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development of novel plasmid vectors and a promoter trap system in francisella tularensis compatible with the pfln10 based plasmids.francisella tularensis is a category a bioterror pathogen which in some cases can cause a severe and fatal human infection. very few virulence factors are known in this species due to the difficulty in working with it as well as the lack of tools for genetic manipulation. this work describes the construction of a shuttle vector that can replicate in escherichia coli and f. tularensis as well as two distinct promoter trap constructs based on the shuttle vector backbone. replication in f. tularens ...200717459476
the biblical plague of the philistines now has a name, tularemia.an epidemic thought to have been the first instance of bubonic plague in the mediterranean reveals to have been an episode of tularemia. the deadly epidemic took place in the aftermath of the removal of a wooden box from an isolated hebrew sanctuary. death, tumors, and rodents thereafter plagued philistine country. unlike earlier explanations proposed, tularemia caused by francisella tularensis exhaustively explains the outbreak. tularemia fits all the requirements indicated in the biblical text ...200717467189
new approaches to diagnosis and therapy of tularemia.francisella tularensis is a potent pathogen and a cause of severe human disease. the outcome of tularemia will depend on rapid insertion of appropriate antibiotics. until recently, effective clinical handling was hampered by shortcomings in laboratory diagnostics. no suitable direct methods were available and, because of risks and isolate recovery difficulties associated with laboratory work, culture has been rarely practiced. due to achievements from work on modern technology, however, tularemi ...200717468229
innate and adaptive immunity to francisella.studies of immune responses to francisella have been conducted for well over 50 years. here, the basic parameters of innate and adaptive immune responses to francisella are reviewed, with an emphasis on those that may contribute directly to protection against infection. although older literature provides a wealth of information on human immune responses to infection and vaccination, most recent information has been derived largely from studies in animals and using animal cells, particularly mice ...200717468235
evaluating the use of fatty acid profiles to identify francisella tularensis.rapid capillary gas chromatography (gc) with flame-ionization detection was used to determine the cellular fatty acid profiles of francisella tularensis. two subspecies of f. tularensis, the live vaccine strain (lvs) derived from holarctica and a novicida strain utah 112 (u112), were used to compare the extracted fatty acid methyl esters (fames). a data set for the 2 subspecies was prepared using fatty acid profiles of bacteria grown on 2 types of media, mueller-hinton and cysteine heart agar su ...200717474518
diagnostic approaches for oculoglandular tularemia: advantages of pcr.the authors describe a diagnostic approach that proved to be particularly valuable in rare cases of ocular tularemia registered during the tularemia outbreak in 1997-2005 in bulgaria. the authors describe the laboratory findings and diagnosis of four cases with an oculoglandular form of infection.200717475710
detection of francisella tularensis subsp. holarctica in a european brown hare (lepus europaeus) in thuringia, germany.the isolation of francisella tularensis subsp. holarctica biovar ii (strain 06t0001) from a european brown hare (lepus europaeus) from thuringia, germany, is described for the first time. identification of the microorganism was carried out by phenotypic characterisation, partial sequencing of the 16s rrna gene and specific pcr using the primers tul4-435/tul4-863 and ftc1/ftc4. the epidemiology of tularemia in germany is discussed and a risk assessment for humans is made.200717482385
epizootic of tularemia in an outdoor housed group of cynomolgus monkeys (macaca fascicularis).tularemia is a highly contagious infectious zoonosis, transmissible by inoculation, ingestion, or inhalation of the infectious agent francisella tularensis. the disease is perpetuated by infected rodents, blood-sucking arthropods, and by contaminated water. therefore, nonhuman primates housed outdoors may be at risk for exposure. an epizootic of f. tularensis occurred in an indoor/outdoor-housed group of cynomolgus monkeys (macaca fascicularis) at the german primate center. tularemia was diagnos ...200717491074
the 'hittite plague', an epidemic of tularemia and the first record of biological warfare.a long-lasting epidemic that plagued the eastern mediterranean in the 14th century bc was traced back to a focus in canaan along the arwad-euphrates trading route. the symptoms, mode of infection, and geographical area, identified the agent as francisella tularensis, which is also credited for outbreaks in canaan around 1715 bc and 1075 bc. at first, the 14th century epidemic contaminated an area stretching from cyprus to iraq, and from israel to syria, sparing egypt and anatolia due to quaranti ...200717499936
role of primary human alveolar epithelial cells in host defense against francisella tularensis infection.francisella tularensis, an intracellular pathogen, is highly virulent when inhaled. alveolar epithelial type i (ati) and type ii (atii) cells line the majority of the alveolar surface and respond to inhaled pathogenic bacteria via cytokine secretion. we hypothesized that these cells contribute to the lung innate immune response to f. tularensis. results demonstrated that the live vaccine strain (lvs) contacted ati and atii cells by 2 h following intranasal inoculation of mice. in culture, primar ...200717502386
a francisella tularensis pathogenicity island protein essential for bacterial proliferation within the host cell cytosol.francisella tularensis is an intracellular bacterial pathogen, and is a category a bioterrorism agent. within quiescent human macrophages, the f. tularensis pathogenicity island (fpi) is essential for bacterial growth within quiescent macrophages. the f. tularensis-containing phagosome matures to a late endosome-like stage that does not fuse to lysosomes for 1-8 h, followed by gradual bacterial escape into the macrophage cytosol. here we show that the fpi protein igld is essential for intracellu ...200717517064
toll-like receptor 2-mediated signaling requirements for francisella tularensis live vaccine strain infection of murine macrophages.francisella tularensis, an aerobic, non-spore-forming, gram-negative coccobacillus, is the causative agent of tularemia. we reported previously that f. tularensis live vaccine strain (lvs) elicited strong, dose-dependent nf-kappab reporter activity in toll-like receptor 2 (tlr2)-expressing hek293t cells and proinflammatory gene expression in primary murine macrophages. herein, we report that f. tularensis lvs-induced murine macrophage proinflammatory cytokine gene and protein expression are over ...200717517865
[highly sensitive enzyme-linked assay based on monoclonal antibodies for detection of brucella antigens].mice monoclonal antibodies against lypopolysaccharides (lps) of brucella abortus has been obtained and characterized. the antibodies detected lps of b. abortus, b. melitensis and b. suis with high sensivity and specificity and did not react with lps of yersinia enterocolitica o:3, y. enterocolitica o:9, salmonella typhimurium, and francisella tularensis. it has been shown that interaction of monoclonal antibodies and lps of brucella species can be critically dependent from buffer system. obtaine ...200717523430
pcr and in situ hybridization for the detection and localization of a new pathogen francisella-like bacterium (flb) in ornamental cichlids.archived formalin-fixed, paraffin-embedded tissues from 28 diseased ornamental cichlid fish associated with visceral granulomas were examined by polymerase chain reaction (pcr) and in situ hybridization (ish) for detection of francisella-like bacteria (flb). the 16s rdna flb-specific primer pair 180f/465r was used on naturally infected ornamental cichlids, resulting in 11 positive cases (39%). using dna probes, all 28 cases (100%) showed a positive reaction, and most labeled cells were observed ...200717523541
immunodominant francisella tularensis antigens identified using proteome microarray.stimulation of protective immune responses against intracellular pathogens is difficult to achieve using non-replicating vaccines. balb/c mice immunized by intramuscular injection with killed francisella tularensis (live vaccine strain) adjuvanted with preformed immune stimulating complexes admixed with cpg, were protected when systemically challenged with a highly virulent strain of f. tularensis (schu s4). serum from immunized mice was used to probe a whole proteome microarray in order to iden ...200717533643
francisella tularensis has a significant extracellular phase in infected mice.the ability of francisella tularensis to replicate in macrophages has led many investigators to assume that it resides primarily intracellularly in the blood of mammalian hosts. we have found this supposition to be untrue. in almost all cases, the majority of f. tularensis recovered from the blood of infected mice was in plasma rather than leukocytes. this distribution was observed irrespective of size of inoculum, route of inoculation, time after inoculation, or virulence of the infecting strai ...200717538893
a call for renewed research on tick-borne francisella tularensis in the arkansas-missouri primary national focus of tularemia in humans.arkansas-missouri has emerged as the primary u.s. focus of tularemia, which is caused by the national institute of allergy and infectious diseases category a priority pathogen francisella tularensis, over the past 30 yr. there are several pieces of indirect evidence suggesting that a key role of ticks in the transmission of f. tularensis to humans in arkansas-missouri is the primary reason why tularemia has remained a prominent disease of humans in this two-state area while fading away from othe ...200717547223
comparison of francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains.francisella tularensis subspecies tularensis and holarctica are pathogenic to humans, whereas the two other subspecies, novicida and mediasiatica, rarely cause disease. to uncover the factors that allow subspecies tularensis and holarctica to be pathogenic to humans, we compared their genome sequences with the genome sequence of francisella tularensis subspecies novicida u112, which is nonpathogenic to humans.200717550600
francisella tularensis, portugal. 200717561575
[determination of the content of water in dry preparations of the vaccine strain francisella tularensis by nmr-relaxation technique].frozen-dried preparations were studied for the impact of moisture content of the nuclear magnetic resonance parameter that was a ratio of the amplitudes of a slow component and a rapid one of a free induction signal from the protons of samples. it was found that there was a linear correlation between this parameter and the moisture content of biological materials, by using bovine serum albumin (bsa) as examples, with lactose and biomass of francisella tularensis. formulas were derived for calcul ...200717561666
twin rna polymerase-associated proteins control virulence gene expression in francisella tularensis.the mgla protein is the only known regulator of virulence gene expression in francisella tularensis, yet it is unclear how it functions. f. tularensis also contains an mgla-like protein called sspa. here, we show that mgla and sspa cooperate with one another to control virulence gene expression in f. tularensis. using a directed proteomic approach, we show that both mgla and sspa associate with rna polymerase (rnap) in f. tularensis, and that sspa is required for mgla to associate with rnap. fur ...200717571921
proteomic analysis of antibody response in a case of laboratory-acquired infection with francisella tularensis subsp. tularensis.immunoproteomic analysis was applied to study the immunoreactivity of serum samples collected at different time points from a laboratory assistant accidentally infected with highly virulent strain of francisella tularensis subsp. tularensis. immunoblotting showed that the spectrum of f. tularensis antigens recognized specifically by immune sera remained with the exception for 1 antigen stable for up to 16 years after infection. using immunoproteomics approach 10 immunoreactive antigens were succ ...200717575919
tularemia presenting with tonsillopharyngitis and cervical lymphadenitis: report of two cases.tularemia is a zoonotic disease caused by francisella tularensis. francisella tularensis is transmitted to humans by direct contact or ingestion of infected animal tissues, through the bite of infected arthropods, by consumption of contaminated food or water, or from inhalation of aerolized bacteria. in this report we describe 2 cases with oropharyngeal tularemia who presented with tonsillopharyngitis and cervical lymphadenitis.200717577830
prophylactic and therapeutic use of antibodies for protection against respiratory infection with francisella tularensis.the role of abs in protection against respiratory infection with the intracellular bacterium francisella tularensis is not clear. to investigate the ability of abs to clear bacteria from the lungs and prevent systemic spread, immune serum was passively administered i.p. to naive mice before intranasal f. tularensis live vaccine strain infection. it was found that immune serum treatment provided 100% protection against lethal challenge while normal serum or ig-depleted immune serum provided no pr ...200717579074
outbreaks of tularemia in turkey.tularemia, casued by francisella tularensis, is a zoonotic disease presenting various clinical forms. in the present study, three outbreaks of tularemia occurred from january to march and september in 2004 (first and second) and january to march in 2005 (third) are reported from the north-eastern part of turkey. all cases originated from the same geographical location. in total, 56 patients having complaints of fever, malaise, chills and shivering, painful sore throat with swollen tonsils and en ...200717579300
from rabbits to humans: the contributions of dr. theodore e. woodward to tularemia research.tularemia is an endemic zoonotic infection caused by francisella tularensis, which primarily causes infection in humans who have handled contaminated animal tissue or have been bitten by infected arthropods. because of its ease of dispersion and transmission and its high degree of infectivity, f. tularensis is also considered to be a bioterrorism agent. consequently, there is renewed interest in the development of safe, effective measures, such as vaccines, to prevent the morbidity and mortality ...200717582573
a full-genomic sequence-verified protein-coding gene collection for francisella tularensis.the rapid development of new technologies for the high throughput (ht) study of proteins has increased the demand for comprehensive plasmid clone resources that support protein expression. these clones must be full-length, sequence-verified and in a flexible format. the generation of these resources requires automated pipelines supported by software management systems. although the availability of clone resources is growing, current collections are either not complete or not fully sequence-verif ...200717593976
[genotypic heterogeneity and geographic diversity of collection strains of francisella tularensis as determined using the vntr variability analysis and dna sequencing].the analysis of the identification genotypes allowed the strains to be grouped into 61 variants from a to i with the incidence rate 0.002-0.142. the cluster analysis of the identification genotypes allowed the strains to be grouped into 9 clusters with different number of components. actual existence of genotypic heterogeneity and geographic diversity of the f. tularensis strains was demonstrated in addition to territorial attribution of certain strains. the geoinformation system tularemia was d ...200717600922
new species in the genus francisella (gammaproteobacteria; francisellaceae); francisella piscicida sp. nov. isolated from cod (gadus morhua).a francisella strain, gm2212, previously isolated from moribund farmed atlantic cod (gadus morhua) in norway, is closely related to francisella philomiragia among francisella spp. according to its complete 16s rdna, 16s-23s intergenic spacer, 23s rdna, 23s-5s intergenic spacer, 5s rdna, fopa, lipoprotein tul4 (lpna), malate dehydrogenase and hypothetical lipoprotein (lpnb) sequences. a comparison between gm2212 and the type strain of francisella philomiragia were performed by dna-dna hybridizati ...200717619856
q fever community-acquired pneumonia in a patient with crohn's disease on immunosuppressive therapy.community-acquired pneumonia (cap) may be caused by typical or atypical pathogens. the three most common zoonotic atypical pathogens are chlamydophila psittaci (psittacosis), francisella tularensis (tularemia), and coxiella burnetii (q fever). atypical caps are suggested by a distinctive pattern of extrapulmonary organ involvement. zoonotic cap may be differentiated from nonzoonotic cap (chlamydia pneumoniae, mycoplasma pneumoniae, legionnaire's disease) by a recent zoonotic vector contact histo ...200717628200
differential effects of francisella tularensis lipopolysaccharide on b lymphocytes.francisella tularensis, a designated category a biological agent, can cause severe infection in humans. previous studies have demonstrated a significant immunoprotective role for b lymphocytes in animal models, but the responses of human b lymphocytes to f. tularensis components are largely unknown. the lps of f. tularensis is atypical and has been reported to lack biological activity on myeloid cells and mouse b cells. our study characterized the immunological effects of highly purified lps fro ...200717634278
identification of francisella sp. from atlantic salmon, salmo salar l., in chile. 200717640254
mgla regulates francisella tularensis subsp. novicida (francisella novicida) response to starvation and oxidative stress.mgla is a transcriptional regulator of genes that contribute to the virulence of francisella tularensis, a highly infectious pathogen and the causative agent of tularemia. this study used a label-free shotgun proteomics method to determine the f. tularensis subsp. novicida (f. novicida) proteins that are regulated by mgla. the differences in relative protein amounts between wild-type f. novicida and the mgla mutant were derived directly from the average peptide precursor ion intensity values mea ...200717644593
from protein microarrays to diagnostic antigen discovery: a study of the pathogen francisella tularensis.an important application of protein microarray data analysis is identifying a serodiagnostic antigen set that can reliably detect patterns and classify antigen expression profiles. this work addresses this problem using antibody responses to protein markers measured by a novel high-throughput microarray technology. the findings from this study have direct relevance to rapid, broad-based diagnostic and vaccine development.200717646338
proteome cataloging and relative quantification of francisella tularensis tularensis strain schu4 in 2d page using preparative isoelectric focusing.the protein complement of whole cell extract of the bacterium francisella tularensis tularensis was analyzed using two-dimensional electrophoresis with preparative isoelectric focusing in the first dimension. the format allows the quantification of relative protein abundance by linear densitometry and extends the potential dynamic range of protein detection by as much as an order of magnitude. the relative abundance and rank order of 136 unique proteins identified in f. tularensis tularensis wer ...200717658781
activation of the inflammasome upon francisella tularensis infection: interplay of innate immune pathways and virulence factors.tularaemia is a zoonotic disease caused by the facultative intracellular bacterium francisella tularensis. the virulence of this pathogen depends on its ability to escape into the cytosol of host cells. pathogens are detected by the innate immune system's pattern recognition receptors which are activated in response to conserved microbial molecules (pathogen-associated molecular patterns). cytosolic bacteria are sensed intracellularly, often leading to activation of the cysteine protease caspase ...200717662071
[evaluation of immunobiological activity of francisella tularensis c-complex preparations as promising component of subunit vaccines].data on influence of francisella tularensis c-complex preparations on formation of immunity against tularemia are presented. study of cellular immunity characteristics as well as dynamics of antibody response was carried out on white mice and guinea pigs models. absence of toxicity, pyrogenicity, and negative effects on immunocompetent cells in combination with protective activity points to possibility of use the c-complex as a component of a subunit vaccine.200717672125
cloning and expression of protective antigens of mycobacterium tuberculosis ag85b and esat-6 in francisella tularensis 15/10.the possibility of expression of genes encoding mycobacterial antigens in francisella tularensis 15/10 vaccine strain cells has been shown for the first time. to obtain stable and effective expression of mycobacterial antigens in the f. tularensis cells, the plasmid vector ppmc1 and hybrid genes consisting of the leader part fl of the f. tularensis membrane protein fopa and structural moieties of the mature protein ag85b or the fused protein ag85b-esat-6 were constructed. recombinant strains f. ...200717680765
identification of francisella tularensis himar1-based transposon mutants defective for replication in macrophages.francisella tularensis, the etiologic agent of tularemia in humans, is a potential biological threat due to its low infectious dose and multiple routes of entry. f. tularensis replicates within several cell types, eventually causing cell death by inducing apoptosis. in this study, a modified himar1 transposon (himarft) was used to mutagenize f. tularensis lvs. approximately 7,000 km(r) clones were screened using j774a.1 macrophages for reduction in cytopathogenicity based on retention of the cel ...200717682043
identification of lpxl, a late acyltransferase of francisella tularensis.lipopolysaccharide (lps) is a major component of the outer membrane of gram-negative bacteria, and the lipid a region of lps mediates stimulation of the immune system in a structure-dependent manner. unlike the lps of many other gram-negative bacteria, the lps of francisella tularensis isolated from in vitro cultures is not proinflammatory. this observed lack of proinflammatory prowess may reflect structural features of the lipid a, such as the number and length of the acyl chains and the single ...200717724076
generation and characterization of hybridoma antibodies for immunotherapy of tularemia.tularemia is caused by the gram-negative facultative intracellular bacterium francisella tularensis, which has been classified as a category a select agent-a likely bioweapon. the high virulence of f. tularensis and the threat of engineered antibiotic resistant variants warrant the development of new therapies to combat this disease. we have characterized 14 anti-francisella hybridoma antibodies derived from mice infected with f. tularensis live vaccine strain (lvs) for potential use as immunoth ...200717764754
francisella philomiragia subsp. noatunensis subsp. nov., isolated from farmed atlantic cod (gadus morhua l.).seven bacterial isolates from farmed atlantic cod displaying chronic granulomatous disease were characterized by phenotypic and molecular taxonomic methods. the isolates were gram-negative, facultatively intracellular, non-motile, strictly aerobic coccobacilli which produced h(2)s from cysteine-supplemented media and are therefore phenotypically consistent with members of the genus francisella. comparison of 16s rrna gene sequences and six partial housekeeping gene sequences (groel, shda, rpob, ...200717766855
attenuation and protective efficacy of an o-antigen-deficient mutant of francisella tularensis lvs.francisella tularensis is a zoonotic, gram-negative coccobacillus that causes tularemia in humans and animals. f. tularensis subspecies tularensis (type a) and f. tularensis subspecies holarctica (type b) are antigenically similar and more virulent than francisella novicida in humans. the genetic locus that encodes the lps o antigen was found to be substantially different between the type b live vaccine strain (lvs) and f. novicida. one lvs-specific gene with homology to a galactosyl transferase ...200717768257
toll-like receptor 2 controls the gamma interferon response to francisella tularensis by mouse liver lymphocytes.the production of gamma interferon (ifn-gamma) is a key step in the protective innate immune response to francisella tularensis. natural killer cells and t cells in the liver are important sources of this cytokine during primary f. tularensis infections, and interleukin-12 (il-12) appears to be an essential coactivating cytokine for hepatic ifn-gamma expression. the present study was undertaken to determine whether or not macrophages (mphi) or dendritic cells (dc) provide coactivating signals fo ...200717785474
to activate or not to activate: distinct strategies used by helicobacter pylori and francisella tularensis to modulate the nadph oxidase and survive in human neutrophils.neutrophils accumulate rapidly at sites of infection, and the ability of these cells to phagocytose and kill microorganisms is an essential component of the innate immune response. relatively few microbial pathogens are able to evade neutrophil killing. herein, we describe the novel strategies used by helicobacter pylori and francisella tularensis to disrupt neutrophil function, with a focus on assembly and activation of the nicotinamide adenine dinucleotide phosphate (nadph) oxidase.200717850485
diagnosis of tularemia using piezoelectric biosensor technology.a piezoelectric immunosensor for indirect diagnosis of tularemic infection in mouse serum was developed. francisella tularensis lvs antigen was covalently immobilized on the sensing surface using cystamine and glutaraldehyde for activation and modification of the gold electrode. the normal mouse serum (nms) and serum prepared from mice immunized by escherichia coli were used as negative controls providing signal of 28hz during a 5min interaction. the tularemic infectious (immunized) mouse serum ...200719071403
an immunoaffinity tandem mass spectrometry (imaldi) assay for detection of francisella tularensis.francisella tularensis (f. tularensis) has been designated by the cdc as 1 of the 10 organisms most likely to be engineered for bioterrorism. symptoms of tularemia in humans are non-specific, thus making the disease difficult to diagnose. if not quickly diagnosed and treated, the disease has a high mortality rate--thus methods for early and specific diagnosis are of critical importance. this immunoaffinity maldi ms/ms (imaldi) assay provides unambiguous detection of f. tularensis peptides at att ...200718022413
molecular analysis of francisella tularensis subspecies tularensis and holarctica.rapid methods are needed for public health and military applications to specifically identify francisella tularensis, the causative agent of tularemia in humans. a comparative analysis of the capabilities of multiple technologies was performed using a well-defined set of organisms to determine which approach would provide the most information in the shortest time. high-resolution molecular techniques, including pulsed-field gel electrophoresis, amplified fragment length polymorphism, and ribotyp ...200718024317
[francisella tularensis and tularemia in turkey].francisella tularensis is a small gram-negative aerobic bacillus which was named after edward francis and the location (tulare county, california) where the organism was discovered. f. tularensis includes four [corrected] subspecies known as tularensis (type a biovar), holarctica (type b biovar) and mediasiatica and novicida [corrected] tularemia (rabbit fever) is a rare and primarily rural disease which may be transmitted by ingestion, inhalation, or by direct skin contact with rabbits, other r ...200718173084
canonical insertion-deletion markers for rapid dna typing of francisella tularensis.to develop effective and accurate typing of strains of francisella tularensis, a potent human pathogen and a putative bioterrorist agent, we combined analysis of insertion-deletion (indel) markers with multiple-locus variable-number tandem repeat analysis (mlva). from 5 representative f. tularensis genome sequences, 38 indel markers with canonical properties, i.e., capable of sorting strains into major genetic groups, were selected. to avoid markers with a propensity for homoplasy, we used only ...200718217558
[indication of extremely dangerous infectious pathogens using immunochromatography and digital video analysis].the use of immunochromatographic indicatory elements based on antibody conjugates and colloidal gold was suggested to detect cells and the antigens of extremely dangerous infectious pathogens. the specificity and specific activity (sensitivity) of the mentioned elements were studied on vaccinal strains of plague, anthrax, and tularemia pathogens. the researchers studied a possibility to increase the sensitivity of immunochromatographic analysis using computed scanning and reflecom, a specialized ...200718225501
a piscirickettsiosis-like syndrome in cultured nile tilapia in latin america with francisella spp. as the pathogenic agent.in 2004, cultured nile tilapia oreochromis niloticus in several latin america farms began to succumb to a disease similar to the piscirickettsiosis-like syndrome previously reported in tilapia in taiwan and the united states. mortality increased during 2005; reductions in tilapia biomass ranged from 5% to 80% in individual ponds and averaged 50% overall. all ages of fish have been involved. clinical signs include lethargy, loss of appetite, petechia, exophthalmia, and abnormal swimming behavior. ...200718236629
[fluoroquinolones: antimicrobial activity and chemotherapeutic efficacy with respect to various pathogens in highly dangerous diseases].comparative in vitro and in vivo efficacy of new fluoroquinolones with respect to pathogens of tularemia, glanders, melioidosis and anthrax was estimated. it was shown that the strains of the tularemia, glanders, melioidosis and anthrax pathogens were in vitro highly susceptible to the new agents. the experiments on laboratory animals demonstrated that pefloxacin and sparfloxacin had extremely broad spectra and were of special value in emergency prophylaxis of tularemia, glanders, melioidosis an ...200719275053
structure and biosynthesis of free lipid a molecules that replace lipopolysaccharide in francisella tularensis subsp. novicida.francisella tularensis subsp. novicida u112 phospholipids, extracted without hydrolysis, consist mainly of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, and two lipid a species, designated a1 and a2. these lipid a species, present in a ratio of 7:1, comprise 15% of the total phospholipids, as judged by 32pi labeling. although lipopolysaccharide is detectable in f. tularensis subsp. novicida u112, less than 5% of the total lipid a is covalently linked to it. a1 and a2 were ...200617128982
multiplexed serology in atypical bacterial pneumonia.atypical pneumonia is a term applied to lower respiratory tract infections that are not characterized by signs and symptoms of lobar consolidation. this article will discuss the epidemiology, clinical manifestations, and laboratory diagnoses of mycoplasma pneumoniae, chlamydia sp., legionella sp., francisella tularensis, and coxiella burnetii, which are the agents most commonly associated with atypical pneumonia. because many of these pathogens are intracellular, diagnosis depends upon serologic ...200617114771
genetic tools for highly pathogenic francisella tularensis subsp. tularensis.this paper is the first detailed description of the development and use of new genetic tools specifically for the safe manipulation of highly pathogenic francisella tularensis subsp. tularensis. most of these tools are also demonstrated to work with other f. tularensis subspecies. kanamycin and hygromycin resistance determinants that function as genetic markers in f. tularensis subsp. tularensis strain schu and sets of episomal shuttle vectors that are either unstable or stably maintained in the ...200617074911
large tularaemia outbreak in varmland, central sweden, 2006. 200617075151
comparative proteome analysis of fractions enriched for membrane-associated proteins from francisella tularensis subsp. tularensis and f. tularensis subsp. holarctica strains.the facultative intracellular pathogen francisella tularensis is the causative agent of the serious infectious disease tularemia. despite intensive research, the virulence factors and pathogenetic mechanisms remain largely unknown. to identify novel putative virulence factors, we carried out a comparative proteome analysis of fractions enriched for membrane-associated proteins isolated from the highly virulent subspecies tularensis strain schu s4 and three representatives of subspecies holarctic ...200617081064
akt/protein kinase b modulates macrophage inflammatory response to francisella infection and confers a survival advantage in mice.the gram-negative bacterium francisella novicida infects primarily monocytes/macrophages and is highly virulent in mice. macrophages respond by producing inflammatory cytokines that confer immunity against the infection. however, the molecular details of host cell response to francisella infection are poorly understood. in this study, we demonstrate that f. novicida infection of murine macrophages induces the activation of akt. inhibition of akt significantly decreases proinflammatory cytokine p ...200617056562
development of a real-time pcr assay for detection and quantification of francisella tularensis.the facultative intracellular bacterium, francisella tularensis, is an etiological agent of tularemia and is also considered to be a potential biological threat agent due to its extreme infectivity. we established a real-time pcr assay using the lightcycler (lc) system to detect a francisella-specific sequence of the outer membrane protein (fopa) gene. twenty-five f. tularensis strains including 16 japanese isolates were subjected to this lc-pcr assay, and were tested positive, whereas francisel ...200616495634
innate immune response to francisella tularensis is mediated by tlr2 and caspase-1 activation.francisella tularensis, a gram-negative, facultative, intracellular bacterium, is the etiologic agent of tularemia and a category a bioterrorism agent. little is known about the mechanism of pathogenesis of tularemia. in this paper, we describe the interaction of the live vaccine strain of f. tularensis with the innate immune system. we have found that in human and mouse dendritic cells, f. tularensis elicited a powerful inflammatory response, characterized by production of a number of cytokines ...200616895974
structure of francisella tularensis acpa: prototype of a unique superfamily of acid phosphatases and phospholipases c.acpa is a respiratory burst-inhibiting acid phosphatase from the centers for disease control and prevention category a bioterrorism agent francisella tularensis and prototype of a superfamily of acid phosphatases and phospholipases c. we report the 1.75-a resolution crystal structure of acpa complexed with the inhibitor orthovanadate, which is the first structure of any f. tularensis protein and the first for any member of this superfamily. the core domain is a twisted 8-stranded beta-sheet flan ...200616899453
francisella tularensis lvs evades killing by human neutrophils via inhibition of the respiratory burst and phagosome escape.francisella tularensis is a gram-negative bacterium and the causative agent of tularemia. recent data indicate that f. tularensis replicates inside macrophages, but its fate in other cell types, including human neutrophils, is unclear. we now show that f. tularensis live vaccine strain (lvs), opsonized with normal human serum, was rapidly ingested by neutrophils but was not eliminated. moreover, evasion of intracellular killing can be explained, in part, by disruption of the respiratory burst. a ...200616908516
deletion of tolc orthologs in francisella tularensis identifies roles in multidrug resistance and virulence.the gram-negative bacterium francisella tularensis is the causative agent of tularemia. interest in this zoonotic pathogen has increased due to its classification as a category a agent of bioterrorism, but little is known about the molecular mechanisms underlying its virulence, and especially what secretion systems and virulence factors are present. in this study, we characterized two genes in the f. tularensis genome, tolc and a gene we term ftlc, whose products have high homology with the esch ...200616908853
live vaccine strain francisella tularensis is detectable at the inoculation site but not in blood after vaccination against tularemia.live vaccine strain (lvs) francisella tularensis is a live, attenuated investigational tularemia vaccine that has been used by the us army for decades to protect laboratory workers. postvaccination bacterial kinetic characteristics of lvs at the inoculation site and in the blood are unknown and, therefore, were assessed in a prospective study. lvs vaccination of laboratory workers provided the opportunity to compare culture with polymerase chain reaction (pcr) for the detection of f. tularensis ...200616912944
superoxide dismutase b gene (sodb)-deficient mutants of francisella tularensis demonstrate hypersensitivity to oxidative stress and attenuated virulence.a francisella tularensis live vaccine strain mutant (sodb(ft)) with reduced fe-superoxide dismutase gene expression was generated and found to exhibit decreased sodb activity and increased sensitivity to redox cycling compounds compared to wild-type bacteria. the sodb(ft) mutant also was significantly attenuated for virulence in mice. thus, this study has identified sodb as an important f. tularensis virulence factor.200616923916
attenuated francisella novicida transposon mutants protect mice against wild-type challenge.francisella tularensis is the bacterial pathogen that causes tularemia in humans and a number of animals. to date, there is no approved vaccine for this widespread and life-threatening disease. the goal of this study was to identify f. tularensis mutants that can be used in the development of a live attenuated vaccine. we screened f. novicida transposon mutants to identify mutants that exhibited reduced growth in mouse macrophages, as these cells are the preferred host cells of francisella and a ...200616926401
characterization of the receptor-ligand pathways important for entry and survival of francisella tularensis in human macrophages.inhalational pneumonic tularemia, caused by francisella tularensis, is lethal in humans. f. tularensis is phagocytosed by macrophages followed by escape from phagosomes into the cytoplasm. little is known of the phagocytic mechanisms for francisella, particularly as they relate to the lung and alveolar macrophages. here we examined receptors on primary human monocytes and macrophages which mediate the phagocytosis and intracellular survival of f. novicida. f. novicida association with monocyte-d ...200616926403
tularemia, a reemerging disease in northwest turkey: epidemiological investigation and evaluation of treatment responses.an outbreak of tularemia occurred in three provinces in turkey in february 2004 and reemerged in the same provinces in february 2005. a total of 61 cases, 54 of which were confirmed with the micro-agglutination test, were diagnosed with oropharyngeal tularemia. no culture for francisella tularensis was attempted, but pcr for f. tularensis was positive in aspiration material of suppurated lymphadenitis of 7 patients. f. tularensis detection with pcr was negative in water samples, but epidemiologi ...200616936340
[immunization with cellulose-immobilized antigens. the development of a. e. gurvitch concept].a highly purified tul4-cbd chimeric protein was obtained by one stage purification method. tul4-cbd protein consists of tul4 francisella tularensis mature peptide sequence, gly-ser spacer and cellulose binding domain (cbd) of anaerocellum thermophilum. the tul4-cbd protein was shown to induce production of specific antibodies to tul4 protein in laboratory animals.200616941875
identification of a francisella tularensis lvs outer membrane protein that confers adherence to a549 human lung cells.francisella tularensis is a highly pathogenic bacterium; however, little is known about its initial interactions with mucosal surfaces of the human respiratory tract. to investigate these interactions, we tested whether two francisella strains could adhere to a549 human lung epithelial cells. we found that lvs adhered well to these cells while francisella novicida adhered poorly. we used surface biotinylation to identify bacterial proteins that might mediate this adherence. we report the identif ...200616958857
chromosome rearrangement and diversification of francisella tularensis revealed by the type b (osu18) genome sequence.the gamma-proteobacterium francisella tularensis is one of the most infectious human pathogens, and the highly virulent organism f. tularensis subsp. tularensis (type a) and less virulent organism f. tularensis subsp. holarctica (type b) are most commonly associated with significant disease in humans and animals. here we report the complete genome sequence and annotation for a low-passage type b strain (osu18) isolated from a dead beaver found near red rock, okla., in 1978. a comparison of the f ...200616980500
lack of in vitro and in vivo recognition of francisella tularensis subspecies lipopolysaccharide by toll-like receptors.francisella tularensis is an intracellular gram-negative bacterium that is highly infectious and potentially lethal. several subspecies exist of varying pathogenicity. infection by only a few organisms is sufficient to cause disease depending on the model system. lipopolysaccharide (lps) of gram-negative bacteria is generally recognized by toll-like receptor 4 (tlr4)/md-2 and induces a strong proinflammatory response. examination of human clinical f. tularensis isolates revealed that human virul ...200616982824
autophagy-mediated reentry of francisella tularensis into the endocytic compartment after cytoplasmic replication.intracellular bacterial pathogens evade the bactericidal functions of mammalian cells by physical escape from their phagosome and replication into the cytoplasm or through the modulation of phagosome maturation and biogenesis of a membrane-bound replicative organelle. here, we detail in murine primary macrophages the intracellular life cycle of francisella tularensis, a highly infectious bacterium that survives and replicates within mammalian cells. after transient interactions with the endocyti ...200616983090
type iv pili-mediated secretion modulates francisella virulence.francisella tularensis are the causative agent of the zoonotic disease, tularaemia. among four f. tularensis subspecies, ssp. novicida (f. novicida) is pathogenic only for immunocompromised individuals, while all four subspecies are pathogenic for mice. this study utilized proteomic and bioinformatic approaches to identify seven f. novicida secreted proteins and the corresponding type iv pilus (t4p) secretion system. the secreted proteins were predicted to encode two chitinases, a chitin binding ...200616987180
francisella tularensis lvs grown in macrophages has reduced ability to stimulate the secretion of inflammatory cytokines by macrophages in vitro.the virulence of francisella tularensis lvs is determined in part by its ability to invade and replicate within macrophages and stimulate the production of inflammatory cytokines. the present study determined the effects of growing f. tularensis in macrophages on its ability to stimulate cytokine secretion by macrophages. f. tularensis grown in mueller-hinton broth (ftb) stimulated the secretion of large amounts of tnf-alpha, il-12p40, il-6 and mcp-1/ccl2 when incubated with macrophages overnigh ...200616996713
potential source of francisella tularensis live vaccine strain attenuation determined by genome comparison.francisella tularensis is a bacterial pathogen that causes the zoonotic disease tularemia and is important to biodefense. currently, the only vaccine known to confer protection against tularemia is a specific live vaccine strain (designated lvs) derived from a virulent isolate of francisella tularensis subsp. holarctica. the origin and source of attenuation of this strain are not known. to assist with the design of a defined live vaccine strain, we sought to determine the genetic basis of the at ...200617000723
mac-1+ cells are the predominant subset in the early hepatic lesions of mice infected with francisella tularensis.the cell composition of early hepatic lesions of experimental murine tularemia has not been characterized with specific markers. the appearance of multiple granulomatous-necrotic lesions in the liver correlates with a marked increase in the levels of serum alanine transferase and lactate dehydrogenase. francisella tularensis, detected by specific antibodies, can be first noted by day 1 and becomes associated with the lesions by 5 days postinoculation. these lesions become necrotic, with some evi ...200617000726
identification of mgla-regulated genes reveals novel virulence factors in francisella tularensis.the facultative intracellular bacterium francisella tularensis causes the zoonotic disease tularemia. f. tularensis resides within host macrophages in vivo, and this ability is essential for pathogenesis. the transcription factor mgla is required for the expression of several francisella genes that are necessary for replication in macrophages and for virulence in mice. we hypothesized that the identification of mgla-regulated genes in the francisella genome by transcriptional profiling of wild-t ...200617000729
interview with dr. lee-ann allen regarding pivotal advance: francisella tularensis lvs evades killing by human neutrophils via inhibition of the respiratory burst and phagosome escape. interview by helene f. rosenberg. 200617005906
myeloid differentiation factor-88 (myd88) is essential for control of primary in vivo francisella tularensis lvs infection, but not for control of intra-macrophage bacterial replication.the means by which francisella tularensis, the causative agent of tularemia, are recognized by mammalian immune systems are poorly understood. here we wished to explore the contribution of the myd88/toll-like receptor signaling pathway in initiating murine responses to f. tularensis live vaccine strain (lvs). myd88 knockout (ko) mice, but not tlr2-, tlr4- or tlr9-deficient mice, rapidly succumbed following in vivo bacterial infection via the intradermal route even with a very low dose of lvs (5 ...200616513388
in vivo himar1-based transposon mutagenesis of francisella tularensis.francisella tularensis is the intracellular pathogen that causes human tularemia. it is recognized as a potential agent of bioterrorism due to its low infectious dose and multiple routes of entry. we report the development of a himar1-based random mutagenesis system for f. tularensis (himarft). in vivo mutagenesis of f. tularensis live vaccine strain (lvs) with himarft occurs at high efficiency. approximately 12 to 15% of cells transformed with the delivery plasmid result in transposon insertion ...200616517634
an outbreak of airborne tularaemia in france, august 2004.fifteen tularaemia cases were identified after a holiday spent at a converted mill in the vendee region in france, between 9 and 12 august 2004. the mill was visited, and descriptive, retrospective cohort and environmental investigations were conducted. the 39 people who had stayed at the mill between 24 july and 11 august were asked about symptoms, exposure to food and animals, and leisure activities. a case was defined as a person with evidence of fever and a positive serology (seroconversion ...200616525197
[persistence factors of francisella tularensis].the study of the persistence potential of 64 f. tularensis strains isolated from different sources was carried out. the wide spread of the antilysozyme, antilactoferrin and anticomplementory activities of f. tularensis were detected. f. tularensis, isolated from ticks and water, were characterized by the highest level of the expression of antilysozyme activity, while anticomplementory and antilactoferrin activities of the infective agents were characteristic of those microorganisms which were is ...200616532645
anti-francisella tularensis dna aptamers detect tularemia antigen from different subspecies by aptamer-linked immobilized sorbent assay.aptamers are powerful candidates for molecular detection of targets due to their unique recognition properties. these affinity probes can be used to recognize and bind to their targets in the various types of assays that are currently used to detect and capture molecules of interest. they are short single-stranded (ss) oligonucleotides composed of dna or rna sequences that are selected in vitro based on their affinity and specificity for the target. using combinatorial oligonucleotide libraries, ...200616550191
intranasal vaccination with a defined attenuated francisella novicida strain induces gamma interferon-dependent antibody-mediated protection against tularemia.francisella tularensis is an intracellular gram-negative bacterium that is the causative agent of tularemia and a potential bioweapon. we have characterized the efficacy of a defined f. novicida mutant (deltaiglc) as a live attenuated vaccine against subsequent intranasal challenge with the wild-type organism. animals primed with the f. novicida deltaiglc (kkf24) mutant induced robust splenic gamma interferon (ifn-gamma) and interleukin-12 (il-12) recall responses with negligible il-4 production ...200616552035
direct repeat-mediated deletion of a type iv pilin gene results in major virulence attenuation of francisella tularensis.francisella tularensis, the causative agent of tularaemia, is a highly infectious and virulent intracellular pathogen. there are two main human pathogenic subspecies, francisella tularensis ssp. tularensis (type a), and francisella tularensis ssp. holarctica (type b). so far, knowledge regarding key virulence determinants is limited but it is clear that intracellular survival and multiplication is one major virulence strategy of francisella. in addition, genome sequencing has revealed the presen ...200616553886
tularemia induced bilateral optic neuritis. 200616562762
francisella tularensis lps induces the production of cytokines in human monocytes and signals via toll-like receptor 4 with much lower potency than e. coli lps.francisella tularensis is a virulent gram-negative intracellular pathogen. to address the signaling routes involved in the response of host cells to lps from f. tularensis live vaccine strain (lvs), experiments were performed in transiently transfected 293 cells. induction of kappab-driven transcriptional activity by 2.5 mug ml(-1) f. tularensis lps isolated by phenol-water and ether-water extraction, was observed in cells transfected with toll-like receptor (tlr) 4 and md-2, although cd14 was r ...200616574669
francisella sp. (family francisellaceae) causing mortality in norwegian cod (gadus morhua) farming.in 2004, a new disease was detected in cod (gadus morhua) in western norway. affected cod had white granulomas in the visceral organs and skin. a species of francisella was isolated on blood agar plates from moribund cod. the bacterium could be grown at temperatures ranging from 6 to 22 degrees c, but did not grow at 37 degrees c. challenge experiments showed that francisella sp. was the cause for the new disease. the 16s rdna gene sequence from francisella sp. showed 99.17% similarity to f. phi ...200616614828
[tularaemia as a differential diagnosis in tumour colli].tularaemia is a bacterial zoonosis caused by the bacterium francisella tularensis. different species of rodents and small mammals are the main reservoir; the transmission of disease is caused by direct contact with diseased animals, via insect vectors, or by ingestion of contaminated food and water. the disease is known to cause a complex clinical presentation in which head and neck manifestations are common. it occurs at a low annual rate in the northern and middle regions of norway, but in rec ...200616619065
treatment of murine pneumonic francisella tularensis infection with gatifloxacin, moxifloxacin or ciprofloxacin.the efficacies of gatifloxacin and moxifloxacin were assessed in a balb/c mouse model of pneumonic tularemia and compared with the efficacy of ciprofloxacin. the rate of relapse following dexamethasone treatment was also investigated. mice were given 100 mg/kg of the antibiotic by oral administration twice daily for 14 days following an aerosol challenge. all three fluoroquinolones prevented disease during the treatment period, but significant failure rates occurred after the cessation of therap ...200616621457
toll-like receptor 2 is required for inflammatory responses to francisella tularensis lvs.francisella tularensis, a gram-negative bacterium, is the etiologic agent of tularemia and has recently been classified as a category a bioterrorism agent. infections with f. tularensis result in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms mediating this response have not been completely elucidated. in the present study, we determined the role of toll-like receptors (tlrs) in mediating inflammatory responses to f. tul ...200616622218
a simple and rapid protein array based method for the simultaneous detection of biowarfare agents.a protein chip has been developed that allows the simultaneous detection of a multitude of different biowarfare agents. the chip was developed for the arraytube platform providing a cheap and easy to handle technology solution that combines a microtube-integrated protein chip with the classical procedure of a sandwich-enzyme-linked immunosorbent assay and signal amplification by streptavidin-poly-horseradish peroxidase. specific immunoassays for staphylococcus enterotoxin b, ricin, venezuelan eq ...200616622830
the atypical pneumonias: clinical diagnosis and importance.the most common atypical pneumonias are caused by three zoonotic pathogens, chlamydia psittaci (psittacosis), francisella tularensis (tularemia), and coxiella burnetii (q fever), and three nonzoonotic pathogens, chlamydia pneumoniae, mycoplasma pneumoniae, and legionella. these atypical agents, unlike the typical pathogens, often cause extrapulmonary manifestations. atypical caps are systemic infectious diseases with a pulmonary component and may be differentiated clinically from typical caps by ...200616669925
dominance of human innate immune responses in primary francisella tularensis live vaccine strain vaccination. 200616675351
a novel systemic granulomatous inflammatory disease in farmed atlantic cod, gadus morhua l., associated with a bacterium belonging to the genus francisella. 200616677321
environmental survey for four pathogenic bacteria and closely related species using phylogenetic and functional genes.bacterial species with high dna sequence similarity to pathogens could affect the specificity of assays designed to detect biological threat agents in environmental samples. the natural presence of four pathogenic bacteria, bacillus anthracis, clostridium perfringens, francisella tularensis, and yersinia pestis and their closely related species, was determined for a large collection of soil and aerosol samples. polymerase chain reaction (pcr) and gene sequencing were used using group-specific 16 ...200616696701
francisella tularensis: taxonomy, genetics, and immunopathogenesis of a potential agent of biowarfare.tularemia is a zoonosis of humans caused by infection with the facultative intracellular bacterium francisella tularensis. interest in f. tularensis has increased markedly in the past few years because of its potential use as an agent of bioterrorism. five subspecies of this organism are found in the northern hemisphere, but only f. tularensis subsp. tularensis and subsp. holarctica cause disease in humans. this review summarizes what is known about the pathogenesis of tularemia with a focus on ...200616704343
tularemia outbreak, bulgaria, 1997-2005.the 1997-2005 tularemia outbreak in bulgaria affected 285 people. ten strains were isolated from humans, a tick, a hare, and water. amplified fragment length polymorphism typing of the present isolates and of the strain isolated in 1962 suggests that a new genetic variant caused the outbreak.200616704820
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