Adaptive Evolution of Staphylococcus aureus during Chronic Endobronchial Infection of a Cystic Fibrosis Patient

The molecular adaptation of Staphylococcus aureus to its host during chronic infection is not well understood. Comparative genome sequencing of 3 S. aureus isolates obtained sequentially over 26 months from the airways of a cystic fibrosis patient, revealed variation in phage content, and genetic polymorphisms in genes which influence antibiotic resistance, and global regulation of virulence. The majority of polymorphisms were isolate-specific suggesting the existence of an heterogeneous infecting population that evolved from a single infecting strain of S. aureus. The genetic variation identified correlated with differences in growth rate, hemolytic activity, and antibiotic sensitivity, implying a profound effect on the ecology of S. aureus. In particular, a high frequency of mutations in loci associated with the alternate transcription factor SigB, were observed. The identification of genes under diversifying selection during long-term infection may inform the design of novel therapeutics for the control of refractory chronic infections

Subinhibitory Concentrations of Perilla Oil Affect the Expression of Secreted Virulence Factor Genes in Staphylococcus aureus

BACKGROUND: The pathogenicity of staphylococcus aureus is dependent largely upon its ability to secrete a number of virulence factors, therefore, anti-virulence strategy to combat S. aureus-mediated infections is now gaining great interest. It is widely recognized that some plant essential oils could affect the production of staphylococcal exotoxins when used at subinhibitory concentrations. Perilla [Perilla frutescens (L.) Britton], a natural medicine found in eastern Asia, is primarily used as both a medicinal and culinary herb. Its essential oil (perilla oil) has been previously demonstrated to be active against S. aureus. However, there are no data on the influence of perilla oil on the production of S. aureus exotoxins. METHODOLOGY/PRINCIPAL FINDINGS: A broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of perilla oil against S. aureus strains. Hemolysis, tumour necrosis factor (TNF) release, Western blot, and real-time RT-PCR assays were performed to evaluate the effects of subinhibitory concentrations of perilla oil on exotoxins production in S. aureus. The data presented here show that perilla oil dose-dependently decreased the production of α-toxin, enterotoxins A and B (the major staphylococcal enterotoxins), and toxic shock syndrome toxin 1 (TSST-1) in both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). CONCLUSIONS/SIGNIFICANCE: The production of α-toxin, SEA, SEB, and TSST-1 in S. aureus was decreased by perilla oil. These data suggest that perilla oil may be useful for the treatment of S. aureus infections when used in combination with β-lactam antibiotics, which can increase exotoxins production by S. aureus at subinhibitory concentrations. Furthermore, perilla oil could be rationally applied in food systems as a novel food preservative both to inhibit the growth of S. aureus and to repress the production of exotoxins, particularly staphylococcal enterotoxins

Killing by type VI secretion drives genetic phase separation and correlates with increased cooperation

By nature of their small size, dense growth and frequent need for extracellular metabolism, microbes face persistent public goods dilemmas. Genetic assortment is the only general solution stabilizing cooperation, but all known mechanisms structuring microbial populations depend on the availability of free space, an often unrealistic constraint. Here we describe a class of self-organization that operates within densely packed bacterial populations. Through mathematical modelling and experiments with Vibrio cholerae, we show how killing adjacent competitors via the Type VI secretion system (T6SS) precipitates phase separation via the ‘Model A' universality class of order-disorder transition mediated by killing. We mathematically demonstrate that T6SS-mediated killing should favour the evolution of public goods cooperation, and empirically support this prediction using a phylogenetic comparative analysis. This work illustrates the twin role played by the T6SS, dealing death to local competitors while simultaneously creating conditions potentially favouring the evolution of cooperation with kin

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival

Das Ausbreitungsverhalten von Technetium (Selen) in geochemisch unterschiedlichen Grundwasserleitern Abschlussbericht

SIGLEAvailable from TIB Hannover: FR 5106+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Einfluss der autochthonen Mikroflora auf die Sorption und Remobilisierung des Technetiums und des Selens an verschiedenen Sedimenten Abschlussbericht

In this research project the influence of autochthonous micro-organisms on immobilisation and remobilization of Technetium and Selenium was investigated. Both radionuclides are part of the nuclear fuel waste (Tc app. 6%). Former investigations have shown, that immobilisation behaviour of both elements can be influenced by micro-organisms. The autochthonous population of micro-organisms in deep sediments and their influence on immobilisation of Tc and Se was investigated in this study. For this reason recirculation column tests were carried out. Absolutely sterile and anaerobic handling is necessary handling the sediments and waters used for the experiments. Special methods for sampling, storage and handling were developed. More than 30 sediments have been investigated. The number of colony forming units (CFU) has always been relatively low (less than E+06 CFU). The results of recirculation column tests with autochthonous micro-organisms were compared with sterilized (Co-60) parallel tests and were verified with the results of hydrochemical equilibration code PHREEQUE. Instead of the allochthonous micro-orgamisms the autochthonous organisms showed no significant fixation of the radionuclides due to microbial activity. This is true for various temperatures of 10 C (aquifer temperature) and 20 C (normal laboratory temperature). An addition of an inoculum of the autochthonous micro-organisms developed at breeding temperature of 10 and 20 C had no influence on the radionuclide mobility. Performing conventional laboratory experiments you have to consider an overestimated retardation capacity because of an inevitable contamination with allochthonous micro-organisms. (orig.)In dem Forschungsvorhaben wurde der Einfluss der autochthonen Mikroorganismen auf das Immobilisierungsverhalten von Technetium und Selen untersucht. Beide redoxsensitiven Radionuklide sind im Abfall von Kernbrennelementen enthalten (Tc ca. 6%). Aus vorangegangenen Forschungsarbeiten ist bekannt, dass das Immobilisierungsverhalten der beiden Elemente durch Mikroorganismen beeinflusst werden kann. Nicht bekannt jedoch war, welche Mikroorganismen in Sedimenten aus groesseren Teufen vorkommen und welchen Einfluss diese auf das Immobilisierungsverhalten zeigen. In dieser Studie wurden ca. 30 Grundwasserleitermaterialien auf ihre autochthonen Mikroorganismen (MO) untersucht. Die Zahl der Koloniebildenden Einheiten (KBE) war immer relativ gering (weniger als E+06 KBE). Die Ergebnisse aus Umlaufsaeulenversuchen mit autochthonen MO wurden verglichen mit Proben, die durch Co-60-Bestrahlung sterilisiert wurden. Es zeigte sich, dass die im Boden vorhandenen autochthonen Mikroorganismen vor allem aufgrund ihrer geringen Populationsdichte keinen signifikanten Einfluss auf die Mobilitaet zeigen. Dies bestaetigt sich auch bei einer Versuchstemperatur von 20 C (Labortemperatur) gegenueber 10 C (Grundwasserleitertemperatur) sowie nach der Zugabe eines Inokulums aus autochthonen Mikroorganismen, die jeweils bei 10 C und 20 C bebruetet wurden. Bei konventionell durchgefuehrten Laborversuchen zur Abschaetzung der Rueckhaltekapazitaeten von Sedimenten gegenueber Schadstoffen muss, wegen der unvermeidbaren mikrobiellen Kontamination, mit der Moeglichkeit zu hoher Sorptionsraten bei redoxsensitiven Elementen gerechnet werden. (orig.)Available from TIB Hannover: F99B15 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman