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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
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
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
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
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
the inflammasome: a key player in the inflammation triggered in response to bacterial pathogens. 200818354318
mast cells inhibit intramacrophage francisella tularensis replication via contact and secreted products including il-4.francisella tularensis is an intracellular, gram-negative bacterium that is the causative agent of pulmonary tularemia. the pathogenesis and mechanisms related to innate resistance against f. tularensis are not completely understood. mast cells are strategically positioned within mucosal tissues, the major interface with the external environment, to initiate innate responses at the site of infection. mast cell numbers in the cervical lymph nodes and the lungs progressively increased as early as ...200818591675
the membrane form of tumor necrosis factor is sufficient to mediate partial innate immunity to francisella tularensis live vaccine strain.here we characterize francisella tularensis live vaccine strain (lvs) infection in total tumor necrosis factor (tnf) knockout (ko) mice and in transgenic mice expressing only the membrane form of tnf (memtnf). memtnf mice, but not tnf ko mice, survived low-dose, sublethal lvs infections. splenic nitric oxide production was impaired in infected memtnf mice and was absent in infected tnf ko mice. spleen cell production of interferon-gamma, rantes, and monocyte chemotactic protein-1 was elevated in ...200818593295
characterization of the francisella tularensis subsp. novicida type iv pilus.francisella tularensis causes the disease tularaemia. type iv pili (tfp) genes are present in the genomes of all f. tularensis subspecies. we show that the wild-type f. tularensis subsp. novicida expresses pilus fibres on its surface, and mutations in the tfp genes pilf and pilt disrupt pilus biogenesis. mutations in other tfp genes (pilq and pilg) do not eliminate pilus expression. a mutation in pile4 eliminates pilus expression, whereas mutations in the other pilin subunits pile1-3 and pile5 d ...200818599841
detection of a novel francisella in dermacentor reticulatus: a need for careful evaluation of pcr-based identification of francisella tularensis in eurasian ticks.francisella tularensis, the causative agent of tularemia, has been detected in ixodid ticks in some regions of north america, europe, and asia. in the present study, 245 dermacentor reticulatus, 211 ixodes ricinus, and 194 haemaphysalis concinna adults from hungary were tested for the presence of f. tularensis by polymerase chain reaction (pcr) assays based on 16s ribosomal rna (16s rdna) and t-cell epitope of a francisella membrane protein (tul4). no francisella-specific amplification products ...200818945184
tularemia in range sheep: an overlooked syndrome?abortion and death caused by francisella tularensis were well recognized in range flocks of domestic sheep in idaho, montana, and wyoming in the first 6 decades of the 20th century. the current report describes 4 episodes of tularemia in 3 range flocks in wyoming and south dakota in 1997 and 2007 (1 flock was affected twice). flock owners reported that ticks were unusually numerous and commonly present on sheep during outbreaks. tularemia presented as late-term abortions (3 episodes) or listless ...200818599860
generation and characterization of an attenuated mutant in a response regulator gene of francisella tularensis live vaccine strain (lvs).francisella tularensis is a zoonotic bacterium that must exist in diverse environments ranging from arthropod vectors to mammalian hosts. to better understand how virulence genes are regulated in these different environments, a transcriptional response regulator gene (genome locus ftl0552) was deleted in f. tularensis live vaccine strain (lvs). the ftl0552 deletion mutant exhibited slightly reduced rates of extracellular growth but was unable to replicate or survive in mouse macrophages and was ...200818613792
combating the threat of anthrax: a quantitative structure-activity relationship approach.bacterial agents or products more likely to be used as biological weapons of mass destruction are bacillus anthracis, francisella tularensis, yersinia pestis, and the neurotoxin of clostridium botulinum. anthrax is an acute infectious disease with a high mortality rate caused by bacillus anthracis, reinforcing the need for better adjunctive therapy and prevention strategies. in this paper, we developed 7 qsar models on penicillin-based inhibitors of the class a and b beta-lactamases from b. anth ...200818611038
antimicrobial activity of human beta-defensins and induction by francisella.the ability of human beta-defensins hbd-1, hbd-2, and hbd-3 to exert direct in vitro antimicrobial effects was evaluated using francisella tularensis live vaccine strain (lvs) and francisella novicida. while hbd-2 showed some antimicrobial activity in these assays, only hbd-3 demonstrated significant potency against francisella. francisella tularensis lvs infection induced elevated levels of hbd-2 mrna in human airway epithelial (a549) cells, while having no significant impact on the levels of h ...200818452706
neisseria meningitidis porb, a toll-like receptor 2 ligand, improves the capacity of francisella tularensis lipopolysaccharide to protect mice against experimental tularemia.francisella tularensis causes severe pneumonia that can be fatal if it is left untreated. due to its potential use as a biological weapon, research is being conducted to develop an effective vaccine and to select and study adjuvant molecules able to generate a better and long-lasting protective effect. porb, a porin from neisseria meningitidis, is a well-established toll-like receptor 2 ligand and has been shown to be a promising vaccine adjuvant candidate due to its ability to enhance the t-cel ...200818614668
a bioinformatic approach to understanding antibiotic resistance in intracellular bacteria through whole genome analysis.intracellular bacteria survive within eukaryotic host cells and are difficult to kill with certain antibiotics. as a result, antibiotic resistance in intracellular bacteria is becoming commonplace in healthcare institutions. owing to the lack of methods available for transforming these bacteria, we evaluated the mechanisms of resistance using molecular methods and in silico genome analysis. the objective of this review was to understand the molecular mechanisms of antibiotic resistance through i ...200818619818
francisella tularensis: unravelling the secrets of an intracellular pathogen.francisella tularensis has been recognized as the causative agent of tularaemia for almost a century. since its discovery in 1911, it has been shown to infect a wide range of hosts, including humans. as early as the 1920s it was suggested to be an intracellular pathogen, but it has proven to be an enigmatic organism, whose interaction with the host has been difficult to elucidate, and we still have a very limited understanding of the molecular mechanisms of virulence. however, the recent availab ...200818628490
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
macrophage proinflammatory response to francisella tularensis live vaccine strain requires coordination of multiple signaling pathways.the macrophage proinflammatory response to francisella tularensis (ft) live vaccine strain (lvs) was shown previously to be tlr2 dependent. the observation that intracellular ft lvs colocalizes with tlr2 and myd88 inside macrophages suggested that ft lvs might signal from within the phagosome. macrophages infected with lvsdeltaiglc, a ft lvs mutant that fails to escape from the phagosome, displayed greatly increased expression of a subset of tlr2-dependent, proinflammatory genes (e.g., tnf) but ...200818453609
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
seroprevalence study of francisella tularensis among hunters in germany.in 2005 and 2006, francisella tularensis unexpectedly reemerged in western germany, when several semi-free-living marmosets (callithrix jacchus) in a research facility died from tularemia and a group of hare hunters became infected. it is believed that hunters may have an elevated risk to be exposed to zoonotic pathogens, including f. tularensis. a previous cross-sectional study of the german population (n=6883) revealed a prevalence of 0.2%. here, we investigated 286 sera from individuals mainl ...200818462387
the francisella pathogenicity island protein pdpd is required for full virulence and associates with homologues of the type vi secretion system.francisella tularensis is a highly infectious, facultative intracellular bacterial pathogen that is the causative agent of tularemia. nearly a century ago, researchers observed that tularemia was often fatal in north america but almost never fatal in europe and asia. the chromosomes of f. tularensis strains carry two identical copies of the francisella pathogenicity island (fpi), and the fpis of north america-specific biotypes contain two genes, anmk and pdpd, that are not found in biotypes that ...200818469101
mgla and igl proteins contribute to the modulation of francisella tularensis live vaccine strain-containing phagosomes in murine macrophages.the francisella tularensis live vaccine strain (lvs), in contrast to its iglc mutant, replicates in the cytoplasm of macrophages. we studied the outcome of infection of the murine macrophagelike cell line j774a.1 with lvs and with iglc, igld, and mgla mutants, the latter of which is deficient in a global regulator. compared to lvs, all of the mutants showed impaired intracellular replication up to 72 h, and the number of the mgla mutant bacteria even decreased. colocalization with lamp-1 was sig ...200818474647
occurrence of francisella piscicida in farmed and wild atlantic cod, gadus morhua l., in norway.francisellosis, caused by the bacterium francisella piscicida, has become one of the most serious diseases in atlantic cod production in norway. the major aim of this study was to determine the distribution of f. piscicida in farmed and wild fish in areas with cod farming along the norwegian coast, and its occurrence in cod from areas without cod farming. two real-time pcr assays, targeting the 16s rrna gene and the fopa gene of f. piscicida, were developed since sensitive and specific diagnosti ...200818482383
administration of a synthetic tlr4 agonist protects mice from pneumonic tularemia.francisella tularensis is a gram-negative intracellular pathogen that causes the zoonosis tularemia. because f. tularensis lps causes weak tlr4 activation, we hypothesized that administration of a synthetic tlr4 agonist, aminoalkyl glucosaminide phosphate (agp), would boost the innate immune system and compensate for reduced tlr4 stimulation. intranasal administration of agps induced intrapulmonary production of proinflammatory cytokines and chemokines. mice treated with agps before and after in ...200818490759
isolation and characterization of a novel francisella sp. from human cerebrospinal fluid and blood.we describe the isolation of a francisella sp. from normally sterile sites in acutely ill patients in two different states within 2 years. microbiologic and molecular analyses indicate that this organism represents a novel francisella sp. clinicians and microbiologists should be aware of this new potential pathogen, as infection may be more common than recognized.200818495864
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
native outer membrane proteins protect mice against pulmonary challenge with virulent type a francisella tularensis.francisella tularensis is a gram-negative intracellular bacterium and the causative agent of the zoonotic disease tularemia. f. tularensis is a category a select agent and thus a potential agent of bioterrorism. whereas an f. tularensis live, attenuated vaccine strain (lvs) is the basis of an investigational vaccine, this vaccine is not licensed for human use because of efficacy and safety concerns. in the present study, we immunized mice with isolated native outer membrane proteins (omps), etha ...200818505805
tularemia in a park, philadelphia, pennsylvania. 200818760026
microfluidic-based cell sorting of francisella tularensis infected macrophages using optical forces.we have extended the principle of optical tweezers as a noninvasive technique to actively sort hydrodynamically focused cells based on their fluorescence signal in a microfluidic device. this micro fluorescence-activated cell sorter (microfacs) uses an infrared laser to laterally deflect cells into a collection channel. green-labeled macrophages were sorted from a 40/60 ratio mixture at a throughput of 22 cells/s over 30 min achieving a 93% sorting purity and a 60% recovery yield. to rule out po ...200818510341
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
francisella gains a survival advantage within mononuclear phagocytes by suppressing the host ifngamma response.tularemia is a zoonotic disease caused by the gram-negative intracellular pathogen francisella tularensis. these bacteria evade phagolysosomal fusion, escape from the phagosome and replicate in the host cell cytoplasm. ifngamma has been shown to suppress the intra-macrophage growth of francisella through both nitric oxide-dependent and -independent pathways. since francisella is known to subvert host immune responses, we hypothesized that this pathogen could interfere with ifngamma signaling. he ...200818514317
francisella targets cholesterol-rich host cell membrane domains for entry into macrophages.francisella tularensis is a pathogen optimally adapted to efficiently invade its respective host cell and to proliferate intracellularly. we investigated the role of host cell membrane microdomains in the entry of f. tularensis subspecies holarctica vaccine strain (f. tularensis live vaccine strain) into murine macrophages. f. tularensis live vaccine strain recruits cholesterol-rich lipid domains ("lipid rafts") with caveolin-1 for successful entry into macrophages. interference with lipid rafts ...200818523292
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
interaction of b cells with intracellular pathogen francisella tularensis.immunity to francisella tularensis is largely mediated by t lymphocytes but an important role of b lymphocytes in early stage of infection was previously uncovered. we wanted to find out if f. tularensis is able to infect b cells and/or influence them by direct contact. to investigate this possibility we infected b cell lines from mouse (a20) or humans (ramos ra-1), or primary mouse spleen cells, with f. tularensis lvs and f. tularensis fsc200 in vitro. in all cases, we detected bacteria on the ...200818524531
inhalation of francisella novicida delta mgla causes replicative infection that elicits innate and adaptive responses but is not protective against invasive pneumonic tularemia.francisella tularensis causes the zoonosis tularemia in humans, and inhaled f. tularensis ssp. novicida induces lethal murine tularemia. transcription of virulence factors in f. novicida is regulated by macrophage growth locus a (mgla), a global regulator required for bacterial replication in macrophages in vitro. we examined the infectivity and immunogenicity of attenuated f. novicida delta mgla in the lung in vivo. aerosolized delta mgla caused replicative pulmonary infection that peaked at 7 ...200818539500
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
borrelia burgdorferi sensu lato, anaplasma phagocytophilum, francisella tularensis and their co-infections in host-seeking ixodes ricinus ticks collected in serbia.to evaluate the prevalence rate of tick-borne bacterial pathogens, unfed adult ixodes ricinus ticks were collected from vegetation in 2001, 2003, and 2004 at 18 localities throughout serbia. a total of 287 ticks were examined by pcr technique for the presence of borrelia burgdorferi sensu lato, anaplasma phagocytophilum, and francisella tularensis. the highest prevalence rate was that for b. burgdorferi sensu lato (42.5%), followed by a. phagocytophilum (13.9%) and f. tularensis (3.8%). the pres ...200818551370
pericardial effusion as the only manifestation of infection with francisella tularensis: a case report.francisella tularensis, a facultative intracellular gram-negative bacterium, has rarely been reported as an agent of pericarditis, generally described as a complication of tularemia sepsis. f. tularensis is a fastidious organism that grows poorly on standard culture media and diagnosis is usually based on serological tests. however, cross-reactions may occur. western blotting allows the correct diagnosis.200818554395
identification of fevr, a novel regulator of virulence gene expression in francisella novicida.francisella tularensis infects wild animals and humans to cause tularemia. this pathogen targets the cytosol of macrophages, where it replicates using the genes in the francisella pathogenicity island (fpi). virulence gene regulation in francisella is complex, but transcriptional regulators mgla and sspa have been shown to regulate the expression of approximately 100 genes, including the entire fpi. we utilized a francisella novicida transposon mutant library to identify additional regulatory fa ...200818559431
kinetics of the immune response associated with tularemia: comparison of an enzyme-linked immunosorbent assay, a tube agglutination test, and a novel whole-blood lymphocyte stimulation test.we have developed and evaluated a novel and simplified whole-blood lymphocyte stimulation assay that focuses on the measurement of gamma interferon after 24 h of stimulation with whole-cell tularemia antigen and a tularemia enzyme-linked immunosorbent assay (elisa) based on highly purified lipopolysaccharide antigen. comparison of the kinetics of the two assays and those of the traditional tube agglutination test shows that the cellular immune response can be detected earlier by the lymphocyte s ...200818562568
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
characterization of fig operon mutants of francisella novicida u112.francisella species secrete a polycarboxylate siderophore that resembles rhizoferrin to acquire ferric iron. several of the francisella siderophore synthesis genes are contained in a fur-regulated operon (designated fig or fsl) comprised of at least seven orfs including fur. reverse transcriptase-pcr showed transcriptional linkage between figd and fige and between fige and figf. mutations were constructed in four of these orfs (figb, figc, figd, and fige) in francisella novicida u112. all four o ...200818564336
a francisella tularensis schu s4 purine auxotroph is highly attenuated in mice but offers limited protection against homologous intranasal challenge.francisella tularensis is a gram-negative coccobacillus that causes the febrile illness tularemia. subspecies that are pathogenic for humans include those comprising the type a (subspecies tularensis) or type b (subspecies holarctica) biovars. an attenuated live vaccine strain (lvs) developed from a type b isolate has previously been used to vaccinate at-risk individuals, but offers limited protection against high dose (>1000 cfus) challenge with type a strains delivered by the respiratory route ...200818575611
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
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
francisella tularensis subsp. tularensis schu s4 disulfide bond formation protein b, but not an rnd-type efflux pump, is required for virulence.francisella tularensis subsp. tularensis is a highly virulent bacterium that is a cdc select agent. despite advancements in the understanding of its biology, details pertaining to virulence are poorly understood. in previous work, we identified a transposon insertion mutant in the ftt0107c locus that was defective in intracellular survival in hepg2 and j77a.1 cells. here, we report that this mutant was also highly attenuated in vivo. the ftt0107c locus is predicted to encode an ortholog of the d ...200818458069
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
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
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
combined deletion of four francisella novicida acid phosphatases attenuates virulence and macrophage vacuolar escape.francisella tularensis is a facultative intracellular pathogen and the etiologic agent of tularemia. it is capable of escape from macrophage phagosomes and replicates in the host cell cytosol. bacterial acid phosphatases are thought to play a major role in the virulence and intracellular survival of a number of intracellular pathogens. the goal of this study was to delete the four primary acid phosphatases (acps) from francisella novicida and examine the interactions of mutant strains with macro ...200818490464
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
[bubonic tularemia: diagnosis and therapy]. 200818491581
tularemia with vesicular skin lesions may be mistaken for infection with herpes viruses.the original reports of human infection with francisella tularensis noted vesicular skin rash as a manifestation. we present 2 cases of tularemia initially diagnosed as herpes simplex or varicella zoster infection. clinicians must recognize the cutaneous manifestations of tularemia and be able to distinguish these from lesions seen with herpes viruses.200818491968
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
characteristics of the turkish isolates of francisella tularensis.in this study, cultures of patients with tularemia were evaluated, and antimicrobial susceptibilities of two francisella tularensis strains were tested by disk diffusion and e-test methods. a high-resolution multiple-locus variable-number tandem repeat analysis (mlva) comprising six variable-number tandem repeat loci was applied to elucidate the genetic relatedness among turkish and bulgarian isolates which were isolated in a recent outbreak. the patients were diagnosed in two outbreaks in two c ...200818503176
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
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
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
fsle is necessary for siderophore-mediated iron acquisition in francisella tularensis schu s4.strains of francisella tularensis secrete a siderophore in response to iron limitation. siderophore production is dependent on fsla, the first gene in an operon that appears to encode biosynthetic and export functions for the siderophore. transcription of the operon is induced under conditions of iron limitation. the fsl genes lie adjacent to the fur homolog on the chromosome, and there is a canonical fur box sequence in the promoter region of fsla. we generated a deltafur mutant of the schu s4 ...200818539739
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
[phagocytic functional and metabolic activities in the interaction with f. tularensis subspecies of various virulence].there is evidence that the facultatively intracellular pathogen affects the functional capacity of phagocytes, which is associated with their bactericidal against a tularemic microbe with varying phenotypic properties. the tularemic microbe of the subspecies francisella subsp. tularensis and f. tularensis subsp. mediaasiatica is shown to influence the phagocytic capacity of immunocompetent cells, resulting in incomplete phagocytosis. this is corroborated by the lower functional activity of neutr ...200818557359
genetic diversity of francisella tularensis subspecies holarctica strains isolated in japan.the recently developed mlva has high discriminatory power for the typing of individual strains or isolates of francisella tularensis. in the present study, mlva was applied to 33 japanese f. tularensis subspecies holarctica strains to examine the genetic diversity of f. tularensis isolated. among the seven vntr loci analyzed, ft-m2, ft-m10, and ft-m20 loci showed high genetic polymorphism in japanese strains, whereas ft-m3 was most variable in non-japanese strains. these results provide novel ex ...200818557897
application of carbohydrate microarray technology for the detection of burkholderia pseudomallei, bacillus anthracis and francisella tularensis antibodies.we developed a microarray platform by immobilizing bacterial 'signature' carbohydrates onto epoxide modified glass slides. the carbohydrate microarray platform was probed with sera from non-melioidosis and melioidosis (burkholderia pseudomallei) individuals. the platform was also probed with sera from rabbits vaccinated with bacillus anthracis spores and francisella tularensis bacteria. by employing this microarray platform, we were able to detect and differentiate b. pseudomallei, b. anthracis ...200818558401
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
multiplex pathogen detection based on spatially addressable microarrays of barcoded resins.suspension microsphere immunoassays are rapidly gaining recognition in antigen identification and infectious disease biodetection due to their simplicity, versatility and high-throughput multiplex screening. we demonstrate a multiplex assay based on antibody-functionalized barcoded resins (bcrs) to identify pathogen antigens in complex biological fluids. the binding event of a particular antibody on given bead (fluorescence) and the identification of the specific pathogen agent (vibrational fing ...200818566958
diverse myeloid and lymphoid cell subpopulations produce gamma interferon during early innate immune responses to francisella tularensis live vaccine strain.francisella tularensis, a small gram-negative intracellular bacterium responsible for causing tularemia, is highly pathogenic and classified as a category a agent of bioterrorism. as for other intracellular pathogens, successful protective immune responses to francisella tularensis require rapid and efficient induction of gamma interferon (ifn-gamma) production. studies using intracellular bacteria such as listeria monocytogenes as well as francisella suggest that natural killer (nk) and t cells ...200818573901
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
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
outsmarting the host: bacteria modulating the immune response.pathogenic bacteria and their hosts have had a two-way conversation for millions of years. this interaction has led to many measure/counter-measure responses by the host and bacteria. the host immune response has developed many mechanisms to neutralize and remove pathogen bacteria. in turn pathogenic bacteria have developed mechanisms to alter and evade the host immune response. we will review some of the mechanisms utilized by bacteria to accomplish this goal. we will also examine the current s ...200818592144
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
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
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
persistence of category a select agents in the environment. 200818065629
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
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
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
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
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
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
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
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
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
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
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