotic valves and atherosclerotic plaques that may contribute to endocarditis and plaque destabilization.


Asunto(s)
Aterosclerosis/microbiología , Colesterol/metabolismo , Endocarditis/microbiología , Pseudomonas aeruginosa/patogenicidad , Staphylococcus aureus/patogenicidad , Animales , Aterosclerosis/metabolismo , Colesterol/química , Cristalización , Endocarditis/metabolismo , Humanos , Conejos
13.
Arterioscler Thromb Vasc Biol ; 42(3): 261-276, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35109674

RESUMEN

Over the past 10 years, neutrophil extracellular traps (NETs) have become widely accepted as an integral player in immunothrombosis, due to their complex interplay with both pathogens and components of the coagulation system. While the release of NETs is an attempt by neutrophils to trap pathogens and constrain infections, NETs can have bystander effects on the host by inducing uncontrolled thrombosis, inflammation, and tissue damage. From an evolutionary perspective, pathogens have adapted to bypass the host innate immune response. Staphylococcus aureus (S. aureus), in particular, proficiently overcomes NET formation using several virulence factors. Here we review mechanisms of NET formation and how these are intertwined with platelet activation, the release of endothelial von Willebrand factor, and the activation of the coagulation system. We discuss the unique ability of S. aureus to modulate NET formation and alter released NETs, which helps S. aureus to escape from the host's defense mechanisms. We then discuss how platelets and the coagulation system could play a role in NET formation in S. aureus-induced infective endocarditis, and we explain how targeting these complex cellular interactions could reveal novel therapies to treat this disease and other immunothrombotic disorders.


Asunto(s)
Trampas Extracelulares/inmunología , Trampas Extracelulares/microbiología , Staphylococcus aureus/patogenicidad , /etiología , Animales , Factores de Coagulación Sanguínea/inmunología , Interacciones Microbiota-Huesped/inmunología , Humanos , Evasión Inmune , Ratones , Modelos Cardiovasculares , Modelos Inmunológicos , Neutrófilos/inmunología , Neutrófilos/microbiología , Activación Plaquetaria , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/inmunología , /microbiología , Factores de Virulencia/inmunología , Factor de von Willebrand/inmunología
14.
Sci Rep ; 12(1): 1971, 2022 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-35121806

RESUMEN

Various materials are used in bone tissue engineering (BTE). Graphene oxide (GO) is a good candidate for BTE due to its antibacterial activity and biocompatibility. In this study, an innovative biomaterial consists of GO, agarose and hydroxyapatite (HA) was synthesized using electrophoresis system. The characterization of the synthesized biomaterial showed that needle-like crystals with high purity were formed after 10 mA/10 h of electrophoresis treatment. Furthermore, the calcium-phosphate ratio was similar to thermodynamically stable HA. In the synthesized biomaterial with addition of 1.0 wt% of GO, the colony forming units test showed significantly less Staphylococcus aureus. Initial attachment of MC3T3-E1 cells on the synthesized biomaterial was observed which showed the safety of the synthesized biomaterial for cell viability. This study showed that the synthesized biomaterial is a promising material that can be used in BTE.


Asunto(s)
Huesos/efectos de los fármacos , Nanopartículas/química , Infecciones Estafilocócicas/tratamiento farmacológico , Ingeniería de Tejidos , Antibacterianos/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Huesos/química , Supervivencia Celular/efectos de los fármacos , Durapatita/química , Grafito/química , Humanos , Sefarosa/química , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidad
15.
Microbiol Spectr ; 10(1): e0133421, 2022 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-35044202

RESUMEN

Staphylococcus aureus is a prominent nosocomial pathogen that causes several life-threatening diseases, such as pneumonia and bacteremia. S. aureus modulates the expression of its arsenal of virulence factors through sensing and integrating responses to environmental signals. The agr (accessory gene regulator) quorum sensing (QS) system is a major regulator of virulence phenotypes in S. aureus. There are four agr specificity groups each with a different autoinducer peptide sequence encoded by the agrD gene. Although agr is critical for the expression of many toxins, paradoxically, S. aureus strains often have nonfunctional agr activity due to loss-of-function mutations in the four-gene agr operon. To understand patterns in agr variability across S. aureus, we undertook a species-wide genomic investigation. We developed a software tool (AgrVATE; https://github.com/VishnuRaghuram94/AgrVATE) for typing and detecting frameshift mutations in the agr operon. In an analysis of over 40,000 S. aureus genomes, we showed a close association between agr type and S. aureus clonal complex. We also found a strong linkage between agrBDC alleles (encoding the peptidase, autoinducing peptide itself, and peptide sensor, respectively) but not agrA (encoding the response regulator). More than 5% of the genomes were found to have frameshift mutations in the agr operon. While 52% of these frameshifts occurred only once in the entire species, we observed cases where the recurring mutations evolved convergently across different clonal lineages with no evidence of long-term phylogenetic transmission, suggesting that strains with agr frameshifts were evolutionarily short-lived. Overall, genomic analysis of agr operon suggests evolution through multiple processes with functional consequences that are not fully understood. IMPORTANCE Staphylococcus aureus is a globally pervasive pathogen that produces a plethora of toxic molecules that can harm host immune cells. Production of these toxins is mainly controlled by an active agr quorum-sensing system, which senses and responds to bacterial cell density. However, there are many reports of S. aureus strains with genetic changes leading to impaired agr activity that are often found during chronic bloodstream infections and may be associated with increased disease severity. We developed an open-source software called AgrVATE to type agr systems and identify mutations. We used AgrVATE for a species-wide genomic survey of S. aureus, finding that more than 5% of strains in the public database had nonfunctional agr systems. We also provided new insights into the evolution of these genetic mutations in the agr system. Overall, this study contributes to our understanding of a common but relatively understudied means of virulence regulation in S. aureus.


Asunto(s)
Evolución Molecular , Mutación del Sistema de Lectura , Genoma Bacteriano , Filogenia , Staphylococcus aureus/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Humanos , Operón , Programas Informáticos , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/clasificación , Staphylococcus aureus/aislamiento & purificación , Staphylococcus aureus/patogenicidad , Transactivadores/genética , Transactivadores/metabolismo , Virulencia
16.
Int J Mol Sci ; 23(2)2022 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-35055134

RESUMEN

The main purpose of this review is to present justification for the urgent need to implement specific prophylaxis of invasive Staphylococcus aureus infections. We emphasize the difficulties in achieving this goal due to numerous S. aureus virulence factors important for the process of infection and the remarkable ability of these bacteria to avoid host defense mechanisms. We precede these considerations with a brief overview of the global necessitiy to intensify the use of vaccines against other pathogens as well, particularly in light of an impasse in antibiotic therapy. Finally, we point out global trends in research into modern technologies used in the field of molecular microbiology to develop new vaccines. We focus on the vaccines designed to fight the infections caused by S. aureus, which are often resistant to the majority of available therapeutic options.


Asunto(s)
Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas/uso terapéutico , Staphylococcus aureus/inmunología , Farmacorresistencia Bacteriana/efectos de los fármacos , Humanos , Infecciones Estafilocócicas/inmunología , Vacunas Estafilocócicas/inmunología , Vacunas Estafilocócicas/farmacología , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Factores de Virulencia/genética , Factores de Virulencia/inmunología
17.
Cell Immunol ; 372: 104483, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35085880

RESUMEN

The occurring in SR-A/CD204- or CD36-deficient mice increased susceptibility to infections with Staphylococcus aureus (Sa) had traditionally been ascribed to the impairment of macrophage-mediated phagocytosis, which is, however, inconsistent with low effectiveness of unopsonized Sa killing within macrophages and redundant roles of both receptors in this process. We have found that Sa-stimulated cytokine production in mouse macrophages seems to be exclusively mediated by TLR2, mainly from within endosomes in response to Sa-derived lipoteichoic acid. By driving endocytic trafficking of TLR2 and its ligands through the clathrin-dependent pathway, CD36 and SR-A sensitize macrophages to activation by Sa as well as regulate the type and amount of cytokines produced. Additionally, upon direct Sa binding, both receptors autonomously generate anti-inflammatory signaling. Consequently, the delayed induction of acute inflammation in knockout mice may allow for the initial, uncontrolled multiplication of bacteria, stimulating excessive, septic shock-inducing production of inflammatory cytokines in later stages of infection.


Asunto(s)
Antígenos CD36/inmunología , Citocinas/biosíntesis , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/microbiología , Receptores Depuradores de Clase A/inmunología , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad , Animales , Antígenos CD36/deficiencia , Antígenos CD36/genética , Endocitosis/inmunología , Ligandos , Receptores de Lipopolisacáridos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Reconocimiento de Patrones/inmunología , Receptores Depuradores de Clase A/deficiencia , Receptores Depuradores de Clase A/genética , Transducción de Señal/inmunología , Receptor Toll-Like 2/inmunología
18.
Allergol Int ; 71(1): 31-39, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34838450

RESUMEN

The skin microbiome is a key component of pathogenesis in atopic dermatitis (AD). The skin of AD patients is characterized by microbial dysbiosis, with a reduction of microbial diversity and overrepresentation of pathogenic Staphylococcus aureus (S. aureus). Recent exciting studies have elucidated an importance of establishing an appropriate immune response to microbes in early life and uncovered the new mechanisms of microbial community dynamics in modulating our skin microbiome. Several microbes are associated with AD pathogenesis, with proposed pathogenic effects from S. aureus and Malassezia. The complex relationships between microbes within the skin microbiome consortia includes various species, such as Staphylococcal, Roseomonas and Cutibacterium strains, that can inhibit S. aureus and are potential probiotics for AD skin. Numerous microbes are now also reported to modulate host response via communication with keratinocytes, specialized immune cells and adipocytes to improve skin health and barrier function. This increased understanding of skin microbiota bioactives has led to new biotherapeutic approaches that target the skin surface microenvironment for AD treatment.


Asunto(s)
Dermatitis Atópica/microbiología , Microbiota , Piel/microbiología , Adolescente , Adulto , Niño , Preescolar , Dermatitis Atópica/terapia , Femenino , Humanos , Masculino , Staphylococcus aureus/inmunología , Staphylococcus aureus/patogenicidad , Brote de los Síntomas , Adulto Joven
19.
J Clin Lab Anal ; 36(1): e24121, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34837244

RESUMEN

BACKGROUND: Small colony variants (SCVs) of Staphylococcus aureus (S. aureus) frequently lead to chronic and recurrent infections, but they are always ignored and there are few researches on their clinical isolates. We intended to investigate the prevalence and characteristics of S. aureus SCVs. METHODS: None-duplicated S. aureus strains isolated from wound samples were collected from January 2018 to December 2020. The characteristics (i.e. colony morphology, growth rate, coagulase, biofilm formation, and pathogenic characteristics), antimicrobial susceptibilities, and resistance mechanisms of SCVs were also investigated. The genetic background of SCVs was analyzed through staphylococcal protein A (SPA) typing, sequence typing, and pulse field gel electrophoresis (PFGE). RESULTS: Three SCVs were screened from 278 S. aureus strains (1.1%). They formed pinpoint white colonies on blood agar plates with weak hemolysis. The reproduction speed in liquid medium was very slow for SCVs strains. The coagulase weakened or disappeared, and the ability to form biofilm varied greatly. Only slight inflammation was triggered when wound infected. The SPA typing was t2592, t233, and t023, and the sequence typing was ST88, ST239, and ST965, respectively. The PFGE revealed three SCVs were singletons. CONCLUSIONS: The rate of SCVs in wound sample is low in our hospital, and the formation is associated with the usage of antimicrobial. SCVs grow slowly, and their colony morphology and biochemical characteristics are significantly different from classic S. aureus. SCVs may cause chronic infection and weak inflammation. SCVs form in resistant or susceptible strains, and there is no clonal epidemic in this hospital.


Asunto(s)
Infecciones Estafilocócicas/microbiología , Staphylococcus aureus , Infección de Heridas/microbiología , Antibacterianos/farmacología , China , ADN Bacteriano/genética , Farmacorresistencia Bacteriana/genética , Humanos , Pruebas de Sensibilidad Microbiana , Tipificación Molecular , Staphylococcus aureus/clasificación , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Centros de Atención Terciaria
20.
Nat Microbiol ; 7(1): 62-72, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34873293

RESUMEN

Swift recruitment of phagocytic leucocytes is critical in preventing infection when bacteria breach through the protective layers of the skin. According to canonical models, this occurs via an indirect process that is initiated by contact of bacteria with resident skin cells and which is independent of the pathogenic potential of the invader. Here we describe a more rapid mechanism of leucocyte recruitment to the site of intrusion of the important skin pathogen Staphylococcus aureus that is based on direct recognition of specific bacterial toxins, the phenol-soluble modulins (PSMs), by circulating leucocytes. We used a combination of intravital imaging, ear infection and skin abscess models, and in vitro gene expression studies to demonstrate that this early recruitment was dependent on the transcription factor EGR1 and contributed to the prevention of infection. Our findings refine the classical notion of the non-specific and resident cell-dependent character of the innate immune response to bacterial infection by demonstrating a pathogen-specific high-alert mechanism involving direct recruitment of immune effector cells by secreted bacterial products.


Asunto(s)
Toxinas Bacterianas/inmunología , Linfocitos/inmunología , Infiltración Neutrófila/inmunología , Piel/inmunología , Piel/microbiología , Infecciones Cutáneas Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Animales , Femenino , Humanos , Microscopía Intravital/métodos , Ratones Endogámicos C57BL , Staphylococcus aureus/patogenicidad , Factores de Virulencia
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