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tlr4-mediated activation of dendritic cells by the heat shock protein dnak from francisella tularensis.francisella tularensis is the causative agent of tularemia, a severe, debilitating disease of humans and other mammals. as this microorganism is also classified as a "category-a pathogen" and a potential biowarfare agent, there is a need for an effective vaccine. several antigens of f. tularensis, including the heat shock protein dnak, have been proposed for use in a potential subunit vaccine. in this study, we characterized the innate immune response of murine bone marrow-derived dendritic cell ...200818708593
cytokine response in balb/c mice infected with francisella tularensis lvs and the pohang isolate.we investigated the immune response induced by the francisella (f.) tularensis live vaccine strain (lvs) and the pohang isolate. after the balb/c mice were infected intradermally (i.d) with 2 x 10(4) cfu of f. tularensis lvs and pohang, respectively, their blood and organs were collected at different times; 0, 3, 6, 24, 72, 96, 120 and 168 h after infection. using these samples, rt-pcr and elisa analysis were carried out for the comparative study of the cytokines, including tnf-alpha, inf-gamma, ...200818716452
targeting qsec signaling and virulence for antibiotic development.many bacterial pathogens rely on a conserved membrane histidine sensor kinase, qsec, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. using a high-throughput screen, we identified a small molecule, led209, that inhibits the binding of signals to qsec, preventing its autophosphorylation and consequently inhibiting qsec-mediated activation of virulence gene expression. led209 is not toxic and does not inhibit pathogen ...200818719281
tularemia.tularemia is a rare zoonotic infection caused by the bacterium francisella tularensis. the disease is endemic in north america and parts of europe and asia. arthropods (ticks and deer flies) are the main transmission vector, and small animals (rabbits, hares, and muskrats) serve as reservoir hosts. the clinical presentation depends on the bacterial subspecies and the route of infection. recent world events have led to a new recognition of f tularensis as a viable agent of bioterrorism, which has ...200818755386
tularemia in a park, philadelphia, pennsylvania. 200818760026
ripa, a cytoplasmic membrane protein conserved among francisella species, is required for intracellular survival.francisella tularensis is a highly virulent bacterial pathogen that invades and replicates within numerous host cell types, including macrophages and epithelial cells. in an effort to better understand this process, we screened a transposon insertion library of the f. tularensis live vaccine strain (lvs) for mutant strains that invaded but failed to replicate within alveolar epithelial cell lines. one such strain isolated from this screen contained an insertion in the gene ftl_1914, which is con ...200818765722
francisella tularensis live vaccine strain induces macrophage alternative activation as a survival mechanism.francisella tularensis (ft), the causative agent of tularemia, elicits a potent inflammatory response early in infection, yet persists within host macrophages and can be lethal if left unchecked. we report in this study that ft live vaccine strain (lvs) infection of murine macrophages induced tlr2-dependent expression of alternative activation markers that followed the appearance of classically activated markers. intraperitoneal infection with ft lvs also resulted in induction of alternatively a ...200818768873
lymphotoxin-alpha plays only a minor role in host resistance to respiratory infection with virulent type a francisella tularensis in mice.this study examined the role of lymphotoxin (lt)-alpha in host defense against airborne infection with francisella tularensis, a gram-negative facultative intracellular bacterium and the causative agent of tularemia. following a low-dose aerosol infection with the highly virulent type a strain of f. tularensis, mice deficient in ltalpha (ltalpha-/-) consistently harbored approximately 10-fold fewer bacteria in their spleens at day 2 and 10-fold more bacteria in their lungs at day 4 than ltalpha+ ...200818769490
a novel receptor - ligand pathway for entry of francisella tularensis in monocyte-like thp-1 cells: interaction between surface nucleolin and bacterial elongation factor tu.francisella tularensis, the causative agent of tularemia, is one of the most infectious human bacterial pathogens. it is phagocytosed by immune cells, such as monocytes and macrophages. the precise mechanisms that initiate bacterial uptake have not yet been elucidated. participation of c3, cr3, class a scavenger receptors and mannose receptor in bacterial uptake have been already reported. however, contribution of an additional, as-yet-unidentified receptor for f. tularensis internalization has ...200818789156
detection of francisella tularensis in ticks and identification of their genotypes using multiple-locus variable-number tandem repeat analysis.tularemia was reported in china over 50 years ago, however, many epidemical characteristics remain unclear. in the present study, the prevalence of francisella tularensis in ticks was investigated during an epidemiological surveillance in china and then we measured their genetic diversity by conducting multiple-locus variable- number tandem repeat analysis (mlva).200818798995
differential requirements by cd4+ and cd8+ t cells for soluble and membrane tnf in control of francisella tularensis live vaccine strain intramacrophage growth.during primary infection with intracellular bacteria, the membrane-associated form of tnf provides some tnf functions, but the relative contributions during memory responses are not well-characterized. in this study, we determined the role of t cell-derived secreted and membrane-bound tnf (memtnf) during adaptive immunity to francisella tularensis live vaccine strain (lvs). although transgenic mice expressing only the memtnf were more susceptible to primary lvs infection than wild-type (wt) mice ...200718025217
comparison of whole genome amplification methods for detecting pathogenic bacterial genomic dna using microarray.the genetic diagnosis of pathogenic agents using microarrays has the advantage of high-throughput detection, but a relatively large amount of dna sample is required. to obtain a sufficient amount of dna for molecular diagnoses, several whole genome amplification (wga) methods have been proposed. in this study, using francisella tularensis and escherichia coli as models, we compared four wga methods in terms of their efficiency of amplification of whole genomic dna in order to identify the most s ...200718032834
piezoelectric immunosensor for the direct and rapid detection of francisella tularensis.a novel immunosensing device based on a piezoelectric sensor for direct detection of the biological warfare agent francisella tularensis was developed. this sensor includes mouse polyclonal antibody immobilized in a layer of protein a covalently linked to the gold electrode of the sensor. the immunosensor is able to detect f. tularensis with the limit of detection 10(5) cfu/ml with a typical measuring cycle > 5 min. the sensor was successfully evaluated for rapid detection of f. tularensis spike ...200718062180
[mission oriented diagnostic real-time pcr].in out of area military missions soldiers are potentially exposed to bacteria that are endemic in tropical areas and can be used as biological agents. it can be difficult to culture these bacteria due to sample contamination, low number of bacteria or pretreatment with antibiotics. commercial biochemical identification systems are not optimized for these agents which can result in misidentification. immunological assays are often not commercially available or not specific. real-time pcr assays a ...200717987355
a bioinformatic filter for improved base-call accuracy and polymorphism detection using the affymetrix genechip whole-genome resequencing platform.dna resequencing arrays enable rapid acquisition of high-quality sequence data. this technology represents a promising platform for rapid high-resolution genotyping of microorganisms. traditional array-based resequencing methods have relied on the use of specific pcr-amplified fragments from the query samples as hybridization targets. while this specificity in the target dna population reduces the potential for artifacts caused by cross-hybridization, the subsampling of the query genome limits t ...200718006572
tularemia vaccines - an overview.f tularensis is among of the most virulent pathogens known, yet it remains poorly understood. correlates of protection involve robust cd4+ and cd8+ t cell responses, and the production of ifn-gamma, tnf-alpha, and il-12. novel approaches may be required to develop a safe vaccine that achieves these correlates. in contrast to other types of vaccines, epitope-based vaccines combine targeted biologic activity with the practical advantages of platform independence, scalable synthesis and manufacturi ...200718019188
construction of targeted insertion mutations in francisella tularensis subsp. novicida.francisella tularensis is one of the most deadly bacterial agents, yet most of the genetic determinants of pathogenesis are still unknown. we have developed an efficient targeted mutagenesis strategy in the model organism f. tularensis subsp. novicida by utilizing universal priming of optimized antibiotic resistance cassettes and splicing by overlap extension (soe). this process enables fast and efficient construction of targeted insertion mutations in f. tularensis subsp. novicida that have cha ...200718019340
fangia hongkongensis gen. nov., sp. nov., a novel gammaproteobacterium of the order thiotrichales isolated from coastal seawater of hong kong.a gram-negative, coccobacillus-shaped, aerobic bacterium, designated strain ust040201-002t, was isolated in february 2004 from seawater at the outlet of a sandfilter in port shelter, hong kong sar, china. this strain possessed ubiquinone-8; its 16s rrna gene sequence shared only 91% similarity with the sequence from caedibacter taeniospiralis and 89-90% similarity with sequences from francisella tularensis, francisella novicida, francisella philomiragia and wolbachia persica. 16s rrna gene seque ...200717978237
plasmid: a centralized repository for plasmid clone information and distribution.the plasmid information database (plasmid; http://plasmid.hms.harvard.edu) was developed as a community-based resource portal to facilitate search and request of plasmid clones shared with the dana-farber/harvard cancer center (df/hcc) dna resource core. plasmid serves as a central data repository and enables researchers to search the collection online using common gene names and identifiers, keywords, vector features, author names and pubmed ids. as of october 2006, the repository contains >46 ...200717132831
new protein fold revealed by a 1.65 a resolution crystal structure of francisella tularensis pathogenicity island protein iglc.francisella tularensis is a highly infectious gram-negative intracellular pathogen that causes the fulminating disease tularemia and is considered to be a potential bioweapon. f. tularensis pathogenicity island proteins play a key role in modulating phagosome biogenesis and subsequent bacterial escape into the cytoplasm of macrophages. the 23 kda pathogenicity island protein iglc is essential for the survival and proliferation of f. tularensis in macrophages. seeking to gain some insight into it ...200717905833
[investigation of tularemia seroprevalence in the rural area of thrace region in turkey].the first published tularemia epidemic in turkey had been reported in 1936 from luleburgaz (located in european part-thrace region-of turkey), and the second was in 1945 again in the same province. following a long period of time without any tularemia report from thrace region, in 2005 another epidemic occurred in a village of edirne, another province located in the same region. since there is presumptive evidence of circulation of the infectious agent, francisella tularensis in thrace region of ...200717933252
[viable but non-culturable form of bacteria].viable but non-culturable (vbnc) bacteria concept has been defined in 1982 when it has been shown that there exists bacteria whose metabolic activity continue and which can have the ability to reproduce in suitable conditions although they have lost their capability to reproduce in culture. recent studies have shown that most of the human pathogens (campylobacter spp., escherichia coli, francisella tularensis, helicobacter pylori, legionella pneumophila, listeria monocytogenes, mycobacterium tub ...200717933263
immunization with heat-killed francisella tularensis lvs elicits protective antibody-mediated immunity.francisella tularensis (ft) has been classified by the cdc as a category a pathogen because of its high virulence and the high mortality rate associated with infection via the aerosol route. because there is no licensed vaccine available for ft, development of prophylactic and therapeutic regimens for the prevention/treatment of infection is a high priority. in this report, heat-killed ft live vaccine strain (hklvs) was employed as a vaccine immunogen, either alone or in combination with an adju ...200717960662
francisella tularensis strain lvs resides in mhc ii-positive autophagic vacuoles in macrophages.the francisella tularensis strain lvs phagosome disintegrates during the first few hours after bacterial entry and microbes are released to the cytosol. within 12 h both rapid multiplication of microbes and a steep increase of apoptosis of infected macrophages occur. we searched for signals involved in the death of macrophages and detected molecules associated with the autophagy machinery cathepsin d, pten, p53 and lc3, whose levels or modification were influenced by ongoing in vitro tularemic i ...200718450226
seroprevalence of zoonoses in a cree community (canada).cree trappers and hunters are at risk for contracting infectious diseases conveyed by wildlife. we performed a study in a cree community (canada) to determine the seroprevalence of 8 zoonotic infections among hunters and trappers for evidence of exposure to trichinella sp., toxoplasma gondii, toxocara canis, echinococcus granulosus, leptospira sp., coxiella burnetii, francisella tularensis, and sin nombre virus. a total of 50 participants (28 women and 22 men) were included in this study. result ...200717878068
tularaemia in an emergent area in sweden: an analysis of 234 cases in five years.a retrospective study of clinical tularaemia in an emergent area in sweden is presented. 234 patients seen during the y 2000-2004 were studied, using case files and a questionnaire. there was a predominance of ulceroglandular tularaemia (89%), occurring in late summer and early autumn, reflecting the dominance of mosquito-borne transmission. the incubation period varied from a few hours to 11 d, with a median of 3 d. cutaneous manifestations of tularaemia, apart from primary lesions, were noted ...200717886125
genomic deletion marking an emerging subclone of francisella tularensis subsp. holarctica in france and the iberian peninsula.francisella tularensis subsp. holarctica is widely disseminated in north america and the boreal and temperate regions of the eurasian continent. comparative genomic analyses identified a 1.59-kb genomic deletion specific to f. tularensis subsp. holarctica isolates from spain and france. phylogenetic analysis of strains carrying this deletion by multiple-locus variable-number tandem repeat analysis showed that the strains comprise a highly related set of genotypes, implying that these strains wer ...200717890329
a 55 kda hypothetical membrane protein is an iron-regulated virulence factor of francisella tularensis subsp. novicida u112.iron is an important nutritional requirement for bacteria due to its conserved role in many essential metabolic processes. as a consequence of the lack of freely available iron in the mammalian host, bacteria upregulate a range of virulence factors during infection. transcriptional analysis of francisella tularensis subsp. novicida u112 grown in iron-deficient medium identified 21 genes upregulated in response to this condition, four of which were attributed to a siderophore operon. in addition, ...200717893160
complete genomic characterization of a pathogenic a.ii strain of francisella tularensis subspecies tularensis.francisella tularensis is the causative agent of tularemia, which is a highly lethal disease from nature and potentially from a biological weapon. this species contains four recognized subspecies including the north american endemic f. tularensis subsp. tularensis (type a), whose genetic diversity is correlated with its geographic distribution including a major population subdivision referred to as a.i and a.ii. the biological significance of the a.i - a.ii genetic differentiation is unknown, th ...200717895988
oral immunization of mice with the live vaccine strain (lvs) of francisella tularensis protects mice against respiratory challenge with virulent type a f. tularensis.francisella tularensis is a gram-negative intracellular bacterium, and the causative agent of tularemia. the infection can be initiated by various routes and can manifest itself in several clinical forms with the disseminated typhoidal form initiated by inhalation being most fatal. the attenuated live vaccine strain (lvs), developed almost 50 years ago, remains the sole effective tularemia vaccine, which is still only available as an investigational new drug for at-risk individuals. this vaccine ...200717346863
tularemia in deer mice (peromyscus maniculatus) during a population irruption in saskatchewan, canada.type b tularemia caused by francisella tularensis subsp. holarctica was diagnosed in deer mice (peromyscus maniculatus) found dead at four sites in west-central saskatchewan during april and may 2005. the occurrence of tularemia coincided with a decline in the number of deer mice in part of a large area (>22000 km(2) ) in which deer mice had been extremely abundant during the autumn of 2004 and spring of 2005, and in which mice caused damage to crops in the autumn of 2004. this is apparently the ...200717347390
pathobiology and management of laboratory rodents administered cdc category a agents.the centers for disease control and prevention category a infectious agents include bacillus anthracis (anthrax), clostridium botulinum toxin (botulism), yersinia pestis (plague), variola major virus (smallpox), francisella tularensis (tularemia), and the filoviruses and arenaviruses that induce viral hemorrhagic fevers. these agents are regarded as having the greatest potential for adverse impact on public health and therefore are a focus of renewed attention in infectious disease research. fre ...200717348288
transcriptome analysis of human immune responses following live vaccine strain (lvs) francisella tularensis vaccination.the live vaccine strain (lvs) of francisella tularensis is the only vaccine against tularemia available for humans, yet its mechanism of protection remains unclear. we probed human immunological responses to lvs vaccination with transcriptome analysis using pbmc samples from volunteers at time points pre- and post-vaccination. gene modulation was highly uniform across all time points, implying commonality of vaccine responses. principal components analysis revealed three highly distinct principa ...200717349694
diversity of francisella tularensis schu4 antigens recognized by t lymphocytes after natural infections in humans: identification of candidate epitopes for inclusion in a rationally designed tularemia vaccine.the t lymphocyte antigens, which may have a role in protection against tularemia, were predicted by immunoinformatics analysis of francisella tularensis schu4. twenty-seven class ii putative promiscuous epitopes and 125 putative class i supertype epitopes were chosen for synthesis; peptides were tested in vitro for their ability to bind hla and to induce immune responses from pbmcs of 23 previously infected subjects. while the immune responses of individual subjects showed heterogeneity, 95% of ...200717291638
simultaneous real-time pcr detection of bacillus anthracis, francisella tularensis and yersinia pestis.this report describes the development of in-house real-time pcr assays using minor groove binding probes for simultaneous detection of the bacillus anthracis pag and cap genes, the francisella tularensis 23 kda gene, as well as the yersinia pestis pla gene. the sensitivities of these assays were at least 1 fg, except for the assay targeting the bacillus anthracis cap gene, which showed a sensitivity of 10 fg when total dna was used as a template in a serial dilution. the clinical value of the ba ...200717294160
inactivated francisella tularensis live vaccine strain protects against respiratory tularemia by intranasal vaccination in an immunoglobulin a-dependent fashion.francisella tularensis is a gram-negative intracellular bacterium that is considered to be a potential category a biological weapon due to its extreme virulence. although vaccination with the attenuated live vaccine strain (lvs) of f. tularensis can protect against lethal challenge, use of inactivated or subunit forms as vaccine candidates for induction of protective antibody responses has not been fully evaluated. in the present study, we examined whether immune protection in the lung could be ...200717296747
a defined o-antigen polysaccharide mutant of francisella tularensis live vaccine strain has attenuated virulence while retaining its protective capacity.francisella tularensis, the causative agent of tularemia, has been designated a cdc category a select agent because of its low infective dose (<10 cfu), its ready transmission by aerosol, and its ability to produce severe morbidity and high mortality. the identification and characterization of this organism's virulence determinants will facilitate the development of a safe and effective vaccine. we report that inactivation of the wbta-encoded dehydratase of the o-antigen polysaccharide (o-ps) lo ...200717296751
re-emergence of francisella tularensis in germany: fatal tularaemia in a colony of semi-free-living marmosets (callithrix jacchus).francisella tularensis was identified as the cause of a die-off which occurred among a colony of semi-free-living common marmosets (callithrix jacchus). during the outbreak 5 out of 62 animals died of tularaemia in a research facility located in the district of goettingen, germany. all animals had been born at the facility suggesting an endemic infection. a total of five culture isolates were recovered and characterized as f. tularensis holarctica, biovar i. these cultures represent the first is ...200717306050
suitability of partial 16s ribosomal rna gene sequence analysis for the identification of dangerous bacterial pathogens.in a bioterrorism event a rapid tool is needed to identify relevant dangerous bacteria. the aim of the study was to assess the usefulness of partial 16s rrna gene sequence analysis and the suitability of diverse databases for identifying dangerous bacterial pathogens.200717309636
comparison of the 2000 and 2005 outbreaks of tularemia in the duzce region of turkey.tularemia caused by francisella tularensis, which is considered a biological warfare agent, is a widely distributed zoonosis. in this study, we aimed to compare a 2005 outbreak of tularemia that was confirmed as waterborne by pcr to outbreak of tularemia that was reported as waterborne in 2000 and to investigate the changes of epidemiological characteristics between these two outbreaks occurring in the same region. in the present study, a total of 11 patients were diagnosed with tularemia. in th ...200717314427
francisella tularensis vaccines.francisella tularensis is the causative agent of tularaemia, a disease which occurs naturally in some countries in the northern hemisphere. recently, there has been a high level of interest in devising vaccines against the bacterium because of the potential for it to be used as a bioterrorism agent. previous human volunteer studies have shown that a strain of f. tularensis [the live vaccine strain (lvs)] that has been attenuated by laboratory passage is effective in humans as a vaccine against a ...200717316369
raman chemical imaging spectroscopy reagentless detection and identification of pathogens: signature development and evaluation.an optical detection method, raman chemical imaging spectroscopy (rcis), is reported, which combines raman spectroscopy, fluorescence spectroscopy, and digital imaging. using this method, trace levels of biothreat organisms are detected in the presence of complex environmental backgrounds without the use of amplification or enhancement techniques. rcis is reliant upon the use of raman signatures and automated recognition algorithms to perform species-level identification. the rationale and steps ...200717338507
an in vitro model system used to study adherence and invasion of francisella tularensis live vaccine strain in nonphagocytic cells.in observing francisella tularensis interactions with nonphagocytic cell lines in vitro, we noted significant adherence, invasion, and intracellular growth of the bacteria within these cells. f. tularensis live vaccine strain invasion of nonprofessional phagocytic cells is inhibited by cytochalasin d and nocodazole, suggesting that both the actin and microtubule cytoskeletons are important for invasion.200717339345
matrix metalloproteinase 9 activity enhances host susceptibility to pulmonary infection with type a and b strains of francisella tularensis.a striking feature of pulmonary infection with the gram-negative intracellular bacterium francisella tularensis, a category a biological threat agent, is an intense accumulation of inflammatory cells, particularly neutrophils and macrophages, at sites of bacterial replication. given the essential role played by host matrix metalloproteinases (mmps) in modulating leukocyte recruitment and the potentially indiscriminate destructive capacity of these cells, we investigated whether mmp-9, an importa ...200717202364
resistance of francisella tularensis strains against reactive nitrogen and oxygen species with special reference to the role of katg.francisella tularensis is a facultative intracellular bacterial pathogen capable of proliferating within host macrophages. the mechanisms that explain the differences in virulence between various strains of the species are not well characterized. in the present study, we show that both attenuated (strain lvs) and virulent (strains fsc200 and schu s4) strains of the pathogen replicate at similar rates in resting murine peritoneal exudate cells (pec). however, when pec were activated by exposure t ...200717210667
a comprehensive transposon mutant library of francisella novicida, a bioweapon surrogate.francisella tularensis, the causative agent of tularemia, is one of the most infectious bacterial pathogens known and is a category a select agent. we created a sequence-defined, near-saturation transposon mutant library of f. tularensis novicida, a subspecies that causes a tularemia-like disease in rodents. the library consists of 16,508 unique insertions, an average of >9 insertions per gene, which is a coverage nearly twice that of the greatest previously achieved for any bacterial species. i ...200717215359
portable 24-analyte surface plasmon resonance instruments for rapid, versatile biodetection.field use of surface plasmon resonance (spr) biosensors for environmental and defense applications such as detection and identification of biological warfare agents has been hampered by lack of rugged, portable, high-performance instrumentation. to meet this need, we have developed compact multi-analyte spr instruments based on texas instruments' spreeta sensing chips. the instruments weigh 3 kg and are built into clamshell enclosures measuring 28 cm x 22 cm x 13 cm. functions are divided betwee ...200717223032
proteomics analysis of the francisella tularensis lvs response to iron restriction: induction of the f. tularensis pathogenicity island proteins iglabc.francisella tularensis is a highly virulent, facultative intracellular pathogen that causes tularemia in humans and animals. although it is one of the most infectious bacterial pathogens, little is known about its virulence mechanisms. in this study, the response of f. tularensis live vaccine strain to iron depletion, which simulates the environment within the host, was investigated. in order to detect alterations in protein synthesis, metabolic labeling, followed by 2d-page analysis was used. g ...200717227466
the francisella pathogenicity island protein igla localizes to the bacterial cytoplasm and is needed for intracellular growth.francisella tularensis is a gram negative, facultative intracellular bacterium that is the etiological agent of tularemia. f. novicida is closely related to f. tularensis but has low virulence for humans while being highly virulent in mice. igla is a 21 kda protein encoded by a gene that is part of an iglabcd operon located on the francisella pathogenicity island (fpi).200717233889
identification of immunoreactive antigens in membrane proteins enriched fraction from francisella tularensis lvs.francisella tularensis is a gram-negative, facultative intracellular bacterium causing disease in many mammalian species. the low infectious dose of f. tularensis and the ease of air-borne transmission are the main features responsible for the classification of this bacterium as a potential biological weapon. the live attenuated strain of f. tularensis live vaccine strain (lvs) is currently only effective vaccine against tularemia, however, this type of vaccine has not been approved for human us ...200717241671
a francisella tularensis subspecies novicida purf mutant, but not a pura mutant, induces protective immunity to tularemia in mice.francisella tularensis subspecies novicida mutants have been made with deletions introduced into the pura or purf genes. these mutants demonstrated the expected growth requirement for purines and complementation with the wild type genes restored the ability to grow on purine deficient media. the mutants were at least 10,000-fold attenuated by the ip challenge route in balb/c mice and defective for survival in j774a.1 mouse macrophages. immunisation with the pura mutant did not provide protection ...200717241711
mouse model of oral infection with virulent type a francisella tularensis.francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. little is known about the immunopathogenesis of oral infection with this pathogen. here, for the first time, we examined the susceptibility of mice to intragastric inoculation with virulent type a f. tularensis and characterized the course of infection and the associated host responses. both immunocompetent and immunodeficient mice were relatively susceptible to intragastric inocula ...200717242058
characterization of francisella sp., gm2212, the first francisella isolate from marine fish, atlantic cod (gadus morhua).a francisella sp., isolate gm2212(t), previously isolated from diseased farmed atlantic cod gadus morhua in norway is characterized. the complete 16s rdna, 16s-23s intergenic spacer, 23s rdna, 23s-5s intergenic spacer, 5s rdna, fopa, lipoprotein tul4 (lpna), malate dehydrogenase and a hypothetical lipoprotein (lpnb) is sequenced and compared with francisella tularensis and francisella philomiragia. all these sequences support a close relationship between gm2212(t) and f. philomiragia. the bacter ...200717160676
a case of tularemia presenting as a dental abscess: case report.objective: the purpose of this report is to present a tularemia case accompanied by a neck mass that easily may be confounded with dental abscess. summary: francisella tularensis is a potential agent of biologic terrorism. thirty percent of the symptoms seen in tularemia localize in the head and neck region and are sometimes mistaken for complications of a dental abscess. to our knowledge, reports of the differential diagnostic characteristics of tularemia are lacking in the dental literature an ...200717178484
coactivating signals for the hepatic lymphocyte gamma interferon response to francisella tularensis.the facultative intracellular bacterium francisella tularensis is capable of causing systemic infections in various hosts, including mice and humans. the liver is a major secondary site of f. tularensis infection, but hepatic immune responses to the pathogen remain poorly defined. immune protection against the pathogen is thought to depend on the cytokine gamma interferon (ifn-gamma), but the cellular basis for this response has not been characterized. here we report that natural killer cells fr ...200717178781
characterization of lipid a acylation patterns in francisella tularensis, francisella novicida, and francisella philomiragia using multiple-stage mass spectrometry and matrix-assisted laser desorption/ionization on an intermediate vacuum source linear ion trap.lipopolysaccharide (lps) is a major component of the outer membrane of gram-negative bacteria. the lipid a region of lps stimulates the immune system in a structure-dependent manner. we have previously identified the two major lipid a species from francisella tularensis as asymmetric tetraacylated structures containing four long acyl chains (16 and 18 carbons) and a single phosphate group that is partially modified by galactosamine (phillips, n. j.; schilling b.; mclendon, m. k.; apicella, m. a. ...200717263332
francisella tularensis-infected macrophages release prostaglandin e2 that blocks t cell proliferation and promotes a th2-like response.francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. in this study, we show that f. tularensis infection of macrophages alters t cell responses in vitro, by blocking t cell proliferation and promoting a th2-like response. we demonstrate that a soluble mediator is responsible for this effect and identify it as pge(2). supernatants from f. tularensis-infected macrophages inhibited il-2 secretion fr ...200717277110
detection of antibodies to francisella tularensis in cats.blood samples were obtained from privately owned cats in connecticut and new york state, usa in 1985-1990, and analyzed for evidence of francisella tularensis, the etiologic agent of tularemia. of the 91 sera tested by microagglutination (ma) methods, 11 (12%) contained antibodies to f. tularensis. analyses of the same sera by indirect fluorescent antibody (ifa) staining methods revealed 22 (24%) positives. there was good agreement in results of both tests (73% concordance). however, we measured ...200716914176
real-time pcr using hybridization probes for the rapid and specific identification of francisella tularensis subspecies tularensis.tularemia is a plague-like infection caused by francisella (f.) tularensis classified as a biological warfare agent. f. tularensis subsp. tularensis is the most virulent subspecies demanding rapid diagnosis. typing systems for this fastidious bacterium to the subspecies level are laborious and time consuming. therefore, the aim of this study was to develop a real-time pcr for the rapid and specific identification of f. tularensis subsp. tularensis. the specificity of the assay was determined usi ...200716893624
comparison of five commercial dna extraction kits for the recovery of francisella tularensis dna from spiked soil samples.francisella tularensis is the etiologic agent of the zoonotic disease tularemia and is thought to be maintained in the environment principally by various terrestrial and aquatic vertebrate animals. the organism is known to persist in water or mud for long periods of time and francisella-specific dna has been identified from water and soil. to gain a better understanding of the ecology and epidemiology of f. tularensis, it will be important to further explore its distribution in the environment. ...200717011748
role of the wbt locus of francisella tularensis in lipopolysaccharide o-antigen biogenesis and pathogenicity.francisella tularensis is a highly infectious bacterial pathogen, responsible for the zoonotic disease tularemia. we screened a bank of transposon insertion mutants of f. tularensis subsp. holarctica lvs for colony morphology alterations and selected a mutant with a transposon insertion in wbta, the first gene of the predicted lipopolysaccharide o-antigen gene cluster. inactivation of wbta led to the complete loss of o antigen, conferred serum sensitivity, impaired intracellular replication, and ...200717030571
acpa is a francisella acid phosphatase that affects intramacrophage survival and virulence.acpa of francisella spp. is a respiratory-burst-inhibiting acid phosphatase that also exhibits phospholipase c activity. to better understand the molecular basis of acpa in virulence, a deletion of acpa was constructed in francisella novicida. the phosphatase and lipase activities were reduced 10-fold and 8-fold, respectively, in the acpa mutant compared to the wild type and were found mostly associated with the outer membrane. the acpa mutant was more susceptible to intracellular killing than t ...200717060465
oligonucleotide fingerprint identification for microarray-based pathogen diagnostic assays.advances in dna microarray technology and computational methods have unlocked new opportunities to identify 'dna fingerprints', i.e. oligonucleotide sequences that uniquely identify a specific genome. we present an integrated approach for the computational identification of dna fingerprints for design of microarray-based pathogen diagnostic assays. we provide a quantifiable definition of a dna fingerprint stated both from a computational as well as an experimental point of view, and the analytic ...200717068088
the immunologically distinct o antigens from francisella tularensis subspecies tularensis and francisella novicida are both virulence determinants and protective antigens.we have determined the sequence of the gene cluster encoding the o antigen in francisella novicida and compared it to the previously reported o-antigen cluster in francisella tularensis subsp. tularensis. immunization with purified lipopolysaccharide (lps) from f. tularensis subsp. tularensis or f. novicida protected against challenge with francisella tularensis subsp. holarctica and f. novicida, respectively. the lps from f. tularensis subsp. tularensis did not confer protection against challen ...200717074846
francisella tularensis replicates within alveolar type ii epithelial cells in vitro and in vivo following inhalation.francisella tularensis replicates in macrophages and dendritic cells, but interactions with other cell types have not been well described. f. tularensis lvs invaded and replicated within alveolar epithelial cell lines. following intranasal inoculation of c57bl/6 mice, francisella localized to the alveolus and replicated within alveolar type ii epithelial cells.200717088343
characterization of francisella tularensis outer membrane proteins.francisella tularensis is a gram-negative coccobacillus that is capable of causing severe, fatal disease in a number of mammalian species, including humans. little is known about the proteins that are surface exposed on the outer membrane (om) of f. tularensis, yet identification of such proteins is potentially fundamental to understanding the initial infection process, intracellular survival, virulence, immune evasion and, ultimately, vaccine development. to facilitate the identification of put ...200717114266
preparation of monoclonal antibodies for detection and identification of francisella tularensis.monoclonal antibodies (mabs) against francisella tularensis were obtained. three mabs specifically reacted with f. tularensis, while four mabs reacted with other members of the genus francisella as well. fluorescent isothiocyanate-conjugated mabs unequivocally stained bacterial cells in specimens from experimentally infected mice. two mabs agglutinated f. tularensis antigen in the agglutination tests. these mabs should improve methods for detection and identification of f. tularensis.200717121981
attenuated virulence of a francisella mutant lacking the lipid a 4'-phosphatase.francisella tularensis causes tularemia, a highly contagious disease of animals and humans, but the virulence features of f. tularensis are poorly defined. f. tularensis and the related mouse pathogen francisella novicida synthesize unusual lipid a molecules lacking the 4'-monophosphate group typically found in the lipid a of gram-negative bacteria. lpxf, a selective phosphatase located on the periplasmic surface of the inner membrane, removes the 4'-phosphate moiety in the late stages of f. nov ...200717360489
cerebral abscesses complicating tularemia meningitis.tularemia meningitis is a distinctly rare entity with only 14 cases reported in the literature, half of which occurred prior to 1950. in this case we provide the first description of cerebral microabscesses which occurred as a complication of tularemia meningitis.200717366059
modulation of virulence factors in francisella tularensis determines human macrophage responses.francisella tularensis, the causative agent of tularemia and category a biodefense agent, is known to replicate within host macrophages, though the pathogenesis of this organism is incompletely understood. we have isolated a variant of f. tularensis live vaccine strain (lvs) based on colony morphology and its effect on macrophages. human monocyte-derived macrophages produced more tumor necrosis factor alpha (tnfalpha), interleukin (il)-1beta, il-6, and il-12 p40 following exposure to the variant ...200717369012
francisella tularensis induces il-23 production in human monocytes.francisella tularensis, the causative agent of tularemia, is phagocytosed by immune cells such as monocytes and macrophages. instead of being destroyed in the phagolysosome, the bacterium escapes the phagosome and replicates within the host cytosol. recent studies indicate that phagosomal escape may have a major impact on the nature of the inflammatory cytokine response to infection. to better understand the host cell response to francisella infection, we exposed human peripheral blood monocytes ...200717372002
active suppression of the pulmonary immune response by francisella tularensis schu4.francisella tularensis is an obligate, intracellular bacterium that causes acute, lethal disease following inhalation. as an intracellular pathogen f. tularensis must invade cells, replicate, and disseminate while evading host immune responses. the mechanisms by which virulent type a strains of francisella tularensis accomplish this evasion are not understood. francisella tularensis has been shown to target multiple cell types in the lung following aerosol infection, including dendritic cells (d ...200717372012
optimized application of surface-enhanced laser desorption/ionization time-of-flight ms to differentiate francisella tularensis at the level of subspecies and individual strains.francisella tularensis, the causative agent of tularaemia, is a potential agent of bioterrorism. the phenotypic discrimination of the closely related f. tularensis subspecies and individual strains with traditional methods is difficult and time consuming, often producing ambiguous results. surface-enhanced laser desorption/ionization time-of-flight ms (seldi-tof ms) was used in this study to discriminate the different species and subspecies of the genus francisella. we tested 18 francisella stra ...200717378900
in vivo negative selection screen identifies genes required for francisella virulence.francisella tularensis subverts the immune system to rapidly grow within mammalian hosts, often causing tularemia, a fatal disease. this pathogen targets the cytosol of macrophages where it replicates by using the genes encoded in the francisella pathogenicity island. however, the bacteria are recognized in the cytosol by the host's asc/caspase-1 pathway, which is essential for host defense, and leads to macrophage cell death and proinflammatory cytokine production. we used a microarray-based ne ...200717389372
the francisella pathogenicity island.the francisella pathogenicity island (fpi) is a cluster of 16-19 genes, which is found duplicated in most of the francisella genomes that have been sequenced. although 16 fpi genes are highly conserved there are 2-3 putative genes that are absent or interrupted by stop codons in some strains. francisella strains with experimentally induced mutations in fpi genes are highly attenuated in virulence and show defects in intramacrophage growth. there is experimental evidence indicating that the regul ...200717395722
the structure and function of francisella lipopolysaccharide.a key factor in the biology of francisella spp. is lipopolysaccharide (lps). francisella lps has many unique structural properties and poorly activates proinflammatory responses due to its lack of interaction with toll-like receptor 4 (tlr4). the lps of this organism can be modified by various carbohydrates including glucose, mannose and galactosamine, which affect various aspects of virulence. spontaneously occurring colony variants of f. tularensis have altered lps. this altered lps may accoun ...200717395723
francisella tularensis: activation of the inflammasome.francisella tularensis (f. tularensis) is a facultative intracellular pathogen that causes the systemic disease tularemia. this pathogen can replicate in the cytosol of macrophages, an ability that is linked with its virulence. we discuss recent data demonstrating that in macrophages, cytosolic francisella induce the activation of the cysteine protease caspase-1 within a multiprotein complex called the inflammasome. nod-like receptors (nlrs), which may have important roles in innate immunity as ...200717395724
genetics and genetic manipulation in francisella tularensis.francisella tularensis is a gram-negative coccobacillus and the etiological agent of tularemia. the limited knowledge regarding the interaction of f. tularensis with its host is due in part to the previous lack of tools for genetically manipulating the organism. during the past 10 years, the field of f. tularensis genetics has seen a rapid expansion. plasmids capable of stable or conditional replication in francisella have been constructed. methods for the efficient introduction of dna into fran ...200717395725
tularemia: history, epidemiology, pathogen physiology, and clinical manifestations.francisella tularensis has been recognized as a human pathogen for almost 100 years and is the etiological agent of the zoonotic disease tularemia. soon after its discovery, it became recognized as an important pathogen in several parts of the world, for example, in the united states and soviet union. the number of tularemia cases in the two countries peaked in the 1940s and has thereafter steadily declined. despite this decline, there was still much interest in the pathogen in the 1950s and 196 ...200717395726
mucosal immunopathogenesis of francisella tularensis.respiratory infection with francisella tularensis is the deadliest form of disease and represents the most likely route to be used by bioterrorists. although mucosal surfaces represent the first line of defense against respiratory tularemia, and in fact, against the great majority of human pathogens, little is known about protective immunity at these sites. the objective of this chapter is to review recent data examining the importance of various pulmonary immune mechanisms in defense against f. ...200717395728
vaccines against francisella tularensis.francisella tularensis is one of the most pathogenic pathogens known, especially when disseminated as a small particle aerosol. because of this, it was developed into a biological warfare agent by several states during the 20th century. nowadays, concerns remain about the potential of this pathogen to cause widespread disease, tularemia, in the hands of terrorists. this has resurrected interest in methods to combat it. this article reviews the current status of vaccine development efforts agains ...200717395730
animal models of francisella tularensis infection.the increased incidence of emerging infections has caused a resurgence in the development of animal models in order to study their pathophysiology and develop therapeutics against them. optimizing these models and improving our ability to extrapolate information from animals to humans is critical because in many cases the animal model will represent the only modality for efficacy testing. francisella tularensis (f. tularensis) is an emerging pathogen that fits this category. while there is a sig ...200717395735
molecular and genetic basis of pathogenesis in francisella tularensis.the genetic means of pathogenesis of francisella tularensis are poorly understood. f. tularensis is able to survive and replicate within macrophages, and a virulence factor, mgla, has been identified that is essential for this ability. mgla regulates the transcription of genes necessary for intracellular growth, including those located within the francisella pathogenicity island (fpi). the fpi genes are required for intramacrophage growth and virulence, and appear to encode a protein secretion s ...200717395737
galleria mellonella as a model host to study infection by the francisella tularensis live vaccine strain.we used the killing of galleria mellonella (lepidoptera: pyralidae; the greater wax moth) caterpillar by the live vaccine strain (lvs) of francisella tularensis to develop an invertebrate host system that can be used to study f. tularensis infection and the in vivo effects of antibacterial compounds on f. tularensis lvs. after injection into the insect hemocoel, f. tularensis lvs, killed caterpillars despite the association of lvs with hemocytes. the rate of killing depended on the number of bac ...200717400503
monochloramine inactivation of bacterial select agents.seven species of bacterial select agents were tested for susceptibility to monochloramine. under test conditions, the monochloramine routinely maintained in potable water would reduce six of the species by 2 orders of magnitude within 4.2 h. bacillus anthracis spores would require up to 3.5 days for the same inactivation with monochloramine.200717400782
genome sequencing shows that european isolates of francisella tularensis subspecies tularensis are almost identical to us laboratory strain schu s4.francisella tularensis causes tularaemia, a life-threatening zoonosis, and has potential as a biowarfare agent. f. tularensis subsp. tularensis, which causes the most severe form of tularaemia, is usually confined to north america. however, a handful of isolates from this subspecies was obtained in the 1980s from ticks and mites from slovakia and austria. our aim was to uncover the origins of these enigmatic european isolates.200717406676
biosafety and selectable markers.francisella tularensis (f. tularensis) is one of the most infectious pathogens known. although the disease caused by this bacterium is rarely fatal with appropriate antibiotic therapy, it is often severely debilitating. laboratory work with f. tularensis poses a significant hazard, and it is essential that appropriate laboratory facilities, trained personnel, and suitable working practices are in place in any organization working with this pathogen. work with human virulent strains should be car ...200717416926
genome-wide identification of francisella tularensis virulence determinants.francisella tularensis is a gram-negative pathogen that causes life-threatening infections in humans and has potential for use as a biological weapon. the genetic basis of the f. tularensis virulence is poorly understood. this study screened a total of 3,936 transposon mutants of the live vaccine strain for infection in a mouse model of respiratory tularemia by signature-tagged mutagenesis. we identified 341 mutants attenuated for infection in the lungs. the transposon disruptions were mapped to ...200717420240
ectoparasite diversity and exposure to vector-borne disease agents in wild rodents in central coastal california.a survey of wild rodents was performed in the morro bay area of central coastal california to determine serological and polymerase chain reaction (pcr) prevalence of anaplasma phagocytophilum dumler, barbet, bekker, dasch, palmer, ray, rikihisa, and rurangirwa, borrelia burgdorferi johnson, schmidt, hyde, steigerwalt, and brenner, francisella tularensis mccoy, and yersinia pestis yersin; to describe the ectoparasitic fauna on important vector-borne disease hosts; and to determine whether pathoge ...200717427705
multiplexed identification of blood-borne bacterial pathogens by use of a novel 16s rrna gene pcr-ligase detection reaction-capillary electrophoresis assay.we have developed a novel high-throughput pcr-ligase detection reaction-capillary electrophoresis (pcr-ldr-ce) assay for the multiplexed identification of 20 blood-borne pathogens (staphylococcus epidermidis, staphylococcus aureus, bacillus cereus, enterococcus faecalis, enterococcus faecium, listeria monocytogenes, streptococcus pneumoniae, streptococcus pyogenes, streptococcus agalactiae, escherichia coli, klebsiella pneumoniae, haemophilus influenzae, pseudomonas aeruginosa, acinetobacter bau ...200717428930
type ii secretion and type iv pili of francisella.francisella tularensis genomes encode homologues of type iv pili. though several f. tularensis genes required for tfp expression are homologous to genes required for type ii secretion (t2s), these gene clusters mainly bear structural signatures that are typical of tfp. there is preliminary evidence that different f. tularensis subspecies express tfp-like surface structures, but there are also some interesting differences between the subspecies. one difference between the nonpathogenic subspecies ...200717435117
uptake and intracellular fate of francisella tularensis in human macrophages.francisella tularensis is an intracellular pathogen that survives and multiplies within host mononuclear phagocytes. we have shown that uptake of the bacterium by human macrophages occurs by a novel process, "looping phagocytosis," in which the bacterium is engulfed in a spacious, asymmetric, pseudopod loop. whereas looping phagocytosis is resistant to treatment of the f. tularensis with formalin, proteases, or heat, the process is abolished by oxidation of the bacterial carbohydrates with perio ...200717435118
molecular epidemiology, evolution, and ecology of francisella.tularemia is a disease caused by several subspecies of francisella tularensis, although the severity of the disease varies greatly from subspecies to subspecies. currently, there are four recognized subspecies (tularensis, holarctica, mediasiatica, and novicida), in addition to a second francisella species, f. philomiragia. it is clear from molecular sampling of the environment that these human pathogens are a mere fraction of the francisella diversity. taxonomic nomenclature is now being based ...200717435120
francisella tularensis genomics and proteomics.the availability of the genome sequences of different strains of francisella tularensis is having a major impact on a wide range of research projects, from understanding the biology of this organism to devising vaccines and diagnostics. comparative genomics and molecular typing methods suggest that the four different subspecies of f. tularensis are genetically distinct groups. although there is a high degree of nucleotide identity between strains, there are numerous dna rearrangements. is elemen ...200717435122
pneumonic tularemia on martha's vineyard: clinical, epidemiologic, and ecological characteristics.martha's vineyard, massachusetts, is the site of the only two recognized outbreaks of primary pneumonic tularemia in the united states. beginning in 2000 and continuing through 2006, 59 presumed or confirmed tularemia cases have been reported from martha's vineyard, with more than 60% of these presumed to be due to inhalation of the agent. a joint cdc/massachusetts department of public health case-control study identified landscaping activities such as lawnmowing or brush cutting to be important ...200717442781
emerging zoonoses and vector-borne infections affecting humans in europe.the purpose of this study was to assess and describe the current spectrum of emerging zoonoses between 2000 and 2006 in european countries. a computerized search of the medline database from january 1966 to august 2006 for all zoonotic agents in european countries was performed using specific criteria for emergence. fifteen pathogens were identified as emerging in europe from 2000 to august 2006: rickettsiae spp., anaplasma phagocytophilum, borrelia burgdorferi, bartonella spp., francisella tula ...200717445320
structural heterogeneity and environmentally regulated remodeling of francisella tularensis subspecies novicida lipid a characterized by tandem mass spectrometry.the structural characterization of environmentally-regulated lipid a derived from francisella tularensis subspecies novicida (fn) u112 is described using negative electrospray ionization with a linear ion trap fourier transform ion cyclotron resonance (it-ft-icr) hybrid mass spectrometer. the results indicate that a unique profile of lipid a molecular structures are synthesized in response to fn growth at 25 degrees c versus 37 degrees c. molecular species were found to be tetra-acylated, sharin ...200717446084
production and characterization of a monoclonal antibody to francisella tularensis lipopolysaccharide.having the capacity to detect and identify pathogens that can be employed in a bioterror attack is critical from both a public health and defence perspective. immunodiagnostic assays are useful tools for enhancing such detection capabilities. in order to develop an immunodiagnostic assay for the detection of francisella tularensis, a murine monoclonal antibody (mab) was developed, using the live vaccine strain (lvs) of f. tularensis as the inoculating antigen. a single mab, f94g2-1, which is spe ...200717451358
identification of an orphan response regulator required for the virulence of francisella spp. and transcription of pathogenicity island genes.francisella tularensis is a category a agent of biowarfare/biodefense. little is known about the regulation of virulence gene expression in francisella spp. comparatively few regulatory factors exist in francisella, including those belonging to two-component systems (tcs). however, orphan members of typical tcs can be identified. to determine if orphan tcs members affect francisella gene expression, a gene encoding a product with high similarity to the salmonella pmra response regulator (ftt1557 ...200717452468
type i interferon signaling is required for activation of the inflammasome during francisella infection.francisella tularensis is a pathogenic bacterium whose virulence is linked to its ability to replicate within the host cell cytosol. entry into the macrophage cytosol activates a host-protective multimolecular complex called the inflammasome to release the proinflammatory cytokines interleukin (il)-1beta and -18 and trigger caspase-1-dependent cell death. in this study, we show that cytosolic f. tularensis subspecies novicida (f. novicida) induces a type i interferon (ifn) response that is essen ...200717452523
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