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1.
Artigo em Inglês | MEDLINE | ID: mdl-31611359

RESUMO

Here, we report a NDM-5-producing ST35 hypervirulent K. pneumoniae strain, isolated from the blood of a male patient. It showed a remarkable resistance to serum killing and neutrophil phagocytosis and a high virulence in a mouse peritonitis infection model. Instead of carrying a pLVPK-like virulence plasmid, chromosomal integration of ICEKp1 (∼76 kb) was identified in a specific asparagine-tRNA gene, harboring the iron acquisition system salmochelin (iroBCDN) and yersiniabactin and a variant of rmpA gene.

2.
Biosens Bioelectron ; 126: 373-380, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30469075

RESUMO

Community-acquired pneumonia (CAP) is the leading cause of mortality in children under five years of age, globally. Given that Streptococcus pneumoniae (S. pneumoniae) and Mycoplasma pneumoniae (M. pneumoniae) are the most common pathogens associated with CAP requiring hospital admission, a simple, low cost, highly sensitive method is in great need for immediate and early diagnosis of CAP. Herein, we report a versatile microfluidic chip platform integrated with loop-mediated isothermal amplification (LAMP) for simultaneous S. pneumoniae and M. pneumoniae testing at the point of care. The platform includes a polymer/paper microfluidic chip and a portable device. On-chip magnetic particle-based nucleic acid extraction is used for concentration of pathogens' genomic DNA and is followed by LAMP. The portable device has the function of heating the microfluidic chip, and photographing and transmitting the result to a smartphone. Complete extraction of the DNA using the microfluidic chip took ~15 min versus >1.5 h with a phenol-chloroform method. The analytical sensitivity of the assay was determined to be 20 fg by testing serial dilutions of target DNA ranging from 2 ng to 2 fg per reaction. We evaluated the clinical sensitivity and specificity of the IPµchip assay using 63 randomly selected oropharyngeal swabs and bronchoalveolar lavage fluid specimens from children. For comparison, these specimens were also tested against real-time PCR assay (M. pneumoniae), conventional PCR assay (S. pneumoniae), and culture tests (S. pneumoniae). These results yielded positive and negative predictive values for M. pneumoniae testing with the IPµchip platform of 96.9% and 100%, respectively. Compared with S. pneumoniae IPµchip, the clinical sensitivity of S. pneumoniae PCR and culture tests was 60% and 40%, respectively, while clinical specificity of the two tests was 100%. This versatile IPµchip platform has great potential for point of care testing of different kinds of pathogens, especially for developing nations.

3.
Gut Pathog ; 10: 37, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214488

RESUMO

Background: Culture-based diagnostic methods cannot achieve rapid and precise diagnoses for the identification of multiple diarrhoeal pathogens (DPs). A high-throughput multiplex genetic detection system (HMGS) was adapted and evaluated for the simultaneous identification and differentiation of infectious DPs and a broad analysis of DP infection aetiology. Results: DP-HMGS was highly sensitive and specific for DP detection compared with culture-based techniques and was similar to singleplex real-time PCR. The uniform level of sensitivity of DP-HMGS for all DPs allowed us to remap the aetiology of acute diarrhoeal infections in Shanghai, correcting incidences of massively underdiagnosed DP species with accuracy approaching that of sequencing-based methods. The most frequent DPs were enteropathogenic Escherichia coli, rotavirus and Campylobacter jejuni. DP-HMGS detected two additional causes of infectious diarrhoea that were previously missed by routine culture-based methods: enterohemorrhagic E. coli and Yersinia enterocolitica. We demonstrated the age dependence of specific DP distributions, especially the distributions of rotavirus, intestinal adenovirus and Clostridium difficile in paediatric patients as well as those of dominant bacterial infections in adults, with a distinct "top 3" pattern for each age group. Finally, the multiplexing capability and high sensitivity of DP-HMGS allowed the detection of infections co-induced by multiple pathogens (approximately 1/3 of the cases), with some DPs preferentially co-occurring as infectious agents. Conclusions: DP-HMGS has been shown to be a rapid, specific, sensitive and appropriate method for the simultaneous screening/detection of polymicrobial DP infections in faecal specimens. Widespread use of DP-HMGS is likely to advance routine diagnostic and clinical studies on the aetiology of acute diarrhoea.

4.
Emerg Microbes Infect ; 7(1): 45, 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29593254

RESUMO

Staphylococcus aureus (S. aureus) is an important pathogen of humans and livestock species, but an understanding of the clonal distribution of S. aureus causing different host-species infections in the same geographical environment and within the same period is lacking. By characterizing infections caused by S. aureus in bovine, pediatric, and adult patients in Shanghai, China, between 2012 and 2014, we identified methicillin-sensitive S. aureus (MSSA) ST188 as the major lineage causing infections in multiple host species. Whole-genome sequencing and phenotypic analyses demonstrated that ST188 might evolve from livestock, and there was no significant genomic or virulence difference between ST188 isolated from livestock and humans. The virulence of ST188 is related to its adhesion and nasal colonization ability. This result is in accord with the strong epithelial cell adhesion and biofilm formation properties of ST188. Furthermore, the adhesion- and biofilm-formation-related genes are present in multiple copies and exhibit significantly increased expression in ST188. In conclusion, S. aureus ST188 is the major lineage causing human and livestock infections in Shanghai, China. Due to its high expression of the factors associated with bacterial adhesion and biofilm formation, ST188 has the ability to colonize and infect different host species.


Assuntos
Adaptação Biológica/genética , Filogenia , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Adulto , Animais , Antibacterianos/farmacologia , Aderência Bacteriana/genética , Biofilmes , Bovinos , China/epidemiologia , Genótipo , Interações Hospedeiro-Patógeno/genética , Humanos , Gado/virologia , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/transmissão , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Virulência , Fatores de Virulência/genética , Sequenciamento Completo do Genoma
5.
Front Microbiol ; 9: 164, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556217

RESUMO

Objective: To investigate prevalence of acute diarrhea in Shanghai and analyze virulence associated-genes and antibiotic resistance of major enteropathogens using combination of conventional and molecular epidemiology methods. Method: The 412 stool specimens were obtained by systematic sampling from diarrhea patients throughout entire year 2016. Bacterial and viral pathogens were identified and bacterial isolates were cultured and screened for antibiotic resistance profiles. Two most prevalent bacteria, Vibrio parahaemolyticus and Salmonella were further typed by multi-locus sequence typing (MLST) and analyzed for presence of virulence-associated genes. The association between virulence genes, resistance phenotypes and genetic diversities was analyzed. Results: Among stool specimens testing positive for pathogens (23.1%), 59 bacterial and 36 viral pathogens were identified. V. parahaemolyticus (27/412, 6.6%), Salmonella (23/412, 5.6%) and norovirus GII (21/412, 5.1%) were three most-commonly found. Most bacterial isolates exhibited high levels of antibiotic resistance with high percentage of MDR. The drug resistance rates of V. parahaemolyticus and Salmonella isolates to cephalosporins were high, such as 100.0 and 34.8% to CFX, 55.6 and 43.4% to CTX, 92.6 and 95.7% to CXM, respectively. The most common resistance combination of V. parahaemolyticus and Salmonella was cephalosporins and quinolone. The dominant sequence types (STs) of V. parahaemolyticus and Salmonella were ST3 (70.4%) and ST11 (43.5%), respectively. The detection rates of virulence genes in V. parahaemolyticus were tlh (100%) and tdh (92.6%), without trh and ureR. Most of the Salmonella isolates were positive for the Salmonella pathogenicity islands (SPIs) genes (87-100%), and some for Salmonella plasmid virulence (SPV) genes (34.8% for spvA and spvB, 43.5% for spvC). In addition, just like the drug resistance, virulence genes exhibited wide-spread distribution among the different STs albeit with some detectable frequency linkage among Salmonella STs. Conclusion: Bacterial infections are still the major cause of severe diarrheas in Shanghai. The most common bacteria V. parahaemolyticus and Salmonella show molecular characteristics consistent with preselection of highly virulent types with exceedingly high level of antibiotic resistance.

6.
Genome Med ; 10(1): 5, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29378646

RESUMO

BACKGROUND: Severe infections with highly virulent community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are a global problem. However, the molecular events defining the evolution of CA-MRSA are still poorly understood. MRSA of sequence type (ST) 398 is known to frequently infect livestock, while ST398 isolates infecting humans are commonly methicillin-susceptible or represent MRSA originating from livestock-associated (LA)-MRSA. METHODS: We used whole genome sequencing of newly detected CA-MRSA ST398 isolates, in comparison to geographically matched LA-MRSA and methicillin-sensitive ST398, to determine their evolutionary history. Furthermore, we used phenotypic analyses including animal infection models to gain insight into the evolution of virulence in these CA-MRSA isolates. Finally, we determined methicillin resistance and expression of the methicillin resistance-conferring gene mecA and its penicillin-binding protein product, PBP2a, in a large series of CA-MRSA strains of divergent STs. RESULTS: We report several cases of severe and fatal infections due to ST398 CA-MRSA. The responsible isolates showed the typical genetic characteristics reported for human-adapted methicillin-sensitive ST398. Whole genome sequencing demonstrated that they evolved from human-adapted, methicillin-susceptible clones on several different occasions. Importantly, the isolates had not undergone consistent genetic alterations or changes in virulence as compared to their methicillin-susceptible predecessors. Finally, we observed dramatically and consistently lower methicillin resistance and expression of the resistance gene mecA, as compared to hospital-associated MRSA strains, in a diverse selection of CA-MRSA strains. CONCLUSIONS: Our study presents evidence for the development of highly virulent human-adapted ST398 CA-MRSA isolates from methicillin-susceptible predecessors. Notably, our investigation indicates that, in contrast to widespread notions, the development of CA-MRSA is not necessarily associated with the acquisition of specific virulence genes or other virulence-increasing changes. Rather, our findings emphasize the importance of the CA-MRSA-characteristic staphylococcal cassette chromosome mec types, which provide only low-level methicillin resistance, for that process. Our findings are of particular importance for the diagnosis of CA-MRSA, inasmuch as they indicate that the presence of specific virulence genes cannot generally be used for that purpose.


Assuntos
Infecções Comunitárias Adquiridas/microbiologia , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Análise de Sequência de DNA , Adulto , Idoso , Animais , Infecções Comunitárias Adquiridas/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Filogenia , Virulência
7.
Oncotarget ; 8(41): 71138-71146, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050349

RESUMO

An elevated serum bilirubin has been reported to be associated with a reduced risk of some cancer; however, the prognostic significance of serum bilirubin in colorectal cancer wasn't fully understood. The purpose of this study was to evaluate whether serum bilirubin could predict the prognosis of patients in stages II and III colorectal cancer. A retrospective cohort of 986 patients with colorectal cancer who received surgical resection between January 2005 and December 2010 was included in the study. Levels for serum bilirubin were obtained from medical records. Survival analysis was used to evaluate the predictive value of bilirubin. Serum direct bilirubin (DBIL) was validated as a significant prognostic factor by univariate cox regression test for both overall survival (OS) and disease free survival (DFS) (P < 0.05). X-tile program identified 3.6 as optimal cutoff values for DBIL in terms of OS and DFS. Patients were then divided into DBIL high (DBIL ≥ 3.60 µmol/l) and low group (DBIL < 3.60 µmol/l) according to the optimal cutoff. High DBIL had higher percentage of lymph node metastasis and lymphovascular invasion as compared with low DBIL levels (P < 0.05). Multivariate cox regression analyses confirmed that high DBIL level was an independently prognostic factor for both OS (HR: 1.337, 95% CI: 1.022-1.748, P = 0.034) and DFS (HR: 1.312, 95% CI: 1.049-1.643, P = 0.018). In addition, nomograms on OS and DFS were established according to all significant factors, and c-indexes were 0.715 (95% CI: 0.683-0.748) and 0.704 (95% CI: 0.678-0.730), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients.

8.
Sci Rep ; 7(1): 9627, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851988

RESUMO

Clostridium difficile infection (CDI) is increasingly recognized globally as a cause of significant morbidity and mortality. This study aimed to provide insight into the various dynamics of C. difficile transmission and infection in the hospital. We monitored the toxin and resistance profiles as well as evolutionary relationships of C. difficile strains to determine the epidemiology over time in a teaching hospital in Shanghai, China between May 2014 and August 2015. The CDI incidence of inpatients and outpatients were 67.7 cases and 0.3 cases per 100,000 patient-days, with a nosocomial patient-environment-patient transmission in May and June 2015. C. difficile genotype ST81, a clone with tcdA-negative and tcdB-positive, was not only the most common strain (30.8%, 28/91) but also had much higher resistance rates to clindamycin and moxifloxacin compared with non-ST81 genotypes. Hospitalized patients infected with ST81 genotypes were over 65 years of age and had more comorbidities, however patients infected with ST81 presented with less clinical symptoms than non-ST81 infected patients. This study provides initial epidemiological evidence that C. difficile ST81 is a successful epidemic genotype that deserves continuous surveillance in China.

9.
Front Microbiol ; 8: 819, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28529509

RESUMO

The ESAT-6 secretion system (ESS) has been reported to contribute to the virulence and pathogenicity of several Staphylococcus aureus strains such as USA300 and Newman. However, the role of the ESS in community-associated S. aureus (CA-SA) lineage ST398 in China is not well understood. By comparing the ess locus of ST398 with the published S. aureus sequence in the NCBI database, we found one gene in the ess locus encoding a novel WXG superfamily protein that is highly conserved only in ST398. LC-MS/MS and Western blot analysis revealed that this protein is a novel secreted protein controlled by the ST398 ESS, and we named the protein EsxX. Although EsxX was not under the control of the accessory gene regulator like many other virulence factors and had no influence on several phenotypes of ST398, such as growth, hemolysis, and biofilm formation, it showed important impacts on immune evasion and virulence in ST398. An esxX deletion mutant led to significantly reduced resistance to neutrophil killing and decreased virulence in murine skin and blood infection models, indicating its essential contribution to the evasion of innate host defense and virulence to support the pathogenesis of ST398 infections. The function of this novel secreted protein EsxX might help us better understand the role of the ESS in the virulence and epidemic success of the CA-SA lineage ST398.

10.
Artigo em Inglês | MEDLINE | ID: mdl-28555174

RESUMO

Biofilm causes hospital-associated infections on indwelling medical devices. In Staphylococcus aureus, Biofilm formation is controlled by intricately coordinated network of regulating systems, of which the ATP-dependent protease ClpP shows an inhibitory effect. Here, we demonstrate that the inhibitory effect of ClpP on biofilm formation is through Agr and the cell wall hydrolase Sle1. Biofilm formed by clpP mutant consists of proteins and extracellular DNA (eDNA). The increase of the protein was, at least in part, due to the reduced protease activity of the mutant, which was caused by the decreased activity of agr. On the other hand, the increase of eDNA was due to increased cell lysis caused by the higher level of Sle1. Indeed, as compared with wild type, the clpP mutant excreted an increased level of eDNA, and showed higher sensitivity to Triton-induced autolysis. The deletion of sle1 in the clpP mutant decreased the biofilm formation, the level of eDNA, and the Triton-induced autolysis to wild-type levels. Despite the increased biofilm formation capability, however, the clpP mutant showed significantly reduced virulence in a murine model of subcutaneous foreign body infection, indicating that the increased biofilm formation capability cannot compensate for the intrinsic functions of ClpP during infection.


Assuntos
Proteínas de Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Endopeptidase Clp/antagonistas & inibidores , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Hidrolases/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Transativadores/efeitos dos fármacos , Animais , Autólise , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Parede Celular/metabolismo , Modelos Animais de Doenças , Endopeptidase Clp/genética , Endopeptidase Clp/fisiologia , Genes Bacterianos/genética , Hidrolases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/fisiologia , Transativadores/metabolismo , Virulência/genética
11.
Biosci Trends ; 11(1): 69-76, 2017 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-28179599

RESUMO

Ankylosing spondylitis (AS) is a spinal arthritic disease that is often associated with human leukocyte antigen (HLA)-B27, while only part of HLA-B27 carriers become AS patients. T cells have been reported to play an important role in the pathology of AS. T-cell immunoglobulin and mucin-domain-containing molecule 3 (Tim-3) and programmed death-1 (PD-1) have been known to negatively regulate the immune response. In this study, we used flow cytometry to analyze the immunological differences of peripheral bloodfrom 21 patients with AS, 22 cases who didn't have AS but were found to be HLA-B27 positive (HLA-B27+ group), and 16 normal healthy individuals (Healthy group). The level of CD4+, CD8+ T cells,and Treg of each group was observed. The expression of Tim-3 and PD-1 and the production of IFN-γ, IL-6, TNF-α, IL-4, and IL-10 were examined as well. We found that the percentage of Treg in AS group was lower than that of healthy group. The expression of PD-1 on CD8+ T cells and Tim-3 on CD4+ T cells was lower in the AS group. AS group had lower IL-10 production by CD4+ T cells and higher IL-6 production by CD8+ T cells. The results of HLA-B27+ group were similar to that of the healthy group. These data suggested that patients with AS had an impairment in the ability to negatively regulate the immune response, which might be related to the etiology of AS. To further investigate the roles of Tim-3 and PD-1 on is a dysfunction of T cells in AS that is associated with PD-1 and Tim-3.


Assuntos
Espondilite Anquilosante/imunologia , Adolescente , Adulto , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Feminino , Antígeno HLA-B27/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Adulto Jovem
13.
Front Microbiol ; 7: 951, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27446000

RESUMO

The highly successful epidemic of healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) ST239 is a growing concern worldwide, due to its progressive adaptation to the highly selective environment of the healthcare system. HA-MRSA ST239 display the reduced virulence and successfully colonize in hospital settings, while the emergent community-associated MRSA (CA-MRSA) maintain full virulence and cause infections in the community environment. Our aim was to investigate what enables S. aureus ST239 to be highly adaptive under hospital circumstances and gradually progress to a series of widespread invasive infections. We found that spa expression of HA-MRSA ST239 is much higher than that of CA-SA ST398. And we discovered that the highly production of staphylococcal protein A (SpA), having no concern with spa gene structure, enhances nasal colonization and cell adhesion in ST239. S. aureus ST239 defends against the adaptive immune response by resisting phagocytosis and inducing apoptosis of B cells through expression of surface-anchored and released protein A, facilitating its dissemination within the circulatory system to other organs. Protein A also plays another key role in subverting the host immune response through its ability to induce early shedding of TNF-α receptor 1 (TNFR1) from phagocytic cells. The increased levels of soluble TNFR1 present during experimental S. aureus ST239 infection may neutralize circulating TNF-α and impair the host inflammatory response. Protein A is also a virulence factor, as tested in our bacteremia model in mice, contributing to the durative tissue damage of abscess formation sites in ST239 infection. These functions of protein A eventually benefit to widespread infections of S. aureus ST239. We draw the conclusion that Staphylococcal Protein A may be a crucial determinant in the colonization and immune evasion of ST239 infections, contributing to persistent spread in the hospital settings. These results suggest that antibodies against protein A may provide insights into the development of novel treatments against S. aureus, especially HA-MRSA.

14.
Oncol Lett ; 12(2): 1329-1336, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27446433

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. Surgical resection is always inapplicable to HCC patients diagnosed at an advanced tumor stage. The mechanisms underlying HCC cell proliferation remain obscure. In the present study, SWItch/sucrose nonfermentable catalytic subunit SNF2 (SNF2H) expression was tested in HCC tissues and Wnt/ß-catenin pathway activation upon overexpression of SNF2H or knockdown of SNF2H expression was investigated in cultured HCC cells. It was demonstrated that SNF2H is a vital factor for HCC growth. The SNF2H expression level is increased in HCC tissues compared with paratumoral liver tissues. SNF2H promotes HCC cell proliferation and colony formation ability in vitro. SNF2H may increase the protein level of ß-catenin and enhance its nuclear accumulation in HCC cells, thereby leading to the activation of the Wnt/ß-catenin signaling pathway. In conclusion, the present results indicate that SNF2H plays a vital role in HCC cell growth, suggesting that SNF2H may be a promising therapeutic target for HCC treatment.

15.
Sci Rep ; 6: 27899, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27296890

RESUMO

Understanding virulence is vital for the development of novel therapeutics to target infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), which cause an ongoing epidemic in the United States and are on a global rise. However, what defines virulence particularly of global CA-MRSA lineages is poorly understood. Threatening a vast population, the predominant Asian CA-MRSA lineage ST59 is of major epidemiological importance. However, there have been no molecular analyses using defined virulence gene deletion mutants in that lineage as of yet. Here, we compared virulence in skin, lung, and blood infection models of ST59 CA-MRSA isolates with geographically matched hospital-associated MRSA isolates. We selected a representative ST59 CA-MRSA isolate based on toxin expression and virulence characteristics, and produced isogenic gene deletion mutants of important CA-MRSA virulence determinants (α-toxin, PSM α, Agr) in that isolate for in-vitro and in-vivo analyses. Our results demonstrate strongly enhanced virulence of ST59 CA-MRSA over hospital-associated lineages, supporting the notion that enhanced virulence is characteristic for CA-MRSA. Furthermore, they show strong and significant contribution of Agr, α-toxin, and PSMα to pathogenesis of ST59 CA-MRSA skin, lung, and blood infection, emphasizing the value of drug development efforts targeted toward those virulence determinants.


Assuntos
Grupo com Ancestrais do Continente Asiático , Infecções Comunitárias Adquiridas/microbiologia , Pulmão/imunologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Neutrófilos/imunologia , Pele/imunologia , Infecções Estafilocócicas/microbiologia , Virulência/genética , Adolescente , Animais , Proteínas de Bactérias/genética , Toxinas Bacterianas/genética , Infecções Comunitárias Adquiridas/epidemiologia , Feminino , Proteínas Hemolisinas/genética , Humanos , Doença Iatrogênica/epidemiologia , Pulmão/microbiologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Pelados , Camundongos Endogâmicos BALB C , Microrganismos Geneticamente Modificados , Neutrófilos/microbiologia , Deleção de Sequência/genética , Pele/microbiologia , Infecções Estafilocócicas/epidemiologia , Transativadores/genética
16.
Sci Rep ; 6: 25163, 2016 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-27112266

RESUMO

Novel Staphylococcus aureus clones continue to emerge that cause infections in otherwise healthy people. One example is the sequence type (ST) 398 lineage, which we show here is increasing in importance as a significant cause of community-associated (CA) human infections in China. We have a profound lack of understanding about what determines the considerable virulence potential of such newly emerging clones. Information about the contribution to virulence of the more recently discovered ESAT-6 secretion system (ESS) has remained particularly scarce. The Chinese ST398 isolates exhibited significantly increased expression of ESS genes as compared to predominant hospital-associated clones, which we found is likely due to increased expression of the accessory gene regulator (Agr) system and control of ESS by Agr. Importantly, deletion of essB in ST398 resulted in significantly reduced resistance to neutrophil killing and decreased virulence in murine skin and blood infection models. Our results demonstrate a key function of ESS in promoting virulence and mechanisms of resistance to innate host defense in an important emerging CA-S. aureus lineage. They suggest that ESS has a so far underestimated role in promoting aggressive virulence and epidemiological success of S. aureus.


Assuntos
Sistemas de Secreção Bacterianos/metabolismo , Infecções Comunitárias Adquiridas/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/patogenicidade , Fatores de Virulência/metabolismo , Animais , Bacteriemia/microbiologia , Bacteriemia/patologia , China , Modelos Animais de Doenças , Deleção de Genes , Humanos , Camundongos , Transporte Proteico , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/patologia , Virulência
17.
Infect Immun ; 84(3): 723-34, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26712209

RESUMO

Staphylococcus aureus is an important human pathogen that can cause two categories of severe infections. Acute infections are characterized by pronounced toxin production, while chronic infections often involve biofilm formation. However, it is poorly understood how S. aureus controls the expression of genes associated with acute versus biofilm-associated virulence. We here identified an AraC-type transcriptional regulator, Rsp, that promotes the production of key toxins while repressing major biofilm-associated genes and biofilm formation. Genome-wide transcriptional analysis and modeling of regulatory networks indicated that upregulation of the accessory gene regulator (Agr) and downregulation of the ica operon coding for the biofilm exopolysaccharide polysaccharide intercellular adhesin (PIA) were central to the regulatory impact of Rsp on virulence. Notably, the Rsp protein directly bound to the agrP2 and icaADBC promoters, resulting in strongly increased levels of the Agr-controlled toxins phenol-soluble modulins (PSMs) and alpha-toxin and reduced production of PIA. Accordingly, Rsp was essential for the development of bacteremia and skin infection, representing major types of acute S. aureus infection. Our findings give important insight into how S. aureus adapts the expression of its broad arsenal of virulence genes to promote different types of disease manifestations and identify the Rsp regulator as a potential target for strategies to control acute S. aureus infection.


Assuntos
Fator de Transcrição AraC/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Fator de Transcrição AraC/metabolismo , Proteínas de Bactérias/genética , Humanos , Regiões Promotoras Genéticas , Staphylococcus aureus/genética
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