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1.
Curr Opin Microbiol ; 53: 51-60, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32172183

RESUMO

Staphylococcus aureus is an opportunistic pathogen that normally colonizes the human anterior nares. At the same time, this pathogen is one of the leading causes of life-threatening bloodstream infections, such as sepsis and endocarditis. In this review we will present the current understanding of the pathogenesis of these invasive infections, focusing on the mechanisms of S. aureus clearance from the bloodstream by the immune system, and how this pathogen hijacks the host defense and coagulation systems and further interacts with the blood vessel endothelium. Additionally, we will delve into the regulatory mechanisms S. aureus employs during an invasive infection. These new insights into host-pathogen interactions show promising avenues for the development of novel therapies for treating bloodstream infections.

2.
Mol Microbiol ; 113(1): 103-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618469

RESUMO

The Gram-positive bacterium, Staphylococcus aureus, is a versatile pathogen that can sense and adapt to a wide variety of environments within the human host, in part through its 16 two-component regulatory systems. The ArlRS two-component system has been shown to affect many cellular processes in S. aureus, including autolysis, biofilm formation, capsule synthesis and virulence. Yet the molecular details of this regulation remained largely unknown. We used RNA sequencing to identify the ArlRS regulon, and found 70% overlap with that of the global regulator MgrA. These genes included cell wall-anchored adhesins (ebh, sdrD), polysaccharide and capsule synthesis genes, cell wall remodeling genes (lytN, ddh), the urease operon, genes involved in metal transport (feoA, mntH, sirA), anaerobic metabolism genes (adhE, pflA, nrdDG) and a large number of virulence factors (lukSF, lukAB, nuc, gehB, norB, chs, scn and esxA). We show that ArlR directly activates expression of mgrA and identify a probable ArlR-binding site (TTTTCTCAT-N4 -TTTTAATAA). A highly similar sequence is also found in the spx P2 promoter, which was recently shown to be regulated by ArlRS. We also demonstrate that ArlS has kinase activity toward ArlR in vitro, although it has slower kinetics than other similar histidine kinases.

3.
J Hist Med Allied Sci ; 75(1): 83-106, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755919

RESUMO

Merit Ptah is widely described as "the first woman physician and scientist" on the Internet and in popular history books. This essay explores the origins of this figure, showing that Merit Ptah came into being in the 1930s when Kate Campbell Hurd-Mead misinterpreted a report about an authentic ancient Egyptian healer. Merit Ptah gradually became a prominent figure in popular historical accounts during second-wave of feminism, and, in the twenty-first century she appeared in Wikipedia and subsequently spread throughout the Internet as a female (sometimes black African) founding figure. The history of Merit Ptah reveals powerful mechanisms of knowledge creation in the network of amateur historians, independently from the scholarly community. The case of Merit Ptah also pinpoints factors enabling the spread of erroneous historical accounts: the absence of professional audience, the development of echo chambers due to an obscured chain of knowledge transmission, the wide reach of the Internet, the coherence with existing preconceptions, the emotional charge of heritage, and even - in the case of ancient Egypt - the tendency to perceive certain pasts through a legendary lens. At the same time, the story of Merit Ptah reveals how important role models have been for women entering science and medicine.


Assuntos
Feminismo/história , Historiografia , Médicas/história , Antigo Egito , História do Século XX , História do Século XXI , História Antiga
4.
J Clin Invest ; 130(3): 1122-1127, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31873074

RESUMO

Staphylococcus aureus remains a leading cause of human infection. These infections frequently recur when the skin is a primary site of infection, especially in infants and children. In contrast, invasive staphylococcal disease is less commonly associated with reinfection, suggesting that tissue-specific mechanisms govern the development of immunity. Knowledge of how S. aureus manipulates protective immunity has been hampered by a lack of antigen-specific models to interrogate the T cell response. Using a chicken egg OVA-expressing S. aureus strain to analyze OVA-specific T cell responses, we demonstrated that primary skin infection was associated with impaired development of T cell memory. Conversely, invasive infection induced antigen-specific memory and protected against reinfection. This defect in adaptive immunity following skin infection was associated with a loss of DCs, attributable to S. aureus α-toxin (Hla) expression. Gene- and immunization-based approaches to protect against Hla during skin infection restored the T cell response. Within the human population, exposure to α-toxin through skin infection may modulate the establishment of T cell-mediated immunity, adversely affecting long-term protection. These studies prompt consideration that vaccination targeting S. aureus may be most effective if delivered prior to initial contact with the organism.

5.
mBio ; 10(6)2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31874913

RESUMO

Staphylococcus aureus is an important pathogen responsible for nosocomial and community-acquired infections in humans, and methicillin-resistant S. aureus (MRSA) infections have continued to increase despite widespread preventative measures. S. aureus can colonize the female vaginal tract, and reports have suggested an increase in MRSA infections in pregnant and postpartum women as well as outbreaks in newborn nurseries. Currently, little is known about specific factors that promote MRSA vaginal colonization and subsequent infection. To study S. aureus colonization of the female reproductive tract in a mammalian system, we developed a mouse model of S. aureus vaginal carriage and demonstrated that both hospital-associated and community-associated MRSA isolates can colonize the murine vaginal tract. Immunohistochemical analysis revealed an increase in neutrophils in the vaginal lumen during MRSA colonization. Additionally, we observed that a mutant lacking fibrinogen binding adhesins exhibited decreased persistence within the mouse vagina. To further identify novel factors that promote vaginal colonization, we performed RNA sequencing to determine the transcriptome of MRSA growing in vivo during vaginal carriage at 5 h, 1 day, and 3 days postinoculation. Over 25% of the bacterial genes were differentially regulated at all time points during colonization compared to laboratory cultures. The most highly induced genes were those involved in iron acquisition, including the Isd system and siderophore transport systems. Mutants deficient in these pathways did not persist as well during in vivo colonization. These results reveal that fibrinogen binding and the capacity to overcome host nutritional limitation are important determinants of MRSA vaginal colonization.IMPORTANCE Staphylococcus aureus is an opportunistic pathogen able to cause a wide variety of infections in humans. Recent reports have suggested an increasing prevalence of MRSA in pregnant and postpartum women, coinciding with the increased incidence of MRSA infections in neonatal intensive care units (NICUs) and newborn nurseries. Vertical transmission from mothers to infants at delivery is a likely route of MRSA acquisition by the newborn; however, essentially nothing is known about host and bacterial factors that influence MRSA carriage in the vagina. Here, we established a mouse model of vaginal colonization and observed that multiple MRSA strains can persist in the vaginal tract. Additionally, we determined that MRSA interactions with fibrinogen and iron uptake can promote vaginal persistence. This study is the first to identify molecular mechanisms which govern vaginal colonization by MRSA, the critical initial step preceding infection and neonatal transmission.

6.
mSphere ; 4(4)2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413175

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) infections impact all patient populations both in the community and in health care settings. Despite advances in our knowledge of MRSA virulence, little is known about the regulatory mechanisms of USA100 health care-associated MRSA isolates, which are the second most frequently identified MRSA isolates found in all infections. This work focused on the contribution of the USA100 agr type II quorum-sensing system to virulence and antibiotic resistance. From a MRSA strain collection, we selected 16 representative USA100 isolates, constructed mutants with Δagr mutations, and characterized selected strain pairs for virulence factor expression, murine skin infection, and antibiotic resistance. For each strain pair, hemolysis and extracellular protease expression were significantly greater in the wild-type (WT) strains than in the Δagr mutants. Similarly, mice challenged with the WT strains had larger areas of dermonecrosis and greater weight loss than those challenged with the Δagr mutants, demonstrating that the USA100 agr system regulates virulence. Although USA100 isolates exhibit a high level of antibiotic resistance, the WT and Δagr strain pairs showed no difference in MICs by MIC testing. However, in the presence of a sub-MIC of vancomycin, most of the USA100 Δagr mutants exhibited slower growth than the WT isolates, and a couple of the Δagr mutants also grew more slowly in the presence of a sub-MIC of cefoxitin. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence, and it may have a contribution to the optimal survival of these MRSA strains in the presence of antibiotics.IMPORTANCE USA100 health care-associated MRSA isolates are highly antibiotic resistant and can cause invasive disease across all patient populations. Even though USA100 strains are some of the most frequently identified causes of infections, little is known about virulence regulation in these isolates. Our study demonstrates that the USA100 agr quorum-sensing system is important for the control of toxin and exoenzyme production and that the agr system has a key role in skin infection. In some USA100 isolates, the agr system is important for growth in the presence of low levels of antibiotics. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence and that it may make a contribution to the optimal survival of these MRSA strains in the presence of antibiotics.


Assuntos
Farmacorresistência Bacteriana Múltipla , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Percepção de Quorum , Virulência , Animais , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Transativadores/genética , Fatores de Virulência/genética
7.
PLoS Pathog ; 15(5): e1007800, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31116795

RESUMO

Staphylococcus aureus is a leading cause of endovascular infections. This bacterial pathogen uses a diverse array of surface adhesins to clump in blood and adhere to vessel walls, leading to endothelial damage, development of intravascular vegetations and secondary infectious foci, and overall disease progression. In this work, we describe a novel strategy used by S. aureus to control adhesion and clumping through activity of the ArlRS two-component regulatory system, and its downstream effector MgrA. Utilizing a combination of in vitro cellular assays, and single-cell atomic force microscopy, we demonstrated that inactivation of this ArlRS-MgrA cascade inhibits S. aureus adhesion to a vast array of relevant host molecules (fibrinogen, fibronectin, von Willebrand factor, collagen), its clumping with fibrinogen, and its attachment to human endothelial cells and vascular structures. This impact on S. aureus adhesion was apparent in low shear environments, and in physiological levels of shear stress, as well as in vivo in mouse models. These effects were likely mediated by the de-repression of giant surface proteins Ebh, SraP, and SasG, caused by inactivation of the ArlRS-MgrA cascade. In our in vitro assays, these giant proteins collectively shielded the function of other surface adhesins and impaired their binding to cognate ligands. Finally, we demonstrated that the ArlRS-MgrA regulatory cascade is a druggable target through the identification of a small-molecule inhibitor of ArlRS signaling. Our findings suggest a novel approach for the pharmacological treatment and prevention of S. aureus endovascular infections through targeting the ArlRS-MgrA regulatory system.


Assuntos
Aderência Bacteriana , Proteínas de Bactérias/metabolismo , Endotélio Vascular/microbiologia , Regulação Bacteriana da Expressão Gênica , Proteínas de Membrana/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Animais , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Fibrinogênio/genética , Fibrinogênio/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/patologia
8.
Infect Dis (Lond) ; 51(6): 446-451, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30985241

RESUMO

BACKGROUND: Biofilms are involved in many Staphylococcus aureus infections, but relation of biofilm formation and the infection types or the clinical outcomes remain unclear. METHODS: We measured biofilm formation, with a microtiter plate assay, of a collection of methicillin-sensitive clinical isolates from 159 invasive S. aureus infections, encompassing all cases occurring within a hospital catchment area during two years, and from additional 49 non-invasive skin infections from the same region. Results were related to available clinical and microbiological documentation. RESULTS: Isolates from medical device infections (intravenous line-associated and prosthetic joint infections), as well as isolates from superficial skin infections, were particularly proficient in forming biofilms. No increased biofilm-forming capacity was seen in isolates from endocarditis, osteomyelitis, or other infections. There was also a correlation of biofilm formation with the agr type of the isolates. Thicker biofilms were more resistant to antibiotic treatment in vitro. No correlation between biofilm formation and clinical outcomes was noted. CONCLUSIONS: S. aureus isolates from 'classical' biofilm-related infections, but also from superficial skin infections, are especially proficient in forming biofilms. There is, however, no obvious relation of biofilm-forming capacity of isolates and the clinical outcome of the infection, and more studies on this issue are needed.


Assuntos
Biofilmes/crescimento & desenvolvimento , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Staphylococcus aureus/patogenicidade , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Genótipo , Humanos , Staphylococcus aureus Resistente à Meticilina , Dermatopatias/microbiologia , Staphylococcus aureus/classificação , Transativadores/genética
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