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persistence of category a select agents in the environment. 200818065629
detection of alpha and gamma-proteobacteria in amblyomma triste (acari: ixodidae) from uruguay.amblyomma triste is the most prevalent tick species reported in human tick bites in uruguay and has been found to be infected with rickettsia parkeri, but no other microorganisms have been reported from this tick. a sample of 254 adults of a. triste was collected by flagging on vegetation in suburban areas in southern uruguay. pools of five ticks were assembled and a screening for the dna from the resulting 51 pools was realized by pcr assays using primers for amplifying a fragment of 16s rrna g ...200818071910
identification of francisella tularensis lipoproteins that stimulate the toll-like receptor (tlr) 2/tlr1 heterodimer.the innate immune response to francisella tularensis is primarily mediated by tlr2, though the bacterial products that stimulate this receptor remain unknown. here we report the identification of two francisella lipoproteins, tul4 and ftt1103, which activate tlr2. we demonstrate that tul4 and ftt1103 stimulate chemokine production in human and mouse cells in a tlr2-dependent way. using an assay that relies on chimeric tlr proteins, we show that tul4 and ftt1103 stimulate exclusively the tlr2/tlr ...200818079113
the presence of infectious extracellular francisella tularensis subsp. novicida in murine plasma after pulmonary challenge. 200818087734
the acrab rnd efflux system from the live vaccine strain of francisella tularensis is a multiple drug efflux system that is required for virulence in mice.the ability of bacterial pathogens to infect and cause disease is dependent upon their ability to resist antimicrobial components produced by their host, such as bile acids, fatty acids and other detergent-like molecules, and products of the innate immune system (e.g. cationic antimicrobial peptides). bacterial resistance to the antimicrobial effects of such compounds is often mediated by active efflux systems belonging to the resistance-nodulation-division (rnd) family of transporters. rnd effl ...200818179581
a functional genomic yeast screen to identify pathogenic bacterial proteins.many bacterial pathogens promote infection and cause disease by directly injecting into host cells proteins that manipulate eukaryotic cellular processes. identification of these translocated proteins is essential to understanding pathogenesis. yet, their identification remains limited. this, in part, is due to their general sequence uniqueness, which confounds homology-based identification by comparative genomic methods. in addition, their absence often does not result in phenotypes in virulenc ...200818208325
an intracellularly inducible gene involved in virulence and polyphosphate production in francisella.francisella tularensis is an intracellular pathogen capable of multiplying to high levels in macrophages. by protein analysis, only a few proteins have been shown previously to be expressed at high levels in macrophages relative to bacteria grown in culture media. to identify additional genes that show increased expression during intracellular growth, we developed a plasmid for use in francisella based on the induction of expression of green fluorescent protein. clones of f. tularensis subsp. no ...200818809544
tularemia in children.tularemia, an infection caused by the coccobacilus francisella tularensis, can be a difficult disease process to diagnose and treat. the aim of this study was to evaluate an epidemic of tularemia in bursa.200818810348
effective host response to francisella tularensis requires functional mast cells.evaluation of: ketavarapu jm, rodriguez ar, yu j et al.: mast cells inhibit intramacrophage francisella tularensis replication via contact and secreted products including il-4. proc. natl acad. sci. usa 105(27), 9313-9318 (2008). the intracellular pathogen francisella tularensis is a highly infectious organism that infects cells of the immune system. mast cells have been known for their role in anaphylaxis, although they are also important for their ability to aid in the defense against pathogen ...200818811234
[interaction of s- and r-lipopolysaccharides of francisella tularensis with lypopolysaccharide-binding protein of human serum].investigation of ability of francisella tularensis s- and r-lypopolysaccharide (lps) preparations as well as the live bacteria with different chemotypes to interact with human lypopolysaccharide-binding protein (lbp) was carried out. it was found that lps preparations derived from virulent(s-lps) or isogenic avirulent mutant (r-lps) strains of f. tularensis had markedly lower affinity to lbp as compared with typical s-lps of salmonella abortus and r-lps of yersinia pestis. it was shown that r-lp ...200818819401
[temperate legionella bacteriophage: discovery and characteristics].for the first time, temperate legionella bacteriophage was isolated from organs of guinea pig infected with philadelphia 1 strain of legionella pneumophila. negative colonies of bactriophage from 1.5 to 2.5 mm in diameter were detected. central part of them was transparent and surrounded by peripheral zone of partial lysis. electron microscopy showed that corpuscles of the phage consist from multifaceted elongated head of stretched hexagonal form and short tail. the bacteriophage lyzed bacteria, ...200818819413
evasion of complement-mediated lysis and complement c3 deposition are regulated by francisella tularensis lipopolysaccharide o antigen.the bacterium francisella tularensis (ft) is a potential weapon of bioterrorism when aerosolized. macrophage infection is necessary for disease progression and efficient phagocytosis by human macrophages requires serum opsonization by complement. microbial complement activation leads to surface deposition of a highly regulated protein complex resulting in opsonization or membrane lysis. the nature of complement component c3 deposition, i.e., c3b (opsonization and lysis) or c3bi (opsonization onl ...200818832715
genetic dissection of the francisella novicida restriction barrier.francisella tularensis is the causative agent of tularemia and is a category a select agent. francisella novicida, considered by some to be one of four subspecies of f. tularensis, is used as a model in pathogenesis studies because it causes a disease similar to tularemia in rodents but is not harmful to humans. f. novicida exhibits a strong restriction barrier which reduces the transformation frequency of foreign dna up to 10(6)-fold. to identify the genetic basis of this barrier, we carried ou ...200818835994
humoral and cell-mediated immunity to the intracellular pathogen francisella tularensis.summary: francisella tularensis can cause fatal respiratory tularemia in humans and animals and is increasingly being isolated in the united states and several european countries. the correlates of protective immunity against this intracellular bacterium are not known, and currently there are no licensed vaccines available for human use. cell-mediated immunity has long been believed to be critical for protection, and the importance of humoral immunity is also now recognized. furthermore, synergy ...200818837786
global transcriptional response to mammalian temperature provides new insight into francisella tularensis pathogenesis.after infecting a mammalian host, the facultative intracellular bacterium, francisella tularensis, encounters an elevated environmental temperature. we hypothesized that this temperature change may regulate genes essential for infection.200818842136
development and application of the active surveillance of pathogens microarray to monitor bacterial gene flux.human and animal health is constantly under threat by emerging pathogens that have recently acquired genetic determinants that enhance their survival, transmissibility and virulence. we describe the construction and development of an active surveillance of pathogens (asp) oligonucleotide microarray, designed to 'actively survey' the genome of a given bacterial pathogen for virulence-associated genes.200818844996
the early phagosomal stage of francisella tularensis determines optimal phagosomal escape and francisella pathogenicity island protein expression.francisella tularensis is an intracellular pathogen that can survive and replicate within macrophages. following phagocytosis and transient interactions with the endocytic pathway, f. tularensis rapidly escapes from its original phagosome into the macrophage cytoplasm, where it eventually replicates. to examine the importance of the nascent phagosome for the francisella intracellular cycle, we have characterized early trafficking events of the f. tularensis subsp. tularensis strain schu s4 in a ...200818852245
infected-host-cell repertoire and cellular response in the lung following inhalation of francisella tularensis schu s4, lvs, or u112.francisella tularensis causes systemic disease in humans and other mammals, with high morbidity and mortality associated with inhalation-acquired infection. f. tularensis is a facultative intracellular pathogen, but the scope and significance of cell types infected during disease is unknown. using flow cytometry, we identified and quantified infected-cell types and assessed the impact of infection on cell populations following inhalation of f. tularensis strains u112, lvs, and schu s4. initially ...200818852251
temporal cytokine profiling of francisella tularensis-infected human peripheral blood mononuclear cells.francisella tularensis is an intracellular bacterium known to replicate in monocytes and macrophages and cause tularemia in humans. because of its infectious nature, f. tularensis is considered a biowarfare agent. early cytokine profiles of francisella-infected human peripheral blood mononuclear cells were evaluated.200818629413
adaptation of francisella tularensis to the mammalian environment is governed by cues which can be mimicked in vitro.the intracellular bacterium francisella tularensis survives in mammals, arthropods, and freshwater amoeba. it was previously established that the conventional media used for in vitro propagation of this microbe do not yield bacteria that mimic those harvested from infected mammals; whether these in vitro-cultivated bacteria resemble arthropod- or amoeba-adapted francisella is unknown. as a foundation for our goal of identifying f. tularensis outer membrane proteins which are expressed during mam ...200818644878
molecular method for discrimination between francisella tularensis and francisella-like endosymbionts.environmental studies on the distribution of francisella spp. are hampered by the frequency of francisella-like endosymbionts that can produce a misleading positive result. a new, efficient molecular method for detection of francisella tularensis and its discrimination from francisella-like endosymbionts, as well as two variants associated with human disease (unusual f. tularensis strain fnsp1 and f. tularensis subsp. novicida-like strain 3523), is described. the method is highly specific and se ...200818650358
[specific effect of attenuated strain of francisella tularensis on the development of radiation induced lesions in experimental animals and effictiveness of antibacterial therapy for lesions induced by radiation combined with virulemt strain of the bacteria].for study of the effects of whole-body gamma-radiation (1 and 4 gy) on the response of the body to administration of vaccines and virulent strains of tularemia 206 outbred white mice were used. the results of the study shown that the administration of attenuated bacterial cells in 5 days after exposure to radiation (1 and 4 gy) caused more severe post-radiation effects and the increase in the number of died animals. the severity of the disease was less if mice were vaccinated in 26 days after ir ...200818666584
transcriptional profiling of francisella tularensis infected peripheral blood mononuclear cells: a predictive tool for tularemia.in this study, we analyzed temporal gene expression patterns in human peripheral blood mononuclear cells (pbmcs) infected with the francisella tularensis live vaccine strain from 1 to 24 h utilizing a whole human affymetrix gene chip. we found that a considerable number of induced genes had similar expression patterns and functions as reported previously for gene expression profiling in patients with ulceroglandular tularemia. among the six uniquely regulated genes reported for tularemia patient ...200818680519
nodular lymphangitis: a distinctive clinical entity with finite etiologies.nodular lymphangitis, characterized by inflammatory nodules along the lymphatics draining a primary skin infection, most commonly follows superficial inoculation with sporothrix schenckii, nocardia brasiliensis, mycobacterium marinum, leishmania (viannia) panamensis/guyanensis, and francisella tularensis. epidemiologic context, clinical presentation, and presumed incubation period help to predict the specific etiologic microorganism. sporotrichosis, often occurring in gardeners, remains the most ...200818687205
an improved vaccine for prevention of respiratory tularemia caused by francisella tularensis schus4 strain.vaccination of mice with francisella tularensis live vaccine strain (lvs) mutants described so far have failed to induce protection in c57bl/6 mice against challenge with the virulent strain f. tularensis schus4. we have previously reported that a mutant of f. tularensis lvs deficient in iron superoxide dismutase (sodb(ft)) is hypersensitive to oxidative stress and attenuated for virulence in mice. herein, we evaluated the efficacy of this mutant as a vaccine candidate against respiratory tulare ...200818692537
microarray analysis of human monocytes infected with francisella tularensis identifies new targets of host response subversion.francisella tularensis is a gram-negative facultative bacterium that causes the disease tularemia, even upon exposure to low numbers of bacteria. one critical characteristic of francisella is its ability to dampen or subvert the host immune response. in order to help understand the mechanisms by which this occurs, we performed affymetrix microarray analysis on transcripts from blood monocytes infected with the virulent type a schu s4 strain. results showed that expression of several host respons ...200818698339
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
rapid diagnosis and quantification of francisella tularensis in organs of naturally infected common squirrel monkeys (saimiri sciureus).francisella tularensis, a small gram-negative facultative intracellular bacterium, is the causative agent of tularaemia, a severe zoonotic disease transmitted to humans mostly by vectors such as ticks, flies and mosquitoes. the disease is endemic in many parts of the northern hemisphere. among animals, the most affected species belong to rodents and lagomorphs, in particular hares. however, in the recent years, many cases of tularaemia among small monkeys in zoos were reported. we have developed ...200817875369
characterization and application of a glucose-repressible promoter in francisella tularensis.francisella tularensis, the causative agent of tularemia, is a category a biodefense agent. the examination of gene function in this organism is limited due to the lack of available controllable promoters. here, we identify a promoter element of f. tularensis lvs that is repressed by glucose (termed the francisella glucose-repressible promoter, or fgrp), allowing the management of downstream gene expression. in bacteria cultured in medium lacking glucose, this promoter induced the expression of ...200818245238
drosophila melanogaster as a model for elucidating the pathogenicity of francisella tularensis.drosophila melanogaster is a widely used model organism for research on innate immunity and serves as an experimental model for infectious diseases. the aetiological agent of the zoonotic disease tularaemia, francisella tularensis, can be transmitted by ticks and mosquitoes and drosophila might be a useful, genetically amenable model host to elucidate the interactions between the bacterium and its arthropod vectors. we found that the live vaccine strain of f. tularensis was phagocytosed by droso ...200818248629
a francisella mutant in lipid a carbohydrate modification elicits protective immunity.francisella tularensis (ft) is a highly infectious gram-negative bacterium and the causative agent of the human disease tularemia. ft is designated a class a select agent by the centers for disease control and prevention. human clinical isolates of ft produce lipid a of similar structure to ft subspecies novicida (fn), a pathogen of mice. we identified three enzymes required for fn lipid a carbohydrate modifications, specifically the presence of mannose (flmf1), galactosamine (flmf2), or both ca ...200818266468
bifunctional nmn adenylyltransferase/adp-ribose pyrophosphatase: structure and function in bacterial nad metabolism.bacterial nadm-nudix is a bifunctional enzyme containing a nicotinamide mononucleotide (nmn) adenylyltransferase and an adp-ribose (adpr) pyrophosphatase domain. while most members of this enzyme family, such as that from a model cyanobacterium synechocystis sp., are involved primarily in nicotinamide adenine dinucleotide (nad) salvage/recycling pathways, its close homolog in a category-a biodefense pathogen, francisella tularensis, likely plays a central role in a recently discovered novel path ...200818275811
the heat-shock protein clpb of francisella tularensis is involved in stress tolerance and is required for multiplication in target organs of infected mice.intracellular bacterial pathogens generally express chaperones such as hsp100s during multiplication in host cells, allowing them to survive potentially hostile conditions. francisella tularensis is a highly infectious bacterium causing the zoonotic disease tularaemia. the ability of f. tularensis to multiply and survive in macrophages is considered essential for its virulence. although previous mutant screens in francisella have identified the hsp100 chaperone clpb as important for intracellula ...200818284578
intracellular localization of brucella abortus and francisella tularensis in primary murine macrophages.intracellular bacterial pathogens have evolved sophisticated strategies to survive and proliferate within cells of their hosts. studying their intracellular life cycle is key to understanding virulence and requires methodologies that can identify the compartments in which they localize and characterize the replicative niche they generate. here, we describe immunofluorescence-based microscopy techniques applied to the intracellular pathogens brucella abortus and francisella tularensis during thei ...200818287753
the tyrosine kinase syk promotes phagocytosis of francisella through the activation of erk.francisella tularensis is a highly infectious, gram-negative intra-cellular pathogen that can cause the zoonotic disease tularemia. although the receptors critical for internalization of francisella by macrophages are beginning to be defined, the identity of the downstream signaling pathways essential for the engulfment are not yet identified. in this study we have tested the role of syk in the phagocytosis of francisella. we report that syk is activated during francisella infection and is criti ...200818295889
a conserved and immunodominant lipoprotein of francisella tularensis is proinflammatory but not essential for virulence.francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. a live vaccine strain (lvs) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. f. tularensis has been classified as a category a agent of bioterrorism. despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. here, we report the deletion of a well-character ...200818304778
inhibition of airway eosinophilia and pulmonary pathology in a mouse model of allergic asthma by the live vaccine strain of francisella tularensis.it has been suggested that exposure to certain microbes and their products, particularly during neonatal and early childhood periods, may shift the immune response towards a t-helper cell (th) 1 phenotype and thereby prevent the development of and/or alleviate the clinical symptoms of allergic airway diseases.200818307525
an improved francisella tularensis live vaccine strain (lvs) is well tolerated and highly immunogenic when administered to rabbits in escalating doses using various immunization routes.tularemia is a severe disease for which there is no licensed vaccine. an attenuated f. tularensis live vaccine strain (lvs) was protective when administered to humans but safety concerns precluded its licensure and use in large-scale immunization. an improved f. tularensis lvs preparation was produced under current good manufacturing practice (cgmp) guidelines for evaluation in clinical trials. preclinical safety, tolerability and immunogenicity were investigated in rabbits that received lvs in ...200818308432
targeted inactivation of francisella tularensis genes by group ii introns.studies of the molecular mechanisms of pathogenesis of francisella tularensis, the causative agent of tularemia, have been hampered by a lack of genetic techniques for rapid targeted gene disruption in the most virulent subspecies. here we describe efficient targeted gene disruption in f. tularensis utilizing mobile group ii introns (targetrons) specifically optimized for f. tularensis. utilizing a targetron targeted to blab, which encodes ampicillin resistance, we showed that the system works a ...200818310413
ifngamma enhances il-23 production during francisella infection of human monocytes.we previously demonstrated that monocytes produce il-23 during francisella infection, and that il-23 induces ifngamma from nk cells. here, we demonstrate that ifngamma-priming of monocytes enhances il-23 production during francisella infection. this effect was seen on the il12/23 p40 subunit. induction of il-12/23 p40 is reported to be enhanced by irf-1 and irf-8. consistently, microarray analysis of ifngamma-treated monocytes revealed a significant induction of the irfs. interestingly, ifngamma ...200818319062
use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections.the ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. ketolides bind to a secondary region on domain ii of the 23s rrna subunit. telithromycin was the first ketolide to be approved by the fda in 2004 for treatment of community-acquired pneumonia (cap), acute exacerbations of chronic bronchitis (aecb) and sinusitis. however, in 2006, after repo ...200818321237
molecular immunology of experimental primary tularemia in mice infected by respiratory or intradermal routes with type a francisella tularensis.the type a subspecies of francisella tularensis is a highly virulent facultative intracellular bacterial pathogen, and a potential biological weapon. recently, there has been renewed interest in developing new vaccines and therapeutics against this bacterium. natural cases of disease, tularemia, caused by the type a subspecies are very rare. therefore, the united states food and drug administration will rely on the so-called animal rule for efficacy testing of anti-francisella medicines. this re ...200818321578
identification of differentially regulated francisella tularensis genes by use of a newly developed tn5-based transposon delivery system.francisella tularensis is the etiologic agent of an intracellular systemic infection of the lymphatic system in humans called tularemia. the organism has become the subject of considerable research interest due to its classification as a category a select agent by the cdc. to aid genetic analysis of this pathogen, we have constructed a temperature-sensitive tn5-based transposon delivery system that is capable of generating chromosomal reporter fusions with lacz or luxcdabe, enabling us to monito ...200818344342
the inflammasome: a key player in the inflammation triggered in response to bacterial pathogens. 200818354318
using 2d-lc-ms/ms to identify francisella tularensis peptides in extracts from an infected mouse macrophage cell line.two dimensional nano-high-performance liquid chromatography (nanohplc) coupled directly to a high-resolution tandem mass spectrometer (2d-nlc-ms/ms) is an excellent method for analyzing very complex peptide mixtures, especially when the quantity of sample available for analysis is severely limited. we describe here a relatively simple 2d-nlc-ms/ms approach that we often use to characterize complex peptide mixtures, such as those produced by the proteolytic digestion of protein extracts. a peptid ...200818370109
rapid polymerase chain reaction-based screening assay for bacterial biothreat agents.to design and evaluate a rapid polymerase chain reaction (pcr)-based assay for detecting eubacteria and performing early screening for selected class a biothreat bacterial pathogens.200818370996
determination and comparison of the francisella tularensis subsp.novicida u112 proteome to other bacterial proteomes.the proteins expressed by francisella tularensis subsp. novicida u112 grown to midexponential phase were surveyed by nanolc-tandem mass spectrometry (lc-ms/ms). to improve annotation of the genome and develop a technology to provide high-throughput analysis of the francisella proteome in multiple conditions, we sought to establish a fast and simple analysis that would reduce as much as possible the false discovery rate. our survey detected expression of 63.0% of the predicted proteome from the s ...200818380474
tularemia: current diagnosis and treatment options.tularemia is an infection caused by francisella tularensis with a worldwide distribution and diverse clinical manifestations. limitations in both culture and serologic testing have led to substantial research into new diagnostic techniques and their clinical application, with pcr testing as the best example. this review focuses on the utility of culture, pcr and serologic testing for tularemia. in addition, we also review the evidence to support different therapeutic options for tularemia, highl ...200818380605
ecoepidemiology of tularemia in the southcentral united states.we combined county-based data for tularemia incidence from 1990 to 2003 for a nine-state region (arkansas, illinois, indiana, kansas, kentucky, missouri, nebraska, oklahoma, and tennessee) in the southcentral united states with geographic information system (gis)-based environmental data to determine associations between coverage by different habitats (especially dry forest representing suitable tick habitat) and tularemia incidence. high-risk counties (> 1 case per 100,000 person-years) cluster ...200818385353
bioterrorism: class a agents and their potential presentations in immunocompromised patients.a bioterrorism attack would be particularly challenging for medical professionals caring for patients with cancer who often have weakened immune systems. knowledge of the class a agents and the potential variable presentations in immunocompromised patients is key to early recognition of an outbreak and prompt reporting. the purpose of this article is to present the class a agents: bacillus anthracis (anthrax), botulinum toxin (botulism), variola virus (smallpox), yersinia pestis (pneumonic plagu ...200818390465
utilization of fc receptors as a mucosal vaccine strategy against an intracellular bacterium, francisella tularensis.numerous studies have demonstrated that targeting ag to fc receptors (fcr) on apcs can enhance humoral and cellular immunity. however, studies are lacking that examine both the use of fcr-targeting in generating immune protection against infectious agents and the use of fcrs in the induction of mucosal immunity. francisella tularensis is a category a intracellular mucosal pathogen. thus, intense efforts are underway to develop a vaccine against this organism. we hypothesized that protection agai ...200818390739
acquisition of the vacuolar atpase proton pump and phagosome acidification are essential for escape of francisella tularensis into the macrophage cytosol.the francisella tularensis-containing phagosome (fcp) matures to a late-endosome-like phagosome prior to bacterial escape into the cytosols of macrophages, where bacterial proliferation occurs. our data show that within the first 15 min after infection of primary human monocyte-derived macrophages (hmdms), approximately 90% of the fcps acquire the proton vacuolar atpase (vatpase) pump and the lysomotropic dye lysotracker, which concentrates in acidic compartments, similar to phagosomes harboring ...200818390995
respiratory francisella tularensis live vaccine strain infection induces th17 cells and prostaglandin e2, which inhibits generation of gamma interferon-positive t cells.two key routes of francisella tularensis infection are through the skin and airway. we wished to understand how the route of inoculation influenced the primary acute adaptive immune response. we show that an intranasal inoculation of the f. tularensis live vaccine strain (lvs) with a 1,000-fold-smaller dose than an intradermal dose results in similar growth kinetics and peak bacterial burdens. in spite of similar bacterial burdens, we demonstrate a difference in the quality, magnitude, and kinet ...200818391003
recovery of francisella tularensis from soil samples by filtration and detection by real-time pcr and celisa.the aim of this study was to develop a specific and highly sensitive method able to detect very low concentrations of francisella tularensis in soil samples by real-time pcr (qpcr) with sybr green i. tul4 gene, which encodes the 17-kda protein (tul4) in f. tularensis strains, was amplified using a lightcycler (lc) device. we achieved a detection limit of 0.69 fg of genomic dna from f. tularensis subp. holarctica live vaccine strain (lvs), corresponding to a value less than 3.4 genome equivalents ...200818392279
susceptibility of 71 french isolates of francisella tularensis subsp. holarctica to eight antibiotics and accuracy of the etest method. 200818397924
respiratory infection with francisella novicida induces rapid dystrophic cardiac calcinosis (dcc).francisella tularensis causes pulmonary tularemia and death in humans when left untreated. here, using a novel aerosol infection model, we show that acute pulmonary francisella novicida infection not only causes pneumonia and liver damage, but also induces dystrophic cardiac calcinosis (dcc) in balb/c mice. c57bl/6 mice also develop pneumonia and hepatic damage, but fail to develop dcc. development of dcc in balb/c mice is associated with significant induction of rankl but not osteopontin in the ...200818400010
a high-throughput pipeline for designing microarray-based pathogen diagnostic assays.we present a methodology for high-throughput design of oligonucleotide fingerprints for microarray-based pathogen diagnostic assays. the oligonucleotide fingerprints, or dna microarray probes, are designed for identifying target organisms in environmental or clinical samples. the design process is implemented in a high-performance computing software pipeline that incorporates major algorithmic improvements over a previous version to both reduce computation time and improve specificity assessment ...200818402679
rapid comparative genomic analysis for clinical microbiology: the francisella tularensis paradigm.it is critical to avoid delays in detecting strain manipulations, such as the addition/deletion of a gene or modification of genes for increased virulence or antibiotic resistance, using genome analysis during an epidemic outbreak or a bioterrorist attack. our objective was to evaluate the efficiency of genome analysis in such an emergency context by using contigs produced by pyrosequencing without time-consuming finishing processes and comparing them to available genomes for the same species. f ...200818407970
initial delay in the immune response to francisella tularensis is followed by hypercytokinemia characteristic of severe sepsis and correlating with upregulation and release of damage-associated molecular patterns."francisella tularensis subsp. novicida" intranasal infection causes a rapid pneumonia in mice with mortality at 4 to 6 days with a low dose of bacteria (10(2) bacteria). the short time to death suggests that there is a failure of the innate immune response. as the neutrophil is often the first cell type to infiltrate sites of infection, we focused on the emigration of neutrophils in this infection, as well as cytokines involved in their recruitment. the results indicated that there was a signif ...200818411294
in vitro susceptibility of isolates of francisella tularensis types a and b from north america.due to concern that francisella tularensis, the causative agent of tularemia, may be used as a bioterrorist weapon, the clinical and laboratory standards institute recently provided a susceptibility testing method with breakpoints. here, 169 isolates (92 type a and 77 type b) from north america were tested against seven antimicrobial agents (streptomycin, gentamicin, tetracycline, doxycycline, ciprofloxacin, levofloxacin, and chloramphenicol) used for the treatment of tularemia. the mics for all ...200818411318
francisella tularensis invasion of lung epithelial cells.francisella tularensis, a gram-negative facultative intracellular bacterial pathogen, causes disseminating infections in humans and other mammalian hosts. macrophages and other monocytes have long been considered the primary site of f. tularensis replication in infected animals. however, recently it was reported that f. tularensis also invades and replicates within alveolar epithelial cells following inhalation in a mouse model of tularemia. tc-1 cells, a mouse lung epithelial cell line, were us ...200818426871
type iv pili in francisella tularensis: roles of pilf and pilt in fiber assembly, host cell adherence, and virulence.francisella tularensis, a highly virulent facultative intracellular bacterium, is the causative agent of tularemia. genome sequencing of all f. tularensis subspecies revealed the presence of genes that could encode type iv pili (tfp). the live vaccine strain (lvs) expresses surface fibers resembling tfp, but it was not established whether these fibers were indeed tfp encoded by the pil genes. we show here that deletion of the pilf putative tfp assembly atpase in the lvs resulted in a complete lo ...200818426883
cd4+ t cells are required during priming but not the effector phase of antibody-mediated ifn-gamma-dependent protective immunity against pulmonary francisella novicida infection.we have previously demonstrated the protective efficacy of intranasal vaccination with a defined francisella tularensis subsp. novicida deltaiglc mutant (kkf24) against pulmonary f. novicida u112 challenge. in this study, we further characterized the mechanisms of kkf24-induced immunity. intranasally vaccinated kkf24 c57bl/6 major histocompatibility class (mhc) class ii-/- mice produced minimal antigen-specific interferon (ifn)-gamma and serum antibodies and were highly susceptible (0% survival) ...200818427567
subversion of complement activation at the bacterial surface promotes serum resistance and opsonophagocytosis of francisella tularensis.francisella tularensis (ft) is resistant to serum but requires complement factor c3-derived opsonins for uptake by phagocytic cells and subsequent intracellular growth. in this study, we show that c3 fragments, deposited on ft, are detected by anti-c3d and -ic3b mab and that the classical and the alternative pathways are involved in this event. this was demonstrated using c2-depleted sera and specific inhibitors of the classical-versus-alternative pathways of complement activation. further, we d ...200818430786
[a small water-borne tularemia outbreak].the aim of this study was to investigate a small tularemia outbreak in a village of karamürsel county of kocaeli province (located in north-west part of turkey), between 22 january - 8 march 2005 and to present the anti-epidemic measures implemented. following diagnosis of oropharyngeal tularemia in two patients living in the same village, a field investigation was performed at this region. all patients have undergone physical examination. blood samples and if possible throat swabs and lymph nod ...200818444562
protection afforded against aerosol challenge by systemic immunisation with inactivated francisella tularensis live vaccine strain (lvs).balb/c mice were immunised with inactivated francisella tularensis live vaccine strain (lvs) and the level of protection afforded against aerosol challenge with virulent strains of f. tularensis ascertained. intramuscular (im) injection of inactivated lvs with an aluminium-hydroxide-based adjuvant-stimulated igg1-biased lvs-specific antibody responses and afforded no protection against aerosol challenge with subspecies holarctica (strain hn63). conversely, im injection of inactivated lvs adjuvan ...200817904793
genomic markers for differentiation of francisella tularensis subsp. tularensis a.i and a.ii strains.tularemia is caused by two subspecies of francisella tularensis, f. tularensis subsp. tularensis (type a) and f. tularensis subsp. holarctica (type b). f. tularensis subsp. tularensis is further subdivided into two genetically distinct populations (a.i and a.ii) that differ with respect to geographical location, anatomical source of recovered isolates, and disease outcome. using two human clinical isolates, suppression subtractive hybridization was performed to identify 13 genomic regions of dif ...200818024683
identification of immunologic and pathologic parameters of death versus survival in respiratory tularemia.francisella tularensis can cause severe disseminated disease after respiratory infection. the identification of factors involved in mortality or recovery following induction of tularemia in the mouse will improve our understanding of the natural history of this disease and facilitate future evaluation of vaccine candidate preparations. balb/c mice were infected intranasally with the live vaccine strain (lvs) of f. tularensis subsp. holarctica and euthanized at different stages of disease to anal ...200818025095
genetic elements for selection, deletion mutagenesis and complementation in francisella spp.francisella novicida is a gram-negative pathogen that can induce disease in mice that mimics human tularemia, and is nearly identical to francisella tularensis at the genomic level. in this work a number of antibiotic marker cassettes that incorporate a strong f. novicida promoter is constructed, which greatly enhances selection in f. novicida and f. tularensis. two low-copy plasmid vectors based on a broad-host-range plasmid, and an integrating vector have also been made, and these can be used ...200818021237
biohealthbase: informatics support in the elucidation of influenza virus host pathogen interactions and virulence.the biohealthbase bioinformatics resource center (brc) (http://www.biohealthbase.org) is a public bioinformatics database and analysis resource for the study of specific biodefense and public health pathogens-influenza virus, francisella tularensis, mycobacterium tuberculosis, microsporidia species and ricin toxin. the biohealthbase serves as an extensive integrated repository of data imported from public databases, data derived from various computational algorithms and information curated from ...200817965094
outbreak of tularemia: a case-control study and environmental investigation in turkey.the aim of this study was to identify the potential factors associated with infection sources and modes of transmission during a recent outbreak (october 2004) of tularemia in suluova, turkey.200817983789
rapid dissemination of francisella tularensis and the effect of route of infection.francisella tularensis subsp. tularensis is classified as a category a bioweapon that is capable of establishing a lethal infection in humans upon inhalation of very few organisms. however, the virulence mechanisms of this organism are not well characterized. francisella tularensis subsp. novicida, which is an equally virulent subspecies in mice, was used in concert with a micropet scanner to better understand its temporal dissemination in vivo upon intranasal infection and how such disseminatio ...200819068128
tularemia in germany: the tip of the iceberg?tularemia is a rare, notifiable zoonosis in germany. since november 2004, several lines of evidence including outbreaks in humans or animals and confirmed infections in indigenous hare and rodent populations have indicated a re-emergence of tularemia in different german federal states. unfortunately, reliable basic information on the seroprevalence in different geographical regions, permitting the identification of risk factors, does not exist. combining a sensitive screening assay with a highly ...200918808726
artificial plasmid engineered to simulate multiple biological threat agents.the objective of this study was to develop a non-virulent simulant to replace several virulent organisms during the development of detection and identification methods for biological threat agents. we identified and selected specific genes to detect yersinia pestis, francisella tularensis, burkholderia mallei, burkholderia pseudomallei, rickettsia sp., coxiella burnetii, brucella sp., enterohemorrhagic escherichia coli o157:h7, bacillus anthracis, and variola (smallpox) virus. we then designed a ...200918923830
classification of select category a and b bacteria by fourier transform infrared spectroscopy.fourier transform infrared (ft-ir) spectroscopy historically is a powerful tool for the taxonomic classification of bacteria by genus, species, and strain when they are grown under carefully controlled conditions. relatively few reports have investigated the determination and classification of pathogens such as the national institute of allergy and infectious diseases (niaid) category a bacillus anthracis spores and cells (ba), yersinia species, francisella tularensis (ft), and category b brucel ...200919146715
glutathione provides a source of cysteine essential for intracellular multiplication of francisella tularensis.francisella tularensis is a highly infectious bacterium causing the zoonotic disease tularemia. its ability to multiply and survive in macrophages is critical for its virulence. by screening a bank of himarft transposon mutants of the f. tularensis live vaccine strain (lvs) to isolate intracellular growth-deficient mutants, we selected one mutant in a gene encoding a putative gamma-glutamyl transpeptidase (ggt). this gene (ftl_0766) was hence designated ggt. the mutant strain showed impaired int ...200919158962
biosynthesis of undecaprenyl phosphate-galactosamine and undecaprenyl phosphate-glucose in francisella novicida.lipid a of francisella tularensis subsp. novicida contains a galactosamine (galn) residue linked to its 1-phosphate group. as shown in the preceding paper, this galn unit is transferred to lipid a from the precursor undecaprenyl phosphate-beta-d-galn. a small portion of the free lipid a of francisella novicida is further modified with a glucose residue at position-6'. we now demonstrate that the two f. novicida homologues of escherichia coli arnc, designated flmf1 and flmf2, are essential for li ...200919166326
identification of undecaprenyl phosphate-beta-d-galactosamine in francisella novicida and its function in lipid a modification.francisella tularensis is a highly infectious pathogen that causes tularemia. francisella lipid a contains an unusual galactosamine (galn) unit, attached to its 1-phosphate moiety. two genes, flmf2 and flmk, are required for the addition of galn to francisella lipid a, but the relevant enzymes and the galn donor substrate have not been characterized. we now report the purification and identification of a novel minor lipid from francisella novicida that functions as the galn donor. on the basis o ...200919166327
francisella tularensis infection-derived monoclonal antibodies provide detection, protection, and therapy.francisella tularensis is the causative agent of tularemia and a potential agent of biowarfare. as an easily transmissible infectious agent, rapid detection and treatment are necessary to provide a positive clinical outcome. as an agent of biowarfare, there is an additional need to prevent infection. we made monoclonal antibodies to the f. tularensis subsp. holarctica live vaccine strain (f. tularensis lvs) by infecting mice with a sublethal dose of bacteria and, following recovery, by boosting ...200919176692
elevation of francisella philomiragia subsp. noatunensis mikalsen et al. (2007) to francisella noatunensis comb. nov. [syn. francisella piscicida ottem et al. (2008) syn. nov.] and characterization of francisella noatunensis subsp. orientalis subsp. nov., two important fish pathogens.this study was conducted to clarify the taxonomic status of francisella sp. strain ehime-1, a fish pathogen, in relation to the fish pathogens f. piscicida and f. philomiragia subsp. noatunensis and to f. philomiragia subsp. philomiragia.200919187160
short report: time course of hematogenous dissemination of francisella tularensis a1, a2, and type b in laboratory mice.tularemia is a tick-borne zoonotic bacterial disease. in the united states, human tularemia infections are caused by francisella tularensis subspecies tularensis (type a, clades a1 and a2) or f. tularensis subspecies holarctica (type b). we developed a mouse model that can be used to study the ability of ticks to acquire and transmit fully virulent strains of f. tularensis (a1, a2, and type b). we showed that 1) bacteremia was evident by 2 days post-infection (dpi) for a1, a2, and b, 2) bacterem ...200919190224
evaluation of ultrafiltration cartridges for a water sampling apparatus.to determine the efficiency of various ultrafiltration cartridges (ufc) in concentrating test micro-organisms from drinking water.200919191977
a tularemia outbreak in an extended family in tokat province, turkey: observing the attack rate of tularemia.we report the first tularemia epidemic occurring in tokat province, located in the middle black sea region of turkey, and some features of the cases. this epidemic has allowed the calculation of the attack rate of this disease because of its appearance in a single large family.200919195917
phylogenomics and protein signatures elucidating the evolutionary relationships among the gammaproteobacteria.the class gammaproteobacteria, which forms one of the largest groups within bacteria, is currently distinguished from other bacteria solely on the basis of its branching in phylogenetic trees. no molecular or biochemical characteristic is known that is unique to the class gammaproteobacteria or its different subgroups (orders). the relationship among different orders of gammaproteobacteria is also not clear. in this study, we present detailed phylogenomic and comparative genomic analyses on gamm ...200919196760
a conserved alpha-helix essential for a type vi secretion-like system of francisella tularensis.francisella tularensis harbors genes with similarity to genes encoding components of a type vi secretion system (t6ss) recently identified in several gram-negative bacteria. these genes include igla and iglb encoding igla and iglb, homologues of which are conserved in most t6sss. we used a yeast two-hybrid system to study the interaction of the igl proteins of f. tularensis lvs. we identified a region of igla, encompassing residues 33 to 132, necessary for efficient binding to iglb, as well as f ...200919201795
the effect of open-air factors on the virulence and viability of airborne francisella tularensis.unidentified open-air factors (oafs) found to be adverse to the survival of microorganisms suspended on microthreads were investigated for their effect on realistic aerosols of francisella tularensis in an open-air environment. this organism was chosen because it is probably the most infectious organism known to be capable of infecting both animals and man via the respiratory route, hence its potential use as a bioterrorist agent. a direct correlation was found between an open-air adverse effect ...200919203408
francisella tularensis genes required for inhibition of the neutrophil respiratory burst and intramacrophage growth identified by random transposon mutagenesis of strain lvs.francisella tularensis is a facultative intracellular pathogen and the causative agent of tularemia. we have shown that f. tularensis subspecies holarctica strain lvs prevents nadph oxidase assembly and activation in human neutrophils, but how this is achieved is unclear. herein, we used random transposon mutagenesis to identify lvs genes that affect neutrophil activation. our initial screen identified cara, carb, and pyrb, which encode the small and large subunits of carbamoylphosphate synthase ...200919204089
nicotinamide mononucleotide synthetase is the key enzyme for an alternative route of nad biosynthesis in francisella tularensis.enzymes involved in the last 2 steps of nicotinamide adenine dinucleotide (nad) cofactor biosynthesis, which catalyze the adenylylation of the nicotinic acid mononucleotide (namn) precursor to nicotinic acid dinucleotide (naad) followed by its amidation to nad, constitute promising drug targets for the development of new antibiotics. these enzymes, namn adenylyltransferase (gene nadd) and nad synthetase (gene nade), respectively, are indispensable and conserved in nearly all bacterial pathogens. ...200919204287
inactivation of yersinia pseudotuberculosis 197 and francisella tularensis lvs in beverages by high pressure processing.in 2003, the u.s. department of health and human services announced a new research program to develop technologies and strategies to prevent and minimize potential food safety and security threats. the threat of terrorist attacks against the nation's food supplies has created the need to study microorganisms not typically associated with foodborne illness. high-pressure processing has been proposed as a treatment to reduce yersinia pestis and francisella tularensis lvs levels in beverages. the o ...200919205479
slow-onset inhibition of the fabi enoyl reductase from francisella tularensis: residence time and in vivo activity.francisella tularensis is a highly virulent and contagious gram-negative intracellular bacterium that causes the disease tularemia in mammals. the high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment have raised the possibility that this organism could be exploited deliberately as a potential biological weapon. fatty acid biosynthesis (fas-ii) is essential for bacterial viability and has been validated as a target for the discovery of novel antibact ...200919206187
a bayesian integration model of high-throughput proteomics and metabolomics data for improved early detection of microbial infections.high-throughput (htp) technologies offer the capability to evaluate the genome, proteome, and metabolome of an organism at a global scale. this opens up new opportunities to define complex signatures of disease that involve signals from multiple types of biomolecules. however, integrating these data types is difficult due to the heterogeneity of the data. we present a bayesian approach to integration that uses posterior probabilities to assign class memberships to samples using individual and mu ...200919209722
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