Staphylococcus aureus Decreases SUMOylation Host Response to Promote Intramacrophage Survival

Staphylococcus aureus is a commensal bacterium that causes severe infections in soft tissue and the bloodstream. During infection, S. aureus manipulates host cell response to facilitate its own replication and dissemination. Here, we show that S. aureus significantly decreases the level of SUMOylation, an essential post-translational modification, in infected macrophages 24 h post-phagocytosis. The reduced level of SUMOylation correlates with a decrease in the SUMO-conjugating enzyme Ubc9. The over-expression of SUMO proteins in macrophages impaired bacterial intracellular proliferation and the inhibition of SUMOylation with ML-792 increased it. Together, these findings demonstrated for the first time the role of host SUMOylation response toward S. aureus infection.

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The Virulence Potential of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Cultured from the Airways of Cystic Fibrosis Patients

Toxins ◽

10.3390/toxins12060360 ◽

2020 ◽

Vol 12 (6) ◽

pp. 360

Author(s):

Janina Treffon ◽

Sarah Ann Fotiadis ◽

Sarah van Alen ◽

Karsten Becker ◽

Barbara C. Kahl

Keyword(s):

Cystic Fibrosis ◽

Staphylococcus Aureus ◽

Airway Epithelial Cells ◽

Farm Animals ◽

Airway Epithelial ◽

Methicillin Resistant ◽

Virulence Potential ◽

Airway Infections ◽

Severe Infections

Staphylococcus aureus is one of the most common pathogens that infects the airways of patients with cystic fibrosis (CF) and contributes to respiratory failure. Recently, livestock-associated methicillin-resistant S. aureus (LA-MRSA), usually cultured in farm animals, were detected in CF airways. Although some of these strains are able to establish severe infections in humans, there is limited knowledge about the role of LA-MRSA virulence in CF lung disease. To address this issue, we analyzed LA-MRSA, hospital-associated (HA-) MRSA and methicillin-susceptible S. aureus (MSSA) clinical isolates recovered early in the course of airway infection and several years after persistence in this hostile environment from pulmonary specimens of nine CF patients regarding important virulence traits such as their hemolytic activity, biofilm formation, invasion in airway epithelial cells, cytotoxicity, and antibiotic susceptibility. We detected that CF LA-MRSA isolates were resistant to tetracycline, more hemolytic and cytotoxic than HA-MRSA, and more invasive than MSSA. Despite the residence in the animal host, LA-MRSA still represent a serious threat to humans, as such clones possess a virulence potential similar or even higher than that of HA-MRSA. Furthermore, we confirmed that S. aureus individually adapts to the airways of CF patients, which eventually impedes the success of antistaphylococcal therapy of airway infections in CF.

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Role of gamma-delta T cells in host response against Staphylococcus aureus-induced pneumonia

BMC Immunology ◽

10.1186/1471-2172-13-38 ◽

2012 ◽

Vol 13 (1) ◽

pp. 38 ◽

Cited By ~ 55

Author(s):

Ping Cheng ◽

Tao Liu ◽

Wei-Ying Zhou ◽

Yuan Zhuang ◽

Liu-sheng Peng ◽

...

Keyword(s):

Staphylococcus Aureus ◽

T Cells ◽

Host Response ◽

Gamma Delta T Cells ◽

Gamma Delta

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Comparison of the Regulation, Metabolic Functions, and Roles in Virulence of the Glyceraldehyde-3-Phosphate Dehydrogenase Homologues gapA and gapB in Staphylococcus aureus

Infection and Immunity ◽

10.1128/iai.00762-10 ◽

2010 ◽

Vol 78 (12) ◽

pp. 5223-5232 ◽

Cited By ~ 46

Author(s):

Joanne Purves ◽

Alan Cockayne ◽

Peter C. E. Moody ◽

Julie A. Morrissey

Keyword(s):

Staphylococcus Aureus ◽

Galleria Mellonella ◽

Positive Bacterium ◽

Gram Positive ◽

Complementary Methods ◽

Metabolic Functions ◽

Regulator Protein ◽

First Time ◽

Gapdh Protein

ABSTRACT The Gram-positive bacterium Staphylococcus aureus contains two glyceraldehyde-3-phosphate dehydrogenase (GAPDH) homologues known as GapA and GapB. GapA has been characterized as a functional GAPDH protein, but currently there is no biological evidence for the role of GapB in metabolism in S. aureus. In this study we show through a number of complementary methods that S. aureus GapA is essential for glycolysis while GapB is essential in gluconeogenesis. These proteins are reciprocally regulated in response to glucose concentrations, and both are influenced by the glycolysis regulator protein GapR, which is the first demonstration of the role of this regulator in S. aureus and the first indication that GapR homologues control genes other than those within the glycolytic operon. Furthermore, we show that both GapA and GapB are important in the pathogenesis of S. aureus in a Galleria mellonella model of infection, showing for the first time in any bacteria that both glycolysis and gluconeogenesis have important roles in virulence.

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The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

Neurotherapeutics ◽

10.1007/s13311-020-00978-4 ◽

2020 ◽

Author(s):

Ilaria Zuliani ◽

Chiara Lanzillotta ◽

Antonella Tramutola ◽

Antonio Francioso ◽

Sara Pagnotta ◽

...

Keyword(s):

Down Syndrome ◽

Molecular Mechanisms ◽

Post Translational Modification ◽

Neuroprotective Effects ◽

Hexosamine Biosynthetic Pathway ◽

Brain Degeneration ◽

First Time ◽

The Brain ◽

Pathway Flux

AbstractProtein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer’s disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently lead to aberrant protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins involves also tau and APP, thus promoting their aberrant phosphorylation in AD brain and the onset of AD pathological markers. Down syndrome (DS) individuals are characterized by the early development of AD by the age of 60 and, although the two conditions present the same pathological hallmarks and share the alteration of many molecular mechanisms driving brain degeneration, no evidence has been sought on the implication of O-GlcNAcylation in DS pathology. Our study aimed to unravel for the first time the role of protein O-GlcNacylation in DS brain alterations positing the attention of potential trisomy-related mechanisms triggering the aberrant regulation of OGT/OGA cycle. We demonstrate the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and confirm the relevance of O-GlcNAcylation in the appearance of AD hallmarks in the brain of a murine model of DS. Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition. Indeed, the rescue of OGA activity was able to restore protein O-GlcNAcylation, and reduce AD-related hallmarks and decreased protein nitration, possibly as effect of induced autophagy.

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Role of Glutathionylation in Infection and Inflammation

Nutrients ◽

10.3390/nu11081952 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1952 ◽

Cited By ~ 9

Author(s):

Paola Checconi ◽

Dolores Limongi ◽

Sara Baldelli ◽

Maria Rosa Ciriolo ◽

Lucia Nencioni ◽

...

Keyword(s):

Protein Function ◽

Host Response ◽

Redox State ◽

Cellular Proteins ◽

Host Responses ◽

Post Translational Modification ◽

Microbial Infections ◽

Infection And Inflammation ◽

Mixed Disulfides

Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.

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Methicillin-resistant Staphylococcus aureus urosepsis: A rare complication of neonatal circumcision

SAGE Open Medical Case Reports ◽

10.1177/2050313x20966122 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2096612

Author(s):

Ahmed Khalil ◽

Eiman Hamid ◽

Khaled Siddiq ◽

Manasik Hassan

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Clinical Course ◽

Rare Complication ◽

Methicillin Resistant ◽

Severe Infections ◽

Neonatal Circumcision

The role of circumcision and its benefits has received increased attention across several disciplines in recent years; however, there is increasing concern that some uncommon complications such as severe infections are being related to post-circumcision. We describe the clinical course of a 14-day-old boy who had Methicillin-resistant Staphylococcus aureus urosepsis after circumcision.

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Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC

10.1101/575217 ◽

2019 ◽

Author(s):

Louise H. Lefrançois ◽

Vera Kalinina ◽

Elena Cardenal-Muñoz ◽

Nabil Hanna ◽

Hendrik Koliwer-Brandl ◽

...

Keyword(s):

Dictyostelium Discoideum ◽

Metal Accumulation ◽

Chemical Warfare ◽

Mycobacterium Marinum ◽

Close Relative ◽

First Time ◽

Intracellular Proliferation ◽

Role Of Zn ◽

Professional Phagocyte

ABSTRACTMacrophages use diverse strategies to kill or restrict intracellular pathogens. Some of these strategies involve the deprivation of bacteria from (micro)nutrients such as transition metals, and the bacteria intoxication through metal accumulation. Little is known about the chemical warfare between Mycobacterium marinum, a close relative of the human pathogen M. tuberculosis, and its hosts. Here we use the professional phagocyte Dictyostelium discoideum to investigate the role of Zn2+ during M. marinum infection. We show that M. marinum infection induces the accumulation of Zn2+ inside the Mycobacterium-containing vacuole (MCV), achieved by the induction and recruitment of the D. discoideum Zn2+ efflux pumps ZntA and ZntB. In cells lacking the ZntA detoxifying transporter there is further attenuation of M. marinum growth, possibly due to a compensatory efflux of Zn2+ into the MCV. This efflux is presumably carried out by ZntB, the main Zn2+ transporter in endosomes and phagosomes. Counterintuitively, M. marinum growth is also impaired in zntB KO cells, where MCVs accumulate less Zn2+. We also demonstrate that M. marinum senses toxic levels of Zn2+ and responds by upregulating its Zn2+ exporter CtpC, which supports bacteria survival under these restrictive conditions. Attenuation of M. marinum intracellular proliferation in zntA and zntB KO cells is accentuated in the absence of CtpC, confirming that mycobacteria face noxious levels of Zn2+. Altogether, we show for the first time that M. marinum infection induces a deleterious Zn2+ elevation in D. discoideum, which is counteracted by the bacteria with the induction of its Zn2+ exporter CtpC.

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Dysregulation of splicing-related proteins in prostate cancer is controlled by FOXA1

10.1101/509034 ◽

2018 ◽

Author(s):

John G. Foster ◽

Rebecca Arkell ◽

Marco Del Giudice ◽

Chinedu Anene ◽

Andrea Lauria ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Patient Outcomes ◽

Transcriptional Networks ◽

Over Expression ◽

Castration Resistant ◽

Related Proteins ◽

First Time

AbstractProstate cancer (PCa) is genomically driven by dysregulation of transcriptional networks involving the transcriptional factors (TFs) FOXA1, ERG, AR, and HOXB13. However, the role of these specific TFs in the regulation of alternative pre-mRNA splicing (AS), which is a proven therapeutic vulnerability for cancers driven by the TF MYC, is not described. Using transcriptomic datasets from PCa patients, we tested for an association between expression of FOXA1, ERG, AR, HOXB13, and MYC, and genes involved in AS - termed splicing-related proteins (SRPs), which have pleiotropic roles in RNA metabolism. We identified FOXA1 as the strongest predictor of dysregulated SRP gene expression, which was associated with PCa disease relapse after treatment. Subsequently, we selected a subset of FOXA1-binding and actively-transcribed SRP genes that phenocopy the FOXA1 dependency of PCa cells, and confirmed in vitro via knockdown and over-expression that FOXA1 regulates SRP gene expression. Finally, we demonstrated the persistence of a FOXA1-SRP gene association in treatment-relapsed castration-resistant PCa (CRPCa) patients. Our data demonstrate, for the first time, that FOXA1 controls dysregulated SRP gene expression, which is associated with poor PCa patient outcomes. Analogous to MYC-driven cancers, our findings implicate the therapeutic targeting of SRPs and AS in FOXA1-overexpressing PCa.

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Platelet depletion in mice increases mortality after thermal injury

Blood ◽

10.1182/blood-2005-09-3776 ◽

2006 ◽

Vol 107 (11) ◽

pp. 4399-4406 ◽

Cited By ~ 34

Author(s):

Satoshi Fujimi ◽

Malcolm P. MacConmara ◽

Adrian A. Maung ◽

Yan Zang ◽

John A. Mannick ◽

...

Keyword(s):

Host Response ◽

Thermal Injury ◽

Total Body Surface Area ◽

Protective Role ◽

Blood Monocytes ◽

Serious Injury ◽

Total Body ◽

First Time ◽

Deficient Mice

AbstractPlatelets play a fundamental role in maintaining hemostasis and have been shown to participate in innate and adaptive immunity. However, the role of platelets in the immune response to injury remains undefined. We tested the importance of platelets in the host response to serious injury in a newly developed platelet-deficient mouse model. Wild-type and platelet-depleted C57BL/6J mice underwent a 25% full-thickness total body surface area thermal or sham injury. Platelet-deficient mice showed survival of 51% at 48 hours after injury compared with 94% to 100% survival in experimental control mice (P < .001). Necropsy and histology ruled out hemorrhage and hypovolemia as causes of death. Percentages of peripheral blood monocytes (P < .01) and neutrophils (P < .05) were increased between 36 and 48 hours after thermal injury in platelet-deficient mice compared with control mice. Plasma levels of TNFα (P < .001), IL-6 (P < .001), and MCP-1 (P < .05) were also elevated by 24 hours whereas levels of TGFβ1 were reduced between 24 and 36 hours following injury in platelet-depleted mice (P < .001) compared with control mice. Our findings demonstrate for the first time that platelets play a critical protective role during the host response to injury. Moreover, our findings suggest that platelets and, more importantly, platelet-derived TGFβ1 modulate the systemic inflammatory response occurring after injury.

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PCR detection of toxic shock syndrome toxin of Staphylococcus aureus from Tripoli, Libya

Journal of Medical Microbiology ◽

10.1099/jmm.0.46162-0 ◽

2006 ◽

Vol 55 (2) ◽

pp. 179-182 ◽

Cited By ~ 11

Author(s):

Abdulmula El-Ghodban ◽

Khalifa Sifaw Ghenghesh ◽

Károly Márialigeti ◽

Hamida Esahli ◽

Abdurrahman Tawil

Keyword(s):

Staphylococcus Aureus ◽

Toxic Shock Syndrome ◽

Pcr Detection ◽

Food Sources ◽

Toxic Shock ◽

Group Ii ◽

Toxic Shock Syndrome Toxin ◽

First Time

Sixty-three Staphylococcus aureus strains (40 from clinical sources and 23 from food sources) were examined for toxic shock syndrome toxin-1 (TSST-1) using PCR, phage typed using the international phage set (IPS) and tested for their susceptibility to antibiotics. Only three strains (all from clinical sources) were positive for the TSST-1 gene (tst). The majority of S. aureus strains that were typeable by IPS belonged to group II. Resistance to one or more antibiotics was detected in 47·5 and 73·9 % of clinical and food strains, respectively. This is the first time that PCR detection of tst in S. aureus has been reported from Libya, and further studies are needed on the occurrence of toxic shock syndrome in the community and the role of TSST-1-producing S. aureus in this disease in Libya.

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