bluuebunny/crossref_metadata_2025_split huggingface dataset:
Borrelia burgdorferi
Resistance to a Major Skin Antimicrobial Peptide Is Independent of Outer Surface Lipoprotein Content
Authors: Sarkar Amit , Tilly Kit , Stewart Philip , Bestor Aaron , Battisti James M. , Rosa Patricia A. 
Published: August 2009

ABSTRACT

We hypothesize a potential role for
Borrelia burgdorferi
OspC in innate immune evasion at the initial stage of mammalian infection. We demonstrate that
B. burgdorferi
is resistant to high levels (>200 μg/ml) of cathelicidin and that this antimicrobial peptide exhibits limited binding to the spirochetal outer membrane, irrespective of OspC or other abundant surface lipoproteins. We conclude that the essential role of OspC is unrelated to resistance to this component of innate immunity.
Large-Scale Sequence Analysis of M Gene of Influenza A Viruses from Different Species: Mechanisms for Emergence and Spread of Amantadine Resistance
Authors: Furuse Yuki , Suzuki Akira , Oshitani Hitoshi 
Published: August 2009

ABSTRACT
Influenza A virus infects many species, and amantadine is used as an antiviral agent. Recently, a substantial increase in amantadine-resistant strains has been reported, most of which have a substitution at amino acid position 31 in the M2 gene. Understanding the mechanism responsible for the emergence and spread of antiviral resistance is important for developing a treatment protocol for seasonal influenza and for deciding on a policy for antiviral stockpiling for pandemic influenza. The present study was conducted to identify the existence of drug pressure on the emergence and spread of amantadine-resistant influenza A viruses. We analyzed data on more than 5,000 virus sequences and constructed a phylogenetic tree to calculate selective pressures on sites in the M2 gene associated with amantadine resistance (positions 26, 27, 30, and 31) among different hosts. The phylogenetic tree revealed that the emergence and spread of the drug-resistant M gene in different hosts and subtypes were independent and not through reassortment. For human influenza virus, positive selection was detected only at position 27. Selective pressures on the sites were not always higher for human influenza virus than for viruses of other hosts. Additionally, selective pressure on position 31 did not increase after the introduction of amantadine. Although there is a possibility of drug pressure on human influenza virus, we could not find positive pressure on position 31. Because the recent rapid increase in drug-resistant virus is associated with the substitution at position 31, the resistance may not be related to drug use.
High-Throughput Identification of New Protective Antigens from a
Yersinia pestis
Live Vaccine by Enzyme-Linked Immunospot Assay
Authors: Li Bei , Zhou Lei , Guo JingYu , Wang Xiaoyi , Ni Bin , Ke Yuehua , Zhu Ziwen , Guo Zhaobiao , Yang Ruifu 
Published: August 2009

ABSTRACT

Yersinia pestis
, the plague pathogen, is a facultative intracellular bacterium. Cellular immunity plays important roles in defense against infections. The identification of T-cell targets is critical for the development of effective vaccines against intracellular bacteria; however, the function of cellular immunity in protection from plague was not clearly understood. In this study, 261 genes from
Y. pestis
were selected on the basis of bioinformatics analysis and previous research results for expression in
Escherichia coli
BL21(DE3). After purification, 101 proteins were qualified for examination of their abilities to induce the production of gamma interferon in mice immunized with live vaccine EV76 by enzyme-linked immunospot assay. Thirty-four proteins were found to stimulate strong T-cell responses. The protective efficiencies for 24 of them were preliminarily evaluated using a mouse plague model. In addition to LcrV, nine proteins (YPO0606, YPO1914, YPO0612, YPO3119, YPO3047, YPO1377, YPCD1.05c, YPO0420, and YPO3720) may provide partial protection against challenge with a low dose (20 times the 50% lethal dose [20× LD
50
]) of
Y. pestis
, but only YPO0606 could partially protect mice from infection with
Y. pestis
at a higher challenge dosage (200× LD
50
). These proteins would be the potential components for
Y. pestis
vaccine development.
Use of
Moraxella catarrhalis
Lipooligosaccharide Mutants To Identify Specific Oligosaccharide Epitopes Recognized by Human Serum Antibodies
Authors: Schwingel Johanna M. , Edwards Katie J. , Cox Andrew D. , Masoud Hussein , Richards James C. , St. Michael Frank , Tekwe Carmen D. , Sethi Sanjay , Murphy Timothy F. , Campagnari Anthony A. 
Published: August 2009

ABSTRACT

Moraxella catarrhalis
is a causative agent of otitis media in children and lower respiratory tract infections in adults suffering from chronic obstructive pulmonary disease (COPD). This strict human pathogen continues to be a significant cause of disease in this broad spectrum of patients because there is no available vaccine. Although numerous putative vaccine antigens have been described, little is known about the human immune response to
M. catarrhalis
infection in vivo. Human serum antibodies are directed at a number of surface proteins, and lipooligosaccharides (LOS) and detoxified LOS may be an effective immunogen in mice. In this study, we used a specific LOS-based enzyme-linked immunosorbent assay (ELISA), containing the three major
M. catarrhalis
serotypes together with a complete series of truncated LOS mutants, to detect the development of new antibodies to specific regions of the oligosaccharide molecule. We compared serum samples from COPD patients who had recently cleared an
M. catarrhalis
infection to serum samples collected prior to their infection. Variability in the antibody response to LOS was observed, as some patients developed serotype-specific antibodies, others developed antibodies to the LOS of each serotype, others developed broadly cross-reactive antibodies, and some did not develop new antibodies. These newly developed human antibodies are directed at both side chains and core structures in the LOS molecule. This LOS-based ELISA can be used to dissect the human antibody response to both internal and external carbohydrate epitopes, thus providing a better understanding of the humoral immune response to
M. catarrhalis
LOS epitopes developed during natural infection.
Establishment of SystemicBrucella melitensisInfection through the Digestive Tract Requires Urease, the Type IV Secretion System, and Lipopolysaccharide O Antigen
Authors: Paixão Tatiane A. , Roux Christelle M. , den Hartigh Andreas B. , Sankaran-Walters Sumathi , Dandekar Satya , Santos Renato L. , Tsolis Renée M. 
Published: August 2009

ABSTRACTHuman brucellosis is caused mainly byBrucella melitensis, which is often acquired by ingesting contaminated goat or sheep milk and cheese. Bacterial factors required for food-borne infection of humans byB. melitensisare poorly understood. In this study, a mouse model of oral infection was characterized to assess the roles of urease, the VirB type IV secretion system, and lipopolysaccharide for establishing infection through the digestive tract.B. melitensisstrain 16M was consistently recovered from the mesenteric lymph node (MLN), spleen, and liver beginning at 3 or 7 day postinfection (dpi). In the gut, persistence of the inoculum was observed up to 21 dpi. No inflammatory lesions were observed in the ileum or colon during infection. Mutant strains lacking theureABCgenes of theure1operon,virB2, orpmmencoding phosphomannomutase were constructed and compared to the wild-type strain for infectivity through the digestive tract. Mutants lacking thevirB2andpmmgenes were attenuated in the spleen (P< 0.05) and MLN (P< 0.001), respectively. The wild-type and mutant strains had similar levels of resistance to low pH and 5 or 10% bile, suggesting that the reduced colonization of mutants was not the result of reduced resistance to acid pH or bile salts. In an in vitro lymphoepithelial cell (M-cell) model,B. melitensistransited rapidly through polarized enterocyte monolayers containing M-like cells; however, transit through monolayers containing only enterocytes was reduced or absent. These results indicate thatB. melitensisis able to spread systemically from the digestive tract after infection, most likely through M cells of the mucosa-associated lymphoid tissue.
The NanI and NanJ Sialidases of
Clostridium perfringens
Are Not Essential for Virulence
Authors: Chiarezza Martina , Lyras Dena , Pidot Sacha J. , Flores-Díaz Marietta , Awad Milena M. , Kennedy Catherine L. , Cordner Leanne M. , Phumoonna Tongted , Poon Rachael , Hughes Meredith L. , Emmins John J. , Alape-Girón Alberto , Rood Julian I. 
Published: August 2009

ABSTRACT

The essential toxin in
Clostridium perfringens
-mediated gas gangrene or clostridial myonecrosis is alpha-toxin, although other toxins and extracellular enzymes may also be involved. In many bacterial pathogens extracellular sialidases are important virulence factors, and it has been suggested that sialidases may play a role in gas gangrene.
C. perfringens
strains have combinations of three different sialidase genes, two of which,
nanI and nanJ
, encode secreted sialidases. The
nanI
and
nanJ
genes were insertionally inactivated by homologous recombination in derivatives of sequenced strain 13 and were shown to encode two functional secreted sialidases, NanI and NanJ. Analysis of these derivatives showed that NanI was the major sialidase in this organism. Mutation of
nanI
resulted in loss of most of the secreted sialidase activity, and the residual activity was eliminated by subsequent mutation of the
nanJ
gene. Only a slight reduction in the total sialidase activity was observed in a
nanJ
mutant. Cytotoxicity assays using the B16 melanoma cell line showed that supernatants containing NanI or overexpressing NanJ enhanced alpha-toxin-mediated cytotoxicity. Finally, the ability of
nanI
,
nanJ
, and
nanIJ
mutants to cause disease was assessed in a mouse myonecrosis model. No attenuation of virulence was observed for any of these strains, providing evidence that neither the NanI sialidase nor the NanJ sialidase is essential for virulence.
The Trehalose Synthesis Pathway Is an Integral Part of the Virulence Composite for
Cryptococcus gattii
Authors: Ngamskulrungroj Popchai , Himmelreich Uwe , Breger Julia A. , Wilson Christabel , Chayakulkeeree Methee , Krockenberger Mark B. , Malik Richard , Daniel Heide-Marie , Toffaletti Dena , Djordjevic Julianne T. , Mylonakis Eleftherios , Meyer Wieland , Perfect John R. 
Published: August 2009

ABSTRACT

The trehalose pathway is essential for stress tolerance and virulence in fungi. We investigated the importance of this pathway for virulence of the pathogenic yeast
Cryptococcus gattii
using the highly virulent Vancouver Island, Canada, outbreak strain R265. Three genes putatively involved in trehalose biosynthesis,
TPS1
(trehalose-6-phosphate [T6P] synthase) and
TPS2
(T6P phosphatase), and degradation,
NTH1
(neutral trehalose), were deleted in this strain, creating the R265
tps1
Δ, R265
tps2
Δ, and R265
nth1
Δ mutants. As in
Cryptococcus neoformans
, cellular trehalose was reduced in the R265
tps1
Δ and R265
tps2
Δ mutants, which could not grow and died, respectively, at 37°C on yeast extract-peptone-dextrose agar, suggesting that T6P accumulation in R265
tps2
Δ is directly toxic. Characterizations of the cryptococcal hexokinases and trehalose mutants support their linkage to the control of glycolysis in this species. However, unlike
C. neoformans
, the
C. gattii
R265
tps1
Δ mutant demonstrated, in addition, defects in melanin and capsule production, supporting an influence of T6P on these virulence pathways. Attenuated virulence of the R265
tps1
Δ mutant was not due solely to its 37°C growth defect, as shown in worm studies and confirmed by suppressor mutants. Furthermore, an intact trehalose pathway controls protein secretion, mating, and cell wall integrity in
C. gattii
. Thus, the trehalose synthesis pathway plays a central role in the virulence composites of
C. gattii
through multiple mechanisms. Deletion of
NTH1
had no effect on virulence, but inactivation of the synthesis genes,
TPS1
and
TPS2
, has profound effects on survival of
C. gattii
in the invertebrate and mammalian hosts. These results highlight the central importance of this pathway in the virulence composites of both pathogenic cryptococcal species.
The 58-Kilodalton Major Virulence Factor of
Francisella tularensis
Is Required for Efficient Utilization of Iron
Authors: Lindgren Helena , Honn Marie , Golovlev Igor , Kadzhaev Konstantin , Conlan Wayne , Sjöstedt Anders 
Published: August 2009

ABSTRACT

We investigated the role of the 58-kDa FTT0918 protein in the iron metabolism of
Francisella tularensis
. The phenotypes of SCHU S4, a prototypic strain of
F. tularensis
subsp.
tularensis
, and the ΔFTT0918 and Δ
fslA
isogenic mutants were analyzed. The gene product missing in the Δ
fslA
mutant is responsible for synthesis of a siderophore. When grown in broth with various iron concentrations, the two deletion mutants generally reached lower maximal densities than SCHU S4. The ΔFTT0918 mutant, but not the Δ
fslA
mutant, upregulated the genes of the
F. tularensis
siderophore locus (
fsl
) operon even at high iron concentrations. A chrome azurol sulfonate plate assay confirmed siderophore production by all strains except the Δ
fslA
strain. In a cross-feeding experiment using medium devoid of free iron, SCHU S4 promoted growth of the Δ
fslA
strain but not of the ΔFTT0918 strain. The sensitivity of SCHU S4 and the ΔFTT0918 and Δ
fslA
strains to streptonigrin demonstrated that the ΔFTT0918 strain contained a smaller free intracellular iron pool and that the Δ
fslA
strain contained a larger one than SCHU S4. In contrast to the marked attenuation of the ΔFTT0918 strain, the Δ
fslA
strain was as virulent as SCHU S4 in a mouse model. Altogether, the data demonstrate that the FTT0918 protein is required for
F. tularensis
to utilize iron bound to siderophores and that it likely has a role also in siderophore-independent iron acquisition. We suggest that the FTT0918 protein be designated Fe utilization protein A, FupA.
The Global Regulator CodY Regulates Toxin Gene Expression inBacillus anthracisand Is Required for Full Virulence
Authors: van Schaik Willem , Château Alice , Dillies Marie-Agnès , Coppée Jean-Yves , Sonenshein Abraham L. , Fouet Agnès 
Published: August 2009

ABSTRACTIn gram-positive bacteria, CodY is an important regulator of genes whose expression changes upon nutrient limitation and acts as a repressor of virulence gene expression in some pathogenic species. Here, we report the role of CodY inBacillus anthracis, the etiologic agent of anthrax. Disruption ofcodYcompletely abolished virulence in a toxinogenic, noncapsulated strain, indicating that the activity of CodY is required for full virulence ofB. anthracis. Global transcriptome analysis of acodYmutant and the parental strain revealed extensive differences. These differences could reflect direct control for some genes, as suggested by the presence of CodY binding sequences in their promoter regions, or indirect effects via the CodY-dependent control of other regulatory proteins or metabolic rearrangements in thecodYmutant strain. The differences included reduced expression of the anthrax toxin genes in the mutant strain, which was confirmed bylacZreporter fusions and immunoblotting. The accumulation of the global virulence regulator AtxA protein was strongly reduced in the mutant strain. However, in agreement with the microarray data, expression ofatxA, as measured using anatxA-lacZtranscriptional fusion and by assayingatxAmRNA, was not significantly affected in thecodYmutant. AnatxA-lacZtranslational fusion was also unaffected. Overexpression ofatxArestored toxin component synthesis in thecodYmutant strain. These results suggest that CodY controls toxin gene expression by regulating AtxA accumulation posttranslationally.
Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo
Authors: Obszynska Jolanta A , Atherfold Paul A , Nanji Manoj , Glancy Deborah , Santander Sonia , Graham Trevor A , Otto William R , West Kevin , Harrison Rebecca F , Jankowski Janusz AZ 
Published: August 2009

BackgroundBarrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man.MethodsWe undertook detailed serological and tissue assessment of gastrin and CCK2 receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa.ResultsGastrin and its cognate receptor CCK2R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml±57 pg/ml to 103 pg/ml±94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)cckr Barrett's oesophagus cells, but not OE21(E)cckr squamous cells, transfected with CCK2R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.ConclusionWhile the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.
Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction
Authors: Distelmaier Klaus , Adlbrecht Christopher , Jakowitsch Johannes , Winkler Susanne , Dunkler Daniela , Gerner Christopher , Wagner Oswald , Lang Irene M. , Kubicek Markus 
Published: August 2009

SummaryAtherosclerotic plaque rupture with subsequent mural thrombus formation is considered the main event compromising epicardial flow in acute myocardial infarction (AMI). However, the precise mechanisms underlying acute coronary occlusion are unknown.We compared the proteomic profiles of systemic plasma and plasma derived from the site of thrombus formation of patients with AMI by two-dimensional gel electrophoresis and ELISA. We identified a local activation of the complement system, with selective accumulation of the complement activator Creactive protein (CRP) and the downstream complement effectors C3a and C5a. CRP in coronary thrombus co-localised with C1q and C3 immunoreactivities, suggesting classical complement activation. In vitro, coronary thrombus derived plasma enhanced neutrophil chemotaxis in a C5a dependent fashion. In vivo, neutrophil accumulation at the site of thrombus formation paralleled the time delay from symptom onset to first balloon inflation or aspiration, and was correlated with C5a and enzymatic infarct size. We present the first direct evidence for localised complement activation in acute coronary thrombi. Our data indicate that local complement effectors amplify the vascular occlusion process in AMI by enhanced neutrophil recruitment.
Red cell distribution width (RDW) as a predictor of long-term mortality in patients undergoing percutaneous coronary intervention
Authors: Poludasu Shyam , Marmur Jonathan D. , Weedon Jeremy , Khan Waqas , Cavusoglu Erdal 
Published: August 2009

SummaryRed cell distribution width (RDW) has been shown to be an independent predictor of mortality in patients with coronary artery disease and in patients with heart failure. The current study evaluated the prognostic utility of RDW in patients undergoing percutaneous coronary intervention (PCI). We evaluated 859 patients who underwent PCI during January 2003 to August 2005. After a median follow up of four (interquartile range 3.1 to 4.4) years, there were a total of 95 (11%) deaths. RDW was analysed as a categorical variable with empirically determined cut points of 13.3 and 15.7 (low RDW <13.3, medium RDW ≥13.3 to <15.7, high RDW ≥15.7) based on differences in hazard ratio (HR) for death among RDW deciles.In univariate analysis, higher RDW was a significant predictor of mortality (p<0.001). In multivariate analysis there was a significant two-way interaction between RDW and haemoglobin (Hgb). RDW was not an independent predictor of mortality in patients with Hgb <10.4. However, among patients with Hgb >10.4, high RDW was a strong and independent predictor of mortality. For patients with Hgb ≥10.4 to <12.7, HR for death in patients with high RDW relative to low RDW was 5.2 (95% confidence intervals [CI]: 2.0–13.3). For patients with Hgb ≥12.7, HR for death in patients with high RDW relative to low RDW was 8.6 (CI:2.8–28.6). Higher RDW was a strong and independent predictor of long-term mortality in patients undergoing PCI who were not anaemic at baseline.
The long pentraxin 3 (PTX3): a novel prognostic inflammatory marker for mortality in acute chest pain
Authors: Brügger-Andersen Trygve , Pönitz Volker , Staines Harry , Grundt Heidi , Sagara Mina , Nilsen Dennis W.T. , Kontny Frederic 
Published: August 2009

SummaryThe long pentraxin 3 (PTX3) is a recently identified member of the pentraxin protein family that includes C-reactive protein. PTX3 is produced by the major cell types involved in atherosclerotic lesions in response to inflammatory stimuli, and elevated plasma levels are found in several conditions including acute coronary syndromes (ACS). The aim of this study was to assess the value of PTX3 as a prognostic marker of mortality and recurrent ischaemic events in a consecutive series of patients admitted with acute chest pain and potential ACS.The patients received follow-up for 24 months. Blood samples were taken on admission for measurement of PTX3, high sensitive C-reactive protein (hsCRP), B-type natriuretic peptide (BNP), and troponin T. All-cause mortality at 24 months in the study cohort was 15.2%. Patients in the upper PTX3 quartiles had a significantly higher death risk than those in the lowest quartile (Q3: hazard ratio [HR] 2.36; 95% CI 1.12–4.99; p=0.024, and Q4: HR 3.60; 95% CI 1.68–7.72; p=0.001). Elevated BNP levels were also significantly associated with a fatal outcome (Q3: HR 3.05; 95% CI 1.16–7.99; p=0.024; and Q4: HR 3.90; 95% CI 1.48–10.26; p=0.006). Elevation in hsCRP was not associated with increased death risk. As PTX3 predicted mortality independently of BNP, the combination of these two biomarkers showed an incremental prognostic value.PTX3 is a new biomarker related to inflammation that, independently of BNP, strongly predicts long-term all-cause mortality in patients with acute chest pain. The combination of these two biomarkers enhances the prognostic value over either marker alone.