1,721,211 research outputs found
Role of prokaryotic Cu,Zn superoxide dismutase in pathogenesis
Full text linkSeveral bacterial pathogens possess sodC genes that encode periplasmic or membrane-associated Cu,Zn superoxide dismutases. Since professional phagocytes generate large amounts of reactive oxygen species to control the growth of invading micro-organisms, Cu,Zn superoxide dismutase might protect infectious bacteria from oxy-radical damage and facilitate their survival within the host. This idea has gained support from studies showing that sodC -null mutants of different bacteria are less virulent than their parental wild-type strains, and from the discovery that, despite apparent dispensability for growth under laboratory conditions, various pathogens (including several highly virulent Salmonella strains) possess multiple copies of sodC. Our studies indicate that Cu,Zn superoxide dismutase effectively protects bacteria from phagocytic killing, and that the role in infection of the redundant sodC genes may vary in distinct Salmonella enterica serovars. More unexpectedly, we have found that Cu,Zn superoxide dismutase also modulates bacterial survival within epithelial cells, where bacterial killing appears to be mediated by an NAD(P)H oxidase resembling the enzyme complex typical of phagocytes. Finally, a striking feature of Cu,Zn superoxide dismutases from bacterial pathogens is their apparent ability to exploit the structural versatility of the enzyme to modulate its function. In fact, several enzyme variants exhibit unique properties that may lead to the acquisition of novel specialized functions distinct from superoxide dismutation
A remarkable zinc acquisition ability contributes to Pseudomonas aeruginosa ability to express virulence features and infect the lung of human patients
No full textThe immune response to microbial pathogens involves numerous strategies aimed at limiting the access of microorganisms to transition metals that are essential for the activity of a large number of bacterial proteins. Metal shortage may be particularly acute in the inflamed airway mucosa of Cystic Fibrosis (CF) patients, where neutrophils release large amounts of the antimicrobial protein Calprotectin that is able to control microbial growth by the sequestration of zinc ions. Pseudomonas aeruginosa, one of the most dangerous pathogens for patients with Cystic Fibrosis, possesses redundant zinc uptake systems that facilitate metal recruitment in environments poor of this metal. We have shown that an adequate supply of zinc is essential for P. aeruginosa ability to express a large number of virulence traits. Virulence features affected by zinc availability include the ability to release different extracellular proteases, the capability to produce flagella, the ability to synthesize alginate and form biofilm and even the capacity to synthesize the siderophore pyoverdine. In agreement with the importance of zinc in the expression of so many virulence-related features, disruption of the most efficient zinc uptake systems severely affects P. aeruginosa ability to cause acute lung and systemic infections in mice.
To verify the importance of zinc uptake systems for the capacity of P. aeruginosa to establish infections in human patients, we have examined the expression of various genes regulated by zinc deficiency in bacteria in the sputum of patients with chronic inflammatory lung diseases. In all the analyzed sputum samples these genes were found to be expressed at levels much higher than those observed in bacteria growing in a Zn-rich medium. This finding supports the hypothesis that P. aeruginosa is under zinc starvation during lung infections. This conclusion is also in agreement with the observation that genes for the major zinc importers are well conserved in the vast majority of clinical isolates from CF patients.
The indispensability of zinc makes the homeostasis of this metal an extremely promising target for the development of new antimicrobial therapies aimed at controlling P. aeruginosa pulmonary infections
Repurposing cardio-metabolic drugs to fight Covid19
Full text linkCovid19 mostly manifests with interstitial pneumonia,
even though it can afect heart and central nervous system as
well. Although the pathophysiology of the clinical manifestations of Covid19 is not yet completely known, it has been
shown that the entry of Sars-CoV-2 into cells is mediated
by angiotensin-converting enzyme 2 (ACE2), expressed also
in pulmonary epithelium [2]. After that, symptoms and the
severity of Covid19 depend on the virus replication but also
on the individual's immune response, often establishing an
immune/infammatory storm leading to tissue damage that
can have severe prognosi
An ERp57-mediated disulphide exchange promotes the interaction between Burkholderia cenocepacia and epithelial respiratory cells
Full text linkPrevious studies have demonstrated that extracellular glutathione reduces the ability of the Cystic Fibrosis pathogen Burkholderia cenocepacia to infect primary or immortalized epithelial respiratory cells. We report here that the adhesion and invasion ability of B. cenocepacia is limited also by thiol-oxidizing and disulphide-reducing agents and by protein disulfide isomerase (PDI) inhibitors. PDI inhibitors also reduce the proinflammatory response elicited by cells in response to Burkholderia. These findings indicate that a membrane-associated PDI catalyzes thiol/disulphide exchange reactions which favor bacterial infection. The combined use of selective PDI inhibitors, RNA silencing and specific antibodies identified ERp57 as a major PDI involved in the interaction between B. cenocepacia and epithelial cells. This study contributes to the elucidation of the Burkholderia pathogenic mechanisms by showing that this microorganism exploits a membrane-associated host protein to infect epithelial cells and identifies ERp57 as a putative pharmacological target for the treatment of Burkholderia lung infections
Deregulation of transition metals homeostasis is a key feature of cadmium toxicity in Salmonella
No full textCadmium is a highly toxic metal whose presence in the environment represents a challenge for all forms of life. To improve our knowledge on cadmium toxicity, we have explored Salmonella Typhimurium responses to this metal. We have found that cadmium induces the concomitant expression of the cation efflux pump ZntA and of the high affinity zinc import system ZnuABC. This observation suggests that cadmium accumulation within the cell induces a condition of apparent zinc starvation, possibly due to the ability of this metal to compete with zinc for the metal binding site of proteins. This hypothesis is supported by the finding that strains lacking ZntA or ZnuABC are hyper-susceptible to cadmium and that the cadmium-induced growth defect of a znuABC mutant strain is largely relieved by zinc supplementation. A similar growth defect was observed for a mutant with impaired ability to acquire iron, whereas cadmium does not affect growth of a strain defective in manganese import. Cadmium also influences the expression and activity of the two cytoplasmic superoxide dismutases FeSOD and MnSOD, which are required to control cadmium-mediate oxidative stress. Exposure to cadmium causes a reduction of FeSOD activity in Salmonella wild type and the complete abrogation of its expression in the strain defective in iron import. In contrast, although MnSOD intracellular levels increase in response to cadmium, we observed discrepancies between protein levels and enzymatic activity which are suggestive of incorporation of non-catalytic metals in the active site or to cadmium-mediated inhibition of manganese import. Our results indicate that cadmium interferes with the ability of cells to manage transition metals and highlight the close interconnections between the homeostatic mechanisms regulating the intracellular levels of different metals
Low-Shear Modeled Microgravity Enhances Salmonella Enterica Resistance to Hydrogen Peroxide Through a Mechanism Involving KatG and KatN
Full text linkStudies carried out in recent years have established that growth under conditions of reduced gravity enhances Salmonella enterica serovar Typhimurium virulence. To analyze the possibility that this microgravity-induced increase in pathogenicity could involve alterations in the ability of Salmonella to withstand oxidative stress, we have compared the resistance to hydrogen peroxide of various Salmonella enterica strains grown under conditions of low shear modeled microgravity (LSMMG) or normal gravity (NG). We have found that growth in LSMMG significantly enhances hydrogen peroxide resistance of all the strains analyzed. This effect is abolished by deletion of the genes encoding for the catalases KatG and KatN, whose activity is markedly modulated by growth in LSMMG. In addition, we have observed that Salmonella enterica serovar Typhimurium strains lacking Hfq, RpoE, RpoS or OxyR are still more resistant to oxidative stress when grown in LSMMG than in NG conditions, indicating that these global gene regulators are not responsible for the microgravity-induced changes in KatG and KatN activity. As Salmonella likely encounters low shear conditions in the intestinal tract, our observations suggest that alterations in the relative activity of KatG and KatN could enhance Salmonella resistance to the reactive oxygen species produced also during natural infections
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
- …
