RESUMEN
SARS-CoV-2 IgG screening of 1,000 antenatal serum samples in the Oxford area, United Kingdom, between 14 April and 15 June 2020, yielded a 5.3% seroprevalence, mirroring contemporaneous regional data. Among the 53 positive samples, 39 showed in vitro neutralisation activity, correlating with IgG titre (Pearson's correlation p<0.0001). While SARS-CoV-2 seroprevalence in pregnancy cohorts could potentially inform population surveillance, clinical correlates of infection and immunity in pregnancy, and antenatal epidemiology evolution over time need further study.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Betacoronavirus/inmunología , Infecciones por Coronavirus/epidemiología , Inmunoglobulina G/sangre , Pandemias , Neumonía Viral/epidemiología , Vigilancia de la Población , Complicaciones Infecciosas del Embarazo/sangre , Primer Trimestre del Embarazo/sangre , Adolescente , Adulto , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/sangre , Inglaterra/epidemiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Persona de Mediana Edad , Neumonía Viral/sangre , Embarazo , Diagnóstico Prenatal , Prevalencia , SARS-CoV-2 , Estudios Seroepidemiológicos , Método Simple Ciego , Adulto JovenRESUMEN
The secretion of proteins that damage host tissue is well established as integral to the infectious processes of many bacterial pathogens. However, recent advances in our understanding of the activity of toxins suggest that the attributes we have assigned to them from early in vitro experimentation have misled us into thinking of them as merely destructive tools. Here, we will discuss the multifarious ways in which toxins contribute to the lifestyle of bacteria and, by considering their activity from an evolutionary perspective, demonstrate how this extends far beyond their ability to destroy host tissue.
Asunto(s)
Adenilil Ciclasas/metabolismo , Bacterias/metabolismo , Toxinas Bacterianas/metabolismo , Evolución Biológica , Interacciones Huésped-Patógeno/inmunología , Animales , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/toxicidad , Humanos , Superantígenos/inmunología , Superantígenos/metabolismoRESUMEN
Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobial resistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections by demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistant to this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin-treated MRSA strains are significantly attenuated in virulence. This effect is based primarily on the oxacillin-dependent repression of the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibility to host killing of MRSA. Our data indicate that ß-lactam antibiotics should be included in the treatment regimen as an adjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinical practice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effective manner.
Asunto(s)
Antibacterianos/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Oxacilina/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Humanos , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Ratones , Pruebas de Sensibilidad Microbiana , Oxacilina/farmacología , Neumonía Estafilocócica/tratamiento farmacológico , Neumonía Estafilocócica/microbiología , Percepción de Quorum/genética , Sepsis/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Virulencia/efectos de los fármacosRESUMEN
Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites. Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen.
Asunto(s)
Genoma Bacteriano , Staphylococcus aureus Resistente a Meticilina/genética , Modelos Genéticos , Virulencia/genética , Estudio de Asociación del Genoma Completo , Mutación INDEL , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Polimorfismo de Nucleótido SimpleRESUMEN
High-level resistance to antimicrobial drugs is a major factor in the pathogenesis of chronic Staphylococcus aureus biofilm-associated, medical device-related infections. Antimicrobial susceptibility analysis revealed that biofilms grown for ≤ 24 hours on biomaterials conditioned with human plasma under venous shear in iron-free cell culture medium were significantly more susceptible to antistaphylococcal antibiotics. Biofilms formed under these physiologically relevant conditions were regulated by SaeRS and dependent on coagulase-catalyzed conversion of fibrinogen into fibrin. In contrast, SarA-regulated biofilms formed on uncoated polystyrene in nutrient-rich bacteriological medium were mediated by the previously characterized biofilm factors poly-N-acetyl glucosamine, fibronectin-binding proteins, or autolytic activity and were antibiotic resistant. Coagulase-mediated biofilms exhibited increased antimicrobial resistance over time (>48 hours) but were always susceptible to dispersal by the fibrinolytic enzymes plasmin or nattokinase. Biofilms recovered from infected central venous catheters in a rat model of device-related infection were dispersed by nattokinase, supporting the important role of the biofilm phenotype and identifying a potentially new therapeutic approach with antimicrobials and fibrinolytic drugs, particularly during the early stages of device-related infection.
Asunto(s)
Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Infecciones Relacionadas con Catéteres/microbiología , Coagulasa/metabolismo , Fibrinolíticos/metabolismo , Staphylococcus aureus/enzimología , Staphylococcus aureus/fisiología , Adulto , Animales , Antibacterianos/metabolismo , Infecciones Relacionadas con Catéteres/prevención & control , Modelos Animales de Enfermedad , Humanos , Ratas Sprague-Dawley , Staphylococcus aureus/efectos de los fármacosRESUMEN
The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a growing cause for concern. These strains are more virulent than health care-associated MRSA (HA-MRSA) due to higher levels of toxin expression. In a previous study, we showed that the high-level expression of PBP2a, the alternative penicillin binding protein encoded by the mecA gene on type II staphylococcal cassette chromosome mec (SCCmec) elements, reduced toxicity by interfering with the Agr quorum sensing system. This was not seen in strains carrying the CA-MRSA-associated type IV SCCmec element. These strains express significantly lower levels of PBP2a than the other MRSA type, which may explain their relatively high toxicity. We hypothesized that as oxacillin is known to increase mecA expression levels, it may be possible to attenuate the toxicity of CA-MRSA by using this antibiotic. Subinhibitory oxacillin concentrations induced PBP2a expression, repressed Agr activity, and, as a consequence, decreased phenol-soluble modulin (PSM) secretion by CA-MRSA strains. However, consistent with other studies, oxacillin also increased the expression levels of alpha-toxin and Panton-Valentine leucocidin (PVL). The net effect of these changes on the ability to lyse diverse cell types was tested, and we found that where the PSMs and alpha-toxin are important, oxacillin reduced overall lytic activity, but where PVL is important, it increased lytic activity, demonstrating the pleiotropic effect of oxacillin on toxin expression by CA-MRSA.
Asunto(s)
Antibacterianos/farmacología , Toxinas Bacterianas/genética , Exotoxinas/genética , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Proteínas Hemolisinas/genética , Leucocidinas/genética , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Oxacilina/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/agonistas , Toxinas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/biosíntesis , Infecciones Comunitarias Adquiridas/microbiología , Exotoxinas/agonistas , Exotoxinas/biosíntesis , Proteínas Hemolisinas/agonistas , Proteínas Hemolisinas/biosíntesis , Humanos , Leucocidinas/agonistas , Leucocidinas/biosíntesis , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/metabolismo , Proteínas de Unión a las Penicilinas/genética , Proteínas de Unión a las Penicilinas/metabolismo , Percepción de Quorum/efectos de los fármacos , Infecciones Estafilocócicas/microbiología , Transactivadores/antagonistas & inhibidores , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Clinical isolates of Staphylococcus aureus can express biofilm phenotypes promoted by the major cell wall autolysin and the fibronectin-binding proteins or the icaADBC-encoded polysaccharide intercellular adhesin/poly-N-acetylglucosamine (PIA/PNAG). Biofilm production in methicillin-susceptible S. aureus (MSSA) strains is typically dependent on PIA/PNAG whereas methicillin-resistant isolates express an Atl/FnBP-mediated biofilm phenotype suggesting a relationship between susceptibility to ß-lactam antibiotics and biofilm. By introducing the methicillin resistance gene mecA into the PNAG-producing laboratory strain 8325-4 we generated a heterogeneously resistant (HeR) strain, from which a homogeneous, high-level resistant (HoR) derivative was isolated following exposure to oxacillin. The HoR phenotype was associated with a R602H substitution in the DHHA1 domain of GdpP, a recently identified c-di-AMP phosphodiesterase with roles in resistance/tolerance to ß-lactam antibiotics and cell envelope stress. Transcription of icaADBC and PNAG production were impaired in the 8325-4 HoR derivative, which instead produced a proteinaceous biofilm that was significantly inhibited by antibodies against the mecA-encoded penicillin binding protein 2a (PBP2a). Conversely excision of the SCCmec element in the MRSA strain BH1CC resulted in oxacillin susceptibility and reduced biofilm production, both of which were complemented by mecA alone. Transcriptional activity of the accessory gene regulator locus was also repressed in the 8325-4 HoR strain, which in turn was accompanied by reduced protease production and significantly reduced virulence in a mouse model of device infection. Thus, homogeneous methicillin resistance has the potential to affect agr- and icaADBC-mediated phenotypes, including altered biofilm expression and virulence, which together are consistent with the adaptation of healthcare-associated MRSA strains to the antibiotic-rich hospital environment in which they are frequently responsible for device-related infections in immuno-compromised patients.
Asunto(s)
Biopelículas/crecimiento & desarrollo , Contaminación de Equipos , Resistencia a la Meticilina/fisiología , Staphylococcus aureus Resistente a Meticilina/metabolismo , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Acetilglucosamina/genética , Acetilglucosamina/metabolismo , Adhesinas Bacterianas/genética , Adhesinas Bacterianas/metabolismo , Animales , Antibacterianos/farmacología , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Regulación Bacteriana de la Expresión Génica/fisiología , Humanos , Masculino , Resistencia a la Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Ratones , N-Acetil Muramoil-L-Alanina Amidasa/genética , N-Acetil Muramoil-L-Alanina Amidasa/metabolismo , Oxacilina/farmacología , Proteínas de Unión a las Penicilinas/genética , Proteínas de Unión a las Penicilinas/metabolismo , Polisacáridos Bacterianos/genética , Polisacáridos Bacterianos/metabolismoRESUMEN
The difficulty in successfully treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has led to them being referred to as highly virulent or pathogenic. In our study of one of the major healthcare-associated MRSA (HA-MRSA) clones, we show that expression of the gene responsible for conferring methicillin resistance (mecA) is also directly responsible for reducing the ability of HA-MRSA to secrete cytolytic toxins. We show that resistance to methicillin induces changes in the cell wall, which affects the bacteria's agr quorum sensing system. This leads to reduced toxin expression and, as a consequence, reduced virulence in a murine model of sepsis. This diminished capacity to cause infection may explain the inability of HA-MRSA to move into the community and help us understand the recent emergence of community-associated MRSA (CA-MRSA). CA-MRSA typically express less penicillin-binding protein 2a (encoded by mecA), allowing them to maintain full virulence and succeed in the community environment.
Asunto(s)
Proteínas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Resistencia a la Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Animales , Proteínas Bacterianas/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/farmacología , Supervivencia Celular , Pared Celular/metabolismo , Infección Hospitalaria , Modelos Animales de Enfermedad , Expresión Génica , Staphylococcus aureus Resistente a Meticilina/metabolismo , Ratones , Proteínas de Unión a las Penicilinas/metabolismo , Péptido Sintasas/metabolismo , Péptidos Cíclicos , Percepción de Quorum/genética , Sepsis/microbiología , Linfocitos T , Transactivadores/efectos de los fármacos , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Understanding the genetic and environmental risk factors for serious bacterial infections in ageing populations remains incomplete. Utilising the UK Biobank (UKB), a prospective cohort study of 500,000 adults aged 40-69 years at recruitment (2006-2010), can help address this. Partial implementation of such a system helped groups around the world make rapid progress understanding risk factors for SARS-CoV-2 infection and COVID-19, with insights appearing as early as May 2020. In principle, such approaches could also to be used for bacterial isolations. Here we report feasibility testing of linking an England-wide dataset of microbial reporting to UKB participants, to enable characterisation of microbial infections within the UKB Cohort. These records pertain mainly to bacterial isolations; SARS-CoV-2 isolations were not included. Microbiological infections occurring in patients in England, as recorded in the Public Health England second generation surveillance system (SGSS), were linked to UKB participants using pseudonymised identifiers. By January 2015, ascertainment of laboratory reports from UKB participants by SGSS was estimated at 98%. 4.5% of English UKB participants had a positive microbiological isolate in 2015. Half of UKB isolates came from 12 laboratories, and 70% from 21 laboratories. Incidence rate ratios for microbial isolation, which is indicative of serious infection, from the UKB cohort relative to the comparably aged general population ranged from 0.6 to 1, compatible with the previously described healthy participant bias in UKB. Data on microbial isolations can be linked to UKB participants from January 2015 onwards. This linked data would offer new opportunities for research into the role of bacterial agents on health and disease in middle to-old age.
Asunto(s)
COVID-19 , Adulto , Humanos , COVID-19/epidemiología , SARS-CoV-2 , Laboratorios , Bancos de Muestras Biológicas , Estudios Prospectivos , Inglaterra/epidemiologíaRESUMEN
Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.
Asunto(s)
Anticuerpos Antivirales/análisis , Prueba de COVID-19/métodos , COVID-19/diagnóstico , Pruebas de Hemaglutinación/métodos , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Pruebas de Aglutinación/métodos , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/inmunología , COVID-19/virología , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Sistemas de Atención de Punto , Reacción en Cadena de la Polimerasa , SARS-CoV-2/inmunología , Sensibilidad y Especificidad , SeroconversiónRESUMEN
UK Biobank (UKB) is an international health resource enabling research into the genetic and lifestyle determinants of common diseases of middle and older age. It comprises 500â000 participants. Public Health England's Second Generation Surveillance System is a centralized microbiology database covering English clinical diagnostics laboratories that provides national surveillance of legally notifiable infections, bacterial isolations and antimicrobial resistance. We previously developed secure, pseudonymized, individual-level linkage of these systems. In this study, we implemented rapid dynamic linkage, which allows us to provide a regular feed of new COVID-19 (SARS-CoV-2) test results to UKB to facilitate rapid and urgent research into the epidemiological and human genetic risk factors for severe infection in the cohort. Here, we have characterized the first 1352 cases of COVID-19 in UKB participants, of whom 895 met our working definition of severe COVID-19 as inpatients hospitalized on or after 16 March 2020. We found that the incidence of severe COVID-19 among UKB cases was 27.4â% lower than the general population in England, although this difference varied significantly by age and sex. The total number of UKB cases could be estimated as 0.6â% of the publicly announced number of cases in England. We considered how increasing case numbers will affect the power of genome-wide association studies. This new dynamic linkage system has further potential to facilitate the investigation of other infections and the prospective collection of microbiological cultures to create a microbiological biobank (bugbank) for studying the interaction of environment, human and microbial genetics on infection in the UKB cohort.
Asunto(s)
Betacoronavirus , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/epidemiología , Bases de Datos Factuales , Almacenamiento y Recuperación de la Información , Neumonía Viral/epidemiología , Vigilancia en Salud Pública , Adulto , Anciano , Bancos de Muestras Biológicas , COVID-19 , Prueba de COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/genética , Inglaterra , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/genética , Estudios Prospectivos , SARS-CoV-2 , Reino Unido/epidemiologíaRESUMEN
Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.
RESUMEN
BACKGROUND: A westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice. RESULTS: We determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver. CONCLUSIONS: We adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Listeria monocytogenes/patogenicidad , Listeriosis/etiología , Microbiota/efectos de los fármacos , Obesidad/genética , Animales , Dieta Occidental/efectos adversos , Modelos Animales de Enfermedad , Heces/microbiología , Femenino , Firmicutes/efectos de los fármacos , Firmicutes/genética , Firmicutes/aislamiento & purificación , Regulación de la Expresión Génica/efectos de los fármacos , Células Caliciformes/citología , Células Caliciformes/efectos de los fármacos , Listeriosis/genética , Listeriosis/inmunología , Metagenoma/efectos de los fármacos , Ratones , Obesidad/complicaciones , Obesidad/etiología , Análisis de Secuencia de ADNRESUMEN
Antibiotic resistance and biofilm-forming capacity contribute to the success of Staphylococcus aureus as a human pathogen in both healthcare and community settings. These virulence factors do not function independently of each other and the biofilm phenotype expressed by clinical isolates of S. aureus is influenced by acquisition of the methicillin resistance gene mecA. Methicillin-sensitive S. aureus (MSSA) strains commonly produce an icaADBC operon-encoded polysaccharide intercellular adhesin (PIA)-dependent biofilm. In contrast, the release of extracellular DNA (eDNA) and cell surface expression of a number of sortase-anchored proteins, and the major autolysin have been implicated in the biofilm phenotype of methicillin-resistant S. aureus (MRSA) isolates. Expression of high level methicillin resistance in a laboratory MSSA strain resulted in (i) repression of PIA-mediated biofilm production, (ii) down-regulation of the accessory gene regulator (Agr) system, and (iii) attenuation of virulence in murine sepsis and device infection models. Here we review the mechanisms of MSSA and MRSA biofilm production and the relationships between antibiotic resistance, biofilm and virulence gene regulation in S. aureus.
Asunto(s)
Biopelículas , Resistencia a la Meticilina , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Humanos , Staphylococcus aureus/genéticaRESUMEN
With the advent of high-throughput whole-genome sequencing, it is now possible to sequence a bacterial genome in a matter of hours. However, although the presence or absence of a particular gene can be determined, we do not yet have the tools to extract information about the true virulence potential of an organism from sequence data alone. Here, we focus on the important human pathogen Staphylococcus aureus and present a framework for the construction of a broad systems biology-based tool that could be used to predict virulence phenotypes from S. aureus genomic sequences using existing technology.
Asunto(s)
Genoma Bacteriano , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Factores de Virulencia/genética , ADN Bacteriano/genética , Variación Genética , Genotipo , Humanos , Resistencia a la Meticilina/genética , Fenotipo , Biología de Sistemas/métodosRESUMEN
The prevalence of diverse MRSA (methicillin-resistant Staphylococcus aureus) types in both hospital and community settings is a major health problem worldwide. Here we compare hospital-acquired MRSAs with large type II SCCmec elements with those prevalent in both hospital and community settings with smaller type IV SCCmec elements. We find that the type II but not the type IV SCCmec element causes the bacteria to reduce their levels of costly toxin expression. We compare the relative growth rates of these MRSA types and show that the type II SCCmec carrying MRSAs are more affected than those carrying type IV elements and from this we hypothesize that offsetting the costs associated with antibiotic resistance and toxin expression is why the type II are confined to hospital environments where antibiotic use, the prevalence of immunocompromised individuals and vector-mediated transmission is high. In contrast, those MRSAs that are also successful in the community can maintain their high levels of toxin expression due to a lower fitness burden associated with the smaller SCCmec element.