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coexistence of pathogens in host-seeking and feeding ticks within a single natural habitat in central germany.the importance of established and emerging tick-borne pathogens in central and northern europe is steadily increasing. in 2007, we collected ixodes ricinus ticks feeding on birds (n = 211) and rodents (n = 273), as well as host-seeking stages (n = 196), in a habitat in central germany. in order to find out more about their natural transmission cycles, the ticks were tested for the presence of lyme disease borreliae, anaplasma phagocytophilum, spotted fever group (sfg) rickettsiae, francisella tu ...201020729315
systems approach to investigating host-pathogen interactions in infections with the biothreat agent francisella. constraints-based model of francisella tularensis.francisella tularensis is a prototypic example of a pathogen for which few experimental datasets exist, but for which copious high-throughout data are becoming available because of its re-emerging significance as biothreat agent. the virulence of francisella tularensis depends on its growth capabilities within a defined environmental niche of the host cell.201020731870
escherichia coli mutants that synthesize dephosphorylated lipid a molecules.the lipid a moiety of escherichia coli lipopolysaccharide is a hexaacylated disaccharide of glucosamine that is phosphorylated at the 1 and 4' positions. expression of the francisella novicida lipid a 1-phosphatase fnlpxe in e. coli results in dephosphorylation of the lipid a proximal unit. coexpression of fnlpxe and the rhizobium leguminosarum lipid a oxidase rllpxq in e. coli converts much of the proximal glucosamine to 2-amino-2-deoxygluconate. expression of the f. novicida lipid a 4'-phospha ...201020795687
the type iv pilin, pila, is required for full virulence of francisella tularensis subspecies tularensis.all four francisella tularensis subspecies possess gene clusters with potential to express type iv pili (tfp). these clusters include putative pilin genes, as well as pilb, pilc and pilq, required for secretion and assembly of tfp. a hallmark of tfp is the ability to retract the pilus upon surface contact, a property mediated by the atpase pilt. interestingly, out of the two major human pathogenic subspecies only the highly virulent type a strains have a functional pilt gene.201020796283
3-deoxy-d-manno-octulosonic acid (kdo) hydrolase identified in francisella tularensis, helicobacter pylori, and legionella pneumophila.3-deoxy-d-manno-octulosonic acid (kdo) is an eight-carbon sugar ubiquitous in gram-negative bacterial lipopolysaccharides (lps). although its biosynthesis is well described, no protein has yet been identified as a kdo hydrolase. however, kdo hydrolase enzymatic activity has been detected in membranes of helicobacter pylori and francisella tularensis and may be responsible for the removal of side-chain kdo from the lps core saccharides. we now report the identification of genes encoding a kdo hyd ...201020801884
transmission dynamics of francisella tularensis subspecies and clades by nymphal dermacentor variabilis (acari: ixodidae).in the united states, the american dog tick, dermacentor variabilis (say) is considered an important biological vector of francisella tularensis, the etiologic agent of tularemia. in this study, we evaluated the vector efficiency of nymphal d. variabilis infected as larvae with differing clades and subspecies (a1b, a2, and type b) of f. tularensis. in all cases, d. variabilis larvae were able to acquire, maintain, and transstadially transmit f. tularensis. significant replication of the bacteria ...201020810833
matrix-assisted laser desorption ionization time-of-flight mass spectrometry: usefulness for taxonomy and epidemiology.matrix-assisted laser desorption ionization time-of-flight (maldi-tof) mass spectrometry (ms) is a powerful tool for the species and subspecies classification of a broad spectrum of bacteria, including gram-positive bacteria such as staphylococcus, streptococcus and listeria, and gram-negative bacteria such as neisseria, salmonella, aeromonas, campylobacter and helicobacter. maldi-tof ms has also been used for the rapid identification and typing of potential bioterrorism agents, including coxiel ...201020825435
phenotypic and genetic characterization of macrolide resistance in francisella tularensis subsp. holarctica biovar i.francisella tularensis subsp. holarctica strains are classified as biovars i and ii, which are susceptible and naturally resistant to the macrolide erythromycin, respectively. the present study was aimed at both selecting biovar i strains with increased levels of erythromycin resistance and characterizing the underlying genetic mechanisms.201020837574
versatile set of orthogonal protecting groups for the preparation of highly branched oligosaccharides.a new set of orthogonal protecting groups has been developed based on the use of a diethylisopropylsilyl (deips), methylnaphthyl (nap), allyl ether, and levulinoyl (lev) ester. the protecting groups are ideally suited for the preparation of highly branched oligosaccharides and their usefulness has been demonstrated by the chemical synthesis of a β-d-man-(1→4)-d-man disaccharide, which is appropriately protected for making a range of part-structures of the unusual core region of the lipopolysacch ...201020845911
monitoring the survival of fish-pathogenic francisella in water microcosms.in this report, the survival behaviour of fish pathogenic francisella in water microcosms was investigated under laboratory conditions. two isolates of francisella noatunensis (ncimb14265(t) and pq 1106), from fish held in seawater and freshwater, were inoculated into natural (nonsterile) and sterile sea- and freshwater microcosms, respectively, and monitored under different temperature conditions (4, 8 and 12 °c) over a period of 60 days. the culturability of the strains was inversely related t ...201020977492
determination of francisella tularensis acpb acid phosphatase substrate preferences.the francisella species encode 4 main acid phosphatases (acp) that are potentially involved in pathogenesis through currently unknown mechanisms. only 2 of these enzymes, acpa and acpc, have been biochemically characterized to date. in this work we describe the catalytic properties of francisella tularensis acpb utilizing an array of 120 phosphorylated substrates. in contrast to most acid phosphatases, the purified enzyme showed a narrow range of substrate preferences, with the highest affinity ...201021042033
structure of the francisella tularensis enoyl-acyl carrier protein reductase (fabi) in complex with nad(+) and triclosan.enoyl-acyl carrier protein reductase (fabi) catalyzes the last rate-limiting step in the elongation cycle of the fatty-acid biosynthesis pathway and has been validated as a potential antimicrobial drug target in francisella tularensis. the development of new antibiotic therapies is important both to combat potential drug-resistant bioweapons and to address the broader societal problem of increasing antibiotic resistance among many pathogenic bacteria. the crystal structure of fabi from f. tulare ...201021045289
comparative proteomic profiling of culture filtrate proteins of less and highly virulent francisella tularensis strains.the facultative intracellular bacterium francisella tularensis is the causal agent of the serious infectious disease tularemia. despite the dynamic progress, which has been made in last few years, important questions regarding francisella pathogenicity still remain to be answered. generally, secreted proteins play an important role in pathogenicity of intracellular microbes. in this study, we investigated the protein composition of the culture filtrate proteins of highly virulent f. tularensis s ...201021061425
[an oropharyngeal tularemia case diagnosed by the isolation of francisella tularensis on human blood agar].tularemia which is a multisystem disease of humans and some animals, is endemic in north america, some parts of europe and asia. the causative agent, francisella tularensis, is a fastidious gram-negative, intracellular bacterium which requires supplementation with sulphydryl compounds (cysteine, cystine, thiosulphate, isovitalex) for growth on common laboratory media. in this report, a case of oropharyngeal tularemia diagnosed by the isolation of the causative agent on non-selective-common micro ...201021063979
identification of small rnas in francisella tularensis.regulation of bacterial gene expression by small rnas (srnas) have proved to be important for many biological processes. francisella tularensis is a highly pathogenic gram-negative bacterium that causes the disease tularaemia in humans and animals. relatively little is known about the regulatory networks existing in this organism that allows it to survive in a wide array of environments and no srna regulators have been identified so far.201021067590
genetic identification of unique immunological responses in mice infected with virulent and attenuated francisella tularensis.francisella tularensis is a category a select agent based on its infectivity and virulence but disease mechanisms in infection remain poorly understood. murine pulmonary models of infection were therefore employed to assess and compare dissemination and pathology and to elucidate the host immune response to infection with the highly virulent type a f. tularensis strain schu4 versus the less virulent type b live vaccine strain (lvs). we found that dissemination and pathology in the spleen was sig ...201021070859
coexistence of emerging bacterial pathogens in ixodes ricinus ticks in serbia.the list of tick-borne pathogens is long, varied and includes viruses, bacteria, protozoa and nematodes. as all of these agents can exist in ticks, their co-infections have been previously reported. we studied co-infections of emerging bacterial pathogens (borrelia burgdorferi sensu lato, anaplasma phagocytophilum and francisella tularensis) in ixodes ricinus ticks in serbia. using pcr technique, we detected species-specific sequences, rrf-rrl rdna intergenic spacer for b. burgdorferi s.l., p44/ ...201021073144
the calcineurin inhibitor rcan1 is involved in cultured macrophage and in vivo immune response.studies on the role of regulator of calcineurin 1 (rcan1) in immunity are limited, but have demonstrated an involvement in t-lymphocyte function. here, we expand these studies to macrophages and in vivo infection. the treatment of raw and primary mouse macrophages with lipopolysaccharide from escherichia coli strongly induced rcan1 isoform 4 (rcan1-4), but not isoform 1. rcan1-4 induction involved calcium, calcineurin, and reactive oxygen species. subsequent analysis with whole bacteria includin ...201021073546
francisella tularensis schu s4 o-antigen and capsule biosynthesis gene mutants induce early cell death in human macrophages.francisella tularensis is capable of rampant intracellular growth and causes a potentially fatal disease in humans. whereas many mutational studies have been performed with avirulent strains of francisella, relatively little has been done with strains that cause human disease. we generated a near-saturating transposon library in the virulent strain schu s4, which was subjected to high-throughput screening by transposon site hybridization through primary human macrophages, negatively selecting 20 ...201021078861
a bacterial two-hybrid system that utilizes gateway cloning for rapid screening of protein-protein interactions.comprehensive clone sets representing the entire genome now exist for a large number of organisms. the gateway entry clone sets are a particularly useful means to study gene function, given the ease of introduction into any gateway-suitable destination vector. we have adapted a bacterial two-hybrid system for use with gateway entry clone sets, such that potential interactions between proteins encoded within these clone sets can be determined by new destination vectors. we show that utilizing the ...201021091448
phosphatidylinositol 3-kinase activation attenuates the tlr2-mediated macrophage proinflammatory cytokine response to francisella tularensis live vaccine strain.an inadequate innate immune response appears to contribute to the virulence of francisella tularensis following pulmonary infection. studies in mice suggest that this poor response results from suppression of proinflammatory cytokine production early during infection, but the mechanisms involved are not understood. pi3k is known to regulate proinflammatory cytokine expression, but its exact role (positive versus negative) is controversial. we sought to clarify the role of pi3k in regulating proi ...201021098227
detection of a novel subspecies of francisella noatunensis as endosymbiont of the ciliate euplotes raikovi.francisella are facultative intracellular bacteria causing severe disease in a broad range of animals. two species are notable: francisella tularensis, the causative organism of tularemia and a putative warfare agent, and francisella noatunensis, an emerging fish pathogen causing significant losses in wild and farmed fish. although various aspects of francisella biology have been intensively studied, their natural reservoir in periods between massive outbreaks remains mysterious. protists have b ...201021110016
quantification of the relationship between bacterial kinetics and host response for monkeys exposed to aerosolized francisella tularensis.francisella tularensis can be disseminated via aerosols, and once inhaled, only a few microorganisms may result in tularemia pneumonia. effective responses to this threat depend on a thorough understanding of the disease development and pathogenesis. in this study, a class of time-dose-response models was expanded to describe quantitatively the relationship between the temporal probability distribution of the host response and the in vivo bacterial kinetics. an extensive literature search was co ...201021115714
rabbit tularemia and hepatic coccidiosis in wild rabbit. 201021122253
attenuated response of aged mice to respiratory francisella novicida is characterized by reduced cell death and absence of subsequent hypercytokinemia.pneumonia and pulmonary infections are major causes of mortality among the growing elderly population. age associated attenuations of various immune parameters, involved with both innate and adaptive responses are collectively known as immune senescence. these changes are likely to be involved with differences in host susceptibility to disease between young and aged individuals.201021124895
molecular diagnosis of francisellosis, a systemic granulomatous inflammatory disease in atlantic cod, gadus morhua l.a pcr-based assay for the detection of francisella noatunensis causing francisellosis in atlantic cod, gadus morhua has been developed. seven sets of primers targeting the flanking regions of the genes (rpoa, sdha, atpa, rpob, pgm, groel and 16s rrna) of the pathogen were designed. among the primers, groel was found to be the most suitable gene candidate for detecting the pathogen, due to its high sensitivity at various annealing temperatures and specificity in detection. the detection limit of ...201021125329
protection afforded by fluoroquinolones in animal models of respiratory infections with bacillus anthracis, yersinia pestis, and francisella tularensis.successful treatment of inhalation anthrax, pneumonic plague and tularemia can be achieved with fluoroquinolone antibiotics, such as ciprofloxacin and levofloxacin, and initiation of treatment is most effective when administered as soon as possible following exposure. bacillus anthracis ames, yersinia pestis co92, and francisella tularensis schu s4 have equivalent susceptibility in vitro to ciprofloxacin and levofloxacin (minimal inhibitory concentration is 0.03 μg/ml); however, limited informat ...201021127743
the intracellular lifestyle of francisella noatunensis in atlantic cod (gadus morhua l.) leucocytes.francisella noatunensis causes the systemic granulomatous inflammatory disease, francisellosis in cod. little is known about the lifestyle of this facultative intracellular bacterium within cod leucocytes. we have examined the interaction of this bacterium with phagocytic cells isolated from cod with emphasis on monocytes, macrophages, neutrophils and phagocytic b-cells. it is clear from confocal microscopy sections through adherent cell preparations that numerous bacteria were located intracell ...201021129488
survival of francisella tularensis type a in brackish-water.martha's vineyard (mv), massachusetts has been the location of two outbreaks of pneumonic tularemia; landscaping activities have been associated with risk, suggesting environmental inhalation exposure. we determined whether salinity or other components of brackish-water present in a location with endemic tularemia may prolong survival of f. tularensis. in addition, we demonstrate for the first time that f. tularensis type a appears similar to type b with respect to environmental stability. the r ...201021136042
comparative proteomic profiling of culture filtrate proteins of less and highly virulent francisella tularensis strains.the facultative intracellular bacterium francisella tularensis is the causal agent of the serious infectious disease tularemia. despite the dynamic progress, which has been made in last few years, important questions regarding francisella pathogenicity still remain to be answered. generally, secreted proteins play an important role in pathogenicity of intracellular microbes. in this study, we investigated the protein composition of the culture filtrate proteins of highly virulent f. tularensis s ...201021136602
cloning, expression, purification, crystallization and preliminary x-ray diffraction analysis of intracellular growth locus e (igle) protein from francisella tularensis subsp. novicida.tularaemia is an uncommon but potentially dangerous zoonotic disease caused by the bacterium francisella tularensis. as few as ten bacterial cells are sufficient to cause disease in a healthy human, making this one of the most infectious disease agents known. the virulence of this organism is dependent upon a genetic locus known as the francisella pathogenicity island (fpi), which encodes components of a secretion system that is related to the type vi secretion system. here, the cloning, express ...201021139203
investigation of the ecology of francisella tularensis during an inter-epizootic period.abstract a 1-year study of the ecological cycle of francisella tularensis was performed in an enzootic area during an inter-epizootic period. the study was based on multiple sampling of all major constituents of the disease cycle. seroprevalence of tularemia in the european brown hare (lepus europaeus) population was 5.1% (10/197) with low antibody titers (1/10 and 1/20), and f. tularensis ssp. holarctica was isolated from four hares. f. tularensis was not detected in the 38 common voles (microt ...201021142970
reliable detection of bacillus anthracis, francisella tularensis and yersinia pestis by using multiplex qpcr including internal controls for nucleic acid extraction and amplification.several pathogens could seriously affect public health if not recognized timely. to reduce the impact of such highly pathogenic micro-organisms, rapid and accurate diagnostic tools are needed for their detection in various samples, including environmental samples.201021143837
differential requirement for caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing.activation of the cysteine protease caspase-1 is a key event in the innate immune response to infections. synthesized as a proprotein, caspase-1 undergoes autoproteolysis within multiprotein complexes called inflammasomes. activated caspase-1 is required for proteolytic processing and for release of the cytokines interleukin-1β and interleukin-18, and it can also cause rapid macrophage cell death. we show that macrophage cell death and cytokine maturation in response to infection with diverse ba ...201021147462
nucleolin, a shuttle protein promoting infection of human monocytes by francisella tularensis.francisella tularensis is a highly virulent facultative intracellular bacterium, disseminating in vivo mainly within host mononuclear phagocytes. after entry into macrophages, f. tularensis initially resides in a phagosomal compartment, whose maturation is then arrested. bacteria escape rapidly into the cytoplasm, where they replicate freely. we recently demonstrated that nucleolin, an eukaryotic protein able to traffic from the nucleus to the cell surface, acted as a surface receptor for f. tul ...201021152024
crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase•dihydropteroate synthase bifunctional enzyme from francisella tularensis.the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (hppk) and dihydropteroate synthase (dhps) enzymes catalyze sequential metabolic reactions in the folate biosynthetic pathway of bacteria and lower eukaryotes. both enzymes represent validated targets for the development of novel anti-microbial therapies. we report herein that the genes which encode fthppk and ftdhps from the biowarfare agent francisella tularensis are fused into a single polypeptide. the potential of simultaneously targeti ...201021152407
questing ticks in suburban forest are infected by at least six tick-borne pathogens.abstract the role of ixodes ricinus ticks in the transmission of pathogens of public health importance such as borrelia burgdorferi s.l. is widely recognized and is suspected in several emerging vector-borne pathogens in europe. here, we assess prevalence rates of several endemic and emerging zoonotic pathogens in tick populations in an area of high human population density in france, to contribute to a risk assessment for potential transmission to humans. pathogen prevalence rates were evaluate ...201021158500
preservation of viable francisella tularensis for forensic analysis.as a preservation solution, (1%) ammonium chloride may be preferred over other conventionally used storage solutions because of its compatibility with analytical techniques such as mass spectrometry. in this study, ammonium chloride performed as well or better than phosphate buffered saline with tween or butterfields/tween for preserving francisella tularensis subsp. novicida.201021167882
il-17 in protective immunity to intracellular pathogens.the identification of a new t cell subset referred to as t helper 17 (th17) cells and its role in protective immunity against extracellular bacterial infections is well established. in contrast, initial studies suggested that the il-23-il-17 pathway was not required for protection against intracellular pathogens such as mycobacterial infections. however, recent studies demonstrate that th17-il-23 pathway may play a crucial role in protective immunity against other intracellular pathogens by regu ...201021178483
fragmentation-free lc-ms can identify hundreds of proteins.one of the most common approaches for large-scale protein identification is lc, followed by ms. if more than a few proteins are to be identified, the additional fragmentation of individual peptides has so far been considered as indispensable, and thus, the associated costs, in terms of instrument time and infrastructure, as unavoidable. here, we present evidence to the contrary. using a combination of (i) highly accurate and precise mass measurements, (ii) modern retention time prediction, and ( ...201021182191
iron content differs between francisella tularensis subspecies tularensis and subspecies holarctica strains and correlates to their susceptibility to h(2)o(2)-induced killing.francisella tularensis, the causative agent of tularemia, is one of the most infectious bacterial pathogens known and is classified as a category a select agent and a facultative intracellular bacterium. why f. tularensis subsp. tularensis causes a more severe form of tularemia than f. tularensis subsp. holarctica does is not known. in this study, we have identified prominent phenotypic differences between the subspecies, since we found that f. tularensis subsp. tularensis strains contained less ...201021189323
glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic th17 cells.cd4(+) t cells are critical for host defense but are also major drivers of immune-mediated diseases. the classical view of th1 and th2 subtypes of cd4(+) t cells was recently revised by the identification of the th17 lineage of cd4(+) t cells that produce il-17, which have been found to be critical in the pathogenesis of autoimmune and other diseases. mechanisms controlling the differentiation of th17 cells have been well described, but few feasible targets for therapeutically reducing th17 cell ...201021191064
identification and characterization of novel and potent transcription promoters of francisella tularensis.two alternative promoter trap libraries, based on the green fluorescence protein (gfp) reporter and on the chloramphenicol acetyltransferase (cat) cassette, were constructed for isolation of potent francisella tularensis promoters. of the 26,000 f. tularensis strain lvs gfp library clones, only 3 exhibited visible fluorescence following uv illumination and all appeared to carry the bacterioferritin promoter (pbfr). out of a total of 2,000 chloramphenicol-resistant lvs clones isolated from the ca ...201021193666
intranasal immunization with an archaeal lipid mucosal vaccine adjuvant and delivery formulation protects against a respiratory pathogen challenge.archaeal lipid mucosal vaccine adjuvant and delivery (amvad) is a safe mucosal adjuvant that elicits long lasting and memory boostable mucosal and systemic immune responses to model antigens such as ovalbumin. in this study, we evaluated the potential of the amvad system for eliciting protective immunity against mucosal bacterial infections, using a mouse model of intranasal francisella tularensis lvs (lvs) challenge. intranasal immunization of mice with cell free extract of lvs (lvsce) adjuvant ...201021206916
tularemia in bulgaria 2003-2004.tularemia is an uncommon but potentially fatal zoonosis. а second outbreak of tularemia in bulgaria, about 40 years after the first, occurred in 1997 in two western regions, near the serbian border. in 2003 tularemia reemerged in the same foci. this retrospective study aimed to evaluate the clinical characteristics and the efficacy of antibiotic therapy in a tularemia resurgence in the slivnitza region in 2003-2004.201021252445
rapid differentiation of francisella species and subspecies by fluorescent in situ hybridization targeting the 23s rrna.francisella (f.) tularensis is the causative agent of tularemia. due to its low infectious dose, ease of dissemination and high case fatality rate, f. tularensis was the subject in diverse biological weapons programs and is among the top six agents with high potential if misused in bioterrorism. microbiological diagnosis is cumbersome and time-consuming. methods for the direct detection of the pathogen (immunofluorescence, pcr) have been developed but are restricted to reference laboratories.201020205957
oropharyngeal tularemia--a differential diagnosis of tonsillopharyngitis and cervical lymphadenitis.francisella tularensis, the causative agent of tularemia, has been recognized as a human and zoonotic pathogen for almost 100 years. the increasing number of tularemia outbreaks in regions of europe outside the classic endemic areas in recent years has prompted renewed interest in this rare infectious disease. we report on a case of oropharyngeal tularemia in an 18-year-old girl from bavaria (germany) who presented with tonsillopharyngitis and cervical lymphadenitis. strongly positive serologica ...201020213378
evaluation of an immunochromatographic test for rapid and reliable serodiagnosis of human tularemia and detection of francisella tularensis-specific antibodies in sera from different mammalian species.tularemia is a highly contagious infectious zoonosis caused by the bacterial agent francisella tularensis. serology is still considered to be a cornerstone in tularemia diagnosis due to the low sensitivity of bacterial culture and the lack of standardization in pcr methodology for the direct identification of the pathogen. we developed a novel immunochromatographic test (ict) to efficiently detect f. tularensis-specific antibodies in sera from humans and other mammalian species (nonhuman primate ...201020220165
statistical assessment of dna extraction reagent lot variability in real-time quantitative pcr.the aim of this study was to evaluate the variability in lots of a dna extraction kit using real-time pcr assays for bacillus anthracis, francisella tularensis and vibrio cholerae.201020070509
large direct repeats flank genomic rearrangements between a new clinical isolate of francisella tularensis subsp. tularensis a1 and schu s4.francisella tularensis subspecies tularensis consists of two separate populations a1 and a2. this report describes the complete genome sequence of ne061598, an f. tularensis subspecies tularensis a1 isolated in 1998 from a human with clinical disease in nebraska, united states of america. the genome sequence was compared to schu s4, an f. tularensis subspecies tularensis a1a strain originally isolated in ohio in 1941. it was determined that there were 25 nucleotide polymorphisms (22 snps and 3 i ...201020140244
interaction of francisella asiatica with tilapia (oreochromis niloticus) innate immunity.members of the genus francisella are facultative intracellular bacteria that cause important diseases in a wide variety of animals worldwide, including humans and fish. several genes that are important for intramacrophage survival have been identified, including the iglc gene, which is found in the iglabcd operon in the francisella sp. pathogenicity island (fpi). in the present study, we examined the interaction of wild-type francisella asiatica and a delta iglc mutant strain with fish serum and ...201020160018
tularaemia in minnesota: case report and brief epidemiology.the 2008 case presented here of tularaemia in a cat and its owner occurred in an urban setting and was associated with animal contact, a relatively rare mode of transmission in minnesota in recent years. response to this case exemplified a 'one health' approach involving pre-existing relationships, cooperation between multiple disciplines and laboratory infrastructure that facilitated information sharing.201020163576
subolesin expression in response to pathogen infection in ticks.ticks (acari: ixodidae) are vectors of pathogens worldwide that cause diseases in humans and animals. ticks and pathogens have co-evolved molecular mechanisms that contribute to their mutual development and survival. subolesin was discovered as a tick protective antigen and was subsequently shown to be similar in structure and function to akirins, an evolutionarily conserved group of proteins in insects and vertebrates that controls nf-kb-dependent and independent expression of innate immune res ...201020170494
detoxified endotoxin vaccine (j5dlps/omp) protects mice against lethal respiratory challenge with francisella tularensis schus4.francisella tularensis is a category a select agent. j5dlps/omp is a novel vaccine construct consisting of detoxified, o-polysaccharide side chain-deficient, lipopolysaccharide non-covalently complexed with the outer membrane protein of n. meningitidis group b. immunization elicits high-titer polyclonal antibodies specific for the highly-conserved epitopes expressed within the glycolipid core that constitutes gram-negative bacteria (e.g., f. tularensis). mice immunized intranasally with j5dlps/o ...201020170768
tularemia pneumonia.francisella tularensis is a zoonotic infection that can be acquired in multiple ways, including a bite from an arthropod, the handling of animal carcasses, consumption of contaminated food and water, or inhalation of infected particles. the most virulent subspecies of f tularensis is type a, which is almost exclusively seen in north america. pneumonia can occur in tularemia, as either a primary process from direct inhalation, or as a secondary manifestation of ulceroglandular or typhoidal diseas ...201020171544
multimethodological approach to identification of glycoproteins from the proteome of francisella tularensis, an intracellular microorganism.it appears that most glycoproteins found in pathogenic bacteria are associated with virulence. despite the recent identification of novel virulence factors, the mechanisms of virulence in francisella tularensis are poorly understood. in spite of its importance, questions about glycosylation of proteins in this bacterium and its potential connection with bacterial virulence have not been answered yet. in the present study, several putative francisella tularensis glycoproteins were characterized t ...201020175567
type i ifn signaling constrains il-17a/f secretion by gammadelta t cells during bacterial infections.recognition of intracellular bacteria by macrophages leads to secretion of type i ifns. however, the role of type i ifn during bacterial infection is still poorly understood. francisella tularensis, the causative agent of tularemia, is a pathogenic bacterium that replicates in the cytosol of macrophages leading to secretion of type i ifn. in this study, we investigated the role of type i ifns in a mouse model of tularemia. mice deficient for type i ifn receptor (ifnar1(-/-)) are more resistant t ...201020176744
cpg oligodeoxyribonucleotides protect mice from burkholderia pseudomallei but not francisella tularensis schu s4 aerosols.abstract: studies have shown that cpg oligodeoxyribonucleotides (odn) protect mice from various bacterial pathogens, including burkholderia pseudomallei and francisella tularensis live vaccine strain (lvs), when administered before parenteral challenge. given the potential to develop cpg odn as a pre-treatment for multiple bacterial biological warfare agents, we examined survival, histopathology, and cytokine data from cpg odn-treated c57bl/6 mice to determine whether previously-reported protect ...201020181102
identification of francisella tularensis by whole-cell matrix-assisted laser desorption ionization-time of flight mass spectrometry: fast, reliable, robust, and cost-effective differentiation on species and subspecies levels.francisella tularensis, the causative agent of tularemia, is a potential agent of bioterrorism. the phenotypic discrimination of closely related, but differently virulent, francisella tularensis subspecies with phenotyping methods is difficult and time-consuming, often producing ambiguous results. as a fast and simple alternative, matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof ms) was applied to 50 different strains of the genus francisella to assess its ...201020181907
modulation of iron homeostasis in macrophages by bacterial intracellular pathogens.intracellular bacterial pathogens depend on acquisition of iron for their success as pathogens. the host cell requires iron as an essential component for cellular functions that include innate immune defense mechanisms. the transferrin receptor tfr1 plays an important part for delivering iron to the host cell during infection. its expression can be modulated by infection, but its essentiality for bacterial intracellular survival has not been directly investigated.201020184753
activation of b cell apoptotic pathways in the course of francisella tularensis infection.francisella tularensis is a facultative intracellular, gram-negative bacterium that induces apoptosis in macrophages and b cells. here we show apoptotic pathways that are activated in the ramos human b cell line in the course of f. tularensis infection. live bacteria f. tularensis fsc200 activate caspases 8, 9 and 3, as well as bid; release cytochrome c and apoptosis-inducing factor from mitochondria; and induce depolarization of mitochondrial membrane potential in the ramos cell line, thus lead ...201020600796
characterization of the o-antigen polymerase (wzy) of francisella tularensis.the o-antigen polymerase of gram-negative bacteria has been difficult to characterize. herein we report the biochemical and functional characterization of the protein product (wzy) of the gene annotated as the putative o-antigen polymerase, which is located in the o-antigen biosynthetic locus of francisella tularensis. in silico analysis (homology searching, hydropathy plotting, and codon usage assessment) strongly suggested that wzy is an o-antigen polymerase whose function is to catalyze the a ...201020605777
multiple mechanisms of nadph oxidase inhibition by type a and type b francisella tularensis.ft is a facultative intracellular pathogen that infects many cell types, including neutrophils. in previous work, we demonstrated that the type b ft strain lvs disrupts nadph oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. here, we used several type a and type b strains to demonstrate that ft-mediated nadph oxidase inhibition is more complex than appreciated previously. we confirm that phagosomes containing ft opsonized with as exclude flavocytoch ...201020610796
method for the isolation of francisella tularensis outer membranes.francisella tularensis is a gram-negative intracellular coccobacillus and the causative agent of the zoonotic disease tularemia. when compared with other bacterial pathogens, the extremely low infectious dose (<10 cfu), rapid disease progression, and high morbidity and mortality rates suggest that the virulent strains of francisella encode for novel virulence factors. surface-exposed molecules, namely outer membrane proteins (omps), have been shown to promote bacterial host cell binding, entry, ...201020613713
biological properties and structure of the lipopolysaccharide of a vaccine strain of francisella tularensis generated by inactivation of a quorum sensing system gene qsec.a knockout mutant with a deletion in a quorum sensing system gene qsec was generated from the vaccine strain francisella tularensis 15 by site-directed mutagenesis. the variant with the inactivated gene qsec differed from the parental strain in growth rate on solid nutrient medium but had the same growth dynamics in liquid nutrient medium. the mutation abolished almost completely the resistance of the vaccine strain to normal rabbit serum and its ability to survive in macrophages; in addition, t ...201020618133
triggering ras signalling by intracellular francisella tularensis through recruitment of pkcα and βi to the sos2/grb2 complex is essential for bacterial proliferation in the cytosol.intracellular proliferation of francisella tularensis is essential for manifestation of the fatal disease tularaemia, and is classified as a category a bioterrorism agent. the f. tularensis-containing phagosome (fcp) matures into a late endosome-like phagosome with limited fusion to lysosomes, followed by rapid bacterial escape into the cytosol. the francisella pathogenicity island (fpi) encodes a type vi-like secretion system, and the fpi-encoded iglc is essential for evasion of lysosomal fusio ...201020618341
construction of a bioluminescence reporter plasmid for francisella tularensis.a francisella tularensis shuttle vector that constitutively expresses the photorhabdus luminescens lux operon in type a and type b strains of f. tularensis was constructed. the bioluminescence reporter plasmid was introduced into the live vaccine strain of f. tularensis and used to follow f. tularensis growth in a murine intranasal challenge model in real-time by bioluminescence imaging. the results show that the new bioluminescence reporter plasmid represents a useful tool for tularemia researc ...201020620161
essential genes from arctic bacteria used to construct stable, temperature-sensitive bacterial vaccines.all bacteria share a set of evolutionarily conserved essential genes that encode products that are required for viability. the great diversity of environments that bacteria inhabit, including environments at extreme temperatures, place adaptive pressure on essential genes. we sought to use this evolutionary diversity of essential genes to engineer bacterial pathogens to be stably temperature-sensitive, and thus useful as live vaccines. we isolated essential genes from bacteria found in the arcti ...201020624965
bioavailability and efficacy of levofloxacin against francisella tularensis in the common marmoset (callithrix jacchus).pharmacokinetic and efficacy studies with levofloxacin were performed in the common marmoset (callithrix jacchus) model of inhalational tularemia. plasma levofloxacin pharmacokinetics were determined in six animals in separate single-dose and multidose studies. plasma drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry-electrospray ionization. on day 7 of a twice-daily dosing regimen of 40 mg/kg, the levofloxacin half-life, maximum concentration, and area under ...201020625157
identification, characterization and immunogenicity of an o-antigen capsular polysaccharide of francisella tularensis.capsular polysaccharides are important factors in bacterial pathogenesis and have been the target of a number of successful vaccines. francisella tularensis has been considered to express a capsular antigen but none has been isolated or characterized. we have developed a monoclonal antibody, 11b7, which recognizes the capsular polysaccharide of f. tularensis migrating on western blot as a diffuse band between 100 kda and 250 kda. the capsule stains poorly on sds-page with silver stain but can be ...201020625403
th17 cytokines in recall responses against francisella tularensis in humans.to determine whether cytokines and t-cell subsets other than th1 cells contribute to secondary immune responses against francisella species, we investigated production of th17-associated cytokines il-17 and il-22 in a recall response to francisella tularensis. peripheral blood mononuclear cells (pbmcs) from volunteers previously immunized with the f. tularensis live vaccine strain (lvs) were stimulated in vitro with bacterial lysates of lvs or a nonpathogenic type a b38 strain. gene expression a ...201020626289
pathology in practice. tularemia. 201020632788
a francisella tularensis live vaccine strain (lvs) mutant with a deletion in capb, encoding a putative capsular biosynthesis protein, is significantly more attenuated than lvs yet induces potent protective immunity in mice against f. tularensis challenge.francisella tularensis, the causative agent of tularemia, is in the top category (category a) of potential agents of bioterrorism. the f. tularensis live vaccine strain (lvs) is the only vaccine currently available to protect against tularemia; however, this unlicensed vaccine is relatively toxic and provides incomplete protection against aerosolized f. tularensis, the most dangerous mode of transmission. hence, a safer and more potent vaccine is needed. as a first step toward addressing this ne ...201020643859
francisella philomiragia septicemia in a dog. 201020649752
deletion of the bacillus anthracis capb homologue in francisella tularensis subspecies tularensis generates an attenuated strain that protects mice against virulent tularaemia.as there is currently no licensed vaccine against francisella tularensis, the causative agent of tularaemia, the bacterium is an agent of concern as a potential bioweapon. although f. tularensis has a low infectious dose and high associated mortality, it possesses few classical virulence factors. an analysis of the f. tularensis subspecies tularensis genome sequence has revealed the presence of a region containing genes with low sequence homology to part of the capbcade operon of bacillus anthra ...201020651039
optimal swab processing recovery method for detection of bioterrorism-related francisella tularensis by real-time pcr.francisella tularensis, the etiological agent of tularemia, is regarded as a potential bioterrorism agent. the advent of bioterrorism has heightened awareness of the need for validated methods for processing environmental samples. in this study we determined the optimal method for processing environmental swabs for the recovery and subsequent detection of f. tularensis by the use of real-time pcr assays. four swab processing recovery methods were compared: heat, sonication, vortexing, and the sw ...201020654658
whole-genome sequencing reveals distinct mutational patterns in closely related laboratory and naturally propagated francisella tularensis strains.the f. tularensis type a strain fsc198 from slovakia and a second strain fsc043, which has attenuated virulence, are both considered to be derivatives of the north american f. tularensis type a strain schu s4. these strains have been propagated under different conditions: the fsc198 has undergone natural propagation in the environment, while the strain fsc043 has been cultivated on artificial media in laboratories. here, we have compared the genome sequences of fsc198, fsc043, and schu s4 to exp ...201020657845
a two-component kdo hydrolase in the inner membrane of francisella novicida.lipid a coats the outer surface of the outer membrane of gram-negative bacteria. in francisella tularensis subspecies novicida lipid a is present either as the covalently attached anchor of lipopolysaccharide (lps) or as free lipid a. the lipid a moiety of francisella lps is linked to the core domain by a single 2-keto-3-deoxy-d-manno-octulosonic acid (kdo) residue. f. novicida kdta is bi-functional, but f. novicida contains a membrane-bound kdo hydrolase that removes the outer kdo unit. the hyd ...201020662782
ulceroglandular tularemia.a 14-year-old boy presented with fevers and nonspecific flulike symptoms, as well as an enlarging ulcerated plaque involving the upper back, lymphadenopathy, and bilateral pulmonary nodules. bacterial cultures of ulcer tissue grew francisella tularensis on enriched chocolate agar plates. making the diagnosis requires a high index of suspicion, and communication with the laboratory to successfully and safely culture these highly pathogenic bacteria is imperative.201020678093
cutting edge: mutation of francisella tularensis mvin leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence.the mechanisms by which the intracellular pathogen francisella tularensis evades innate immunity are not well defined. we have identified a gene with homology to escherichia coli mvin, a putative lipid ii flippase, which f. tularensis uses to evade activation of innate immune pathways. infection of mice with a f. tularensis mvin mutant resulted in improved survival and decreased bacterial burdens compared to infection with wild-type f. tularensis. the mvin mutant also induced increased absent in ...201020679532
mutations of francisella novicida that alter the mechanism of its phagocytosis by murine macrophages.infection with the bacterial pathogen francisella tularensis tularensis (f. tularensis) causes tularemia, a serious and debilitating disease. francisella tularensis novicida strain u112 (abbreviated f. novicida), which is closely related to f. tularensis, is pathogenic for mice but not for man, making it an ideal model system for tularemia. intracellular pathogens like francisella inhibit the innate immune response, thereby avoiding immune recognition and death of the infected cell. because acti ...201020686600
long lived protection against pneumonic tularemia is correlated with cellular immunity in peripheral, not pulmonary, organs.protection against the intracellular bacterium francisella tularensis within weeks of vaccination is thought to involve both cellular and humoral immune responses. however, the relative roles for cellular and humoral immunity in long lived protection against virulent f. tularensis are not well established. here, we dissected the correlates of immunity to pulmonary infection with virulent f. tularensis strain schus4 in mice challenged 30 and 90 days after subcutaneous vaccination with lvs. regard ...201020688042
objections to the transfer of francisella novicida to the subspecies rank of francisella tularensis. 201020688748
objections to the transfer of francisella novicida to the subspecies rank of francisella tularensis - response to johansson et al. 201020688749
deep mitochondrial dna lineage divergences within alberta populations of dermacentor albipictus (acari: ixodidae) do not indicate distinct species.the winter tick dermacentor albipictus (packard) has a single-host life cycle that allows it to reach severe infestation levels on ungulates, particularly moose. genotypic variation within these and related ticks has been a source of taxonomic confusion, although the continuity in their morphology and life history has generally been interpreted as indicating the existence of a single species. to further investigate this variation, we sequenced regions of two mitochondrial dna (mtdna) genes (coi ...201020695271
detection of francisella tularensis in alaskan mosquitoes (diptera: culicidae) and assessment of a laboratory model for transmission.tularemia is a zoonotic disease caused by the category a bioterrorism agent francisella tularensis. in scandinavia, tularemia transmission by mosquitoes has been widely cited in the literature. we tested >2,500 mosquitoes captured in alaska and found francisella dna in 30% of pooled samples. to examine the potential for transmission of francisella by mosquitoes, we developed a mosquito model of francisella infection. larvae of anopheles gambiae giles and aedes aegypti (l.) readily ingest f. tula ...201020695280
the fsle homolog, ftl_0439 (fupa/b), mediates siderophore-dependent iron uptake in francisella tularensis lvs.the gram-negative pathogen francisella tularensis secretes a siderophore to obtain essential iron by a tonb-independent mechanism. the fslabcde locus, encoding siderophore-related functions, is conserved among different francisella strains. in the virulent strain schu s4, fsle is essential for siderophore utilization and for growth under conditions of iron limitation. in contrast, we found that deletion of fsle did not affect siderophore utilization by the attenuated live vaccine strain (lvs). w ...201020696823
binding and activation of host plasminogen on the surface of francisella tularensis.francisella tularensis (ft) is a gram-negative facultative intracellular coccobacillus and is the causal agent of a life-threatening zoonotic disease known as tularemia. although ft preferentially infects phagocytic cells of the host, recent evidence suggests that a significant number of bacteria can be found extracellularly in the plasma fraction of the blood during active infection. this observation suggests that the interaction between ft and host plasma components may play an important role ...201020226053
prevalence and seasonality of tick-borne pathogens in questing ixodes ricinus ticks from luxembourg.in europe, ixodid ticks are important arthropod vectors of human and animal pathogens, but comprehensive studies of the prevalence of all relevant pathogens in central europe are scarce. as a result of ecological changes, the incidences of tick-borne infections are expected to increase. in this study, 1,394 nymphal and adult ixodes ricinus ticks sampled monthly during the active season from 33 ecologically distinct collection sites throughout luxembourg were screened for all human tick-borne pat ...201020228110
regulation of virulence gene transcripts by the francisella novicida orphan response regulator pmra: role of phosphorylation and evidence of mgla/sspa interaction.francisella tularensis subsp. tularensis is the etiologic agent of tularemia and has been designated a category a biothreat agent by the cdc. tularemia is characterized by replication and dissemination within host phagocytes. intramacrophage growth is dependent upon the regulation of francisella pathogenicity island (fpi) virulence genes, which is poorly understood. two-component regulatory systems (tcs) are widely employed by gram-negative bacteria to monitor and respond to environmental signal ...201020231408
francisella acid phosphatases inactivate the nadph oxidase in human phagocytes.francisella tularensis contains four putative acid phosphatases that are conserved in francisella novicida. an f. novicida quadruple mutant (acpa, acpb, acpc, and hap [deltaabch]) is unable to escape the phagosome or survive in macrophages and is attenuated in the mouse model. we explored whether reduced survival of the deltaabch mutant within phagocytes is related to the oxidative response by human neutrophils and macrophages. f. novicida and f. tularensis subspecies failed to stimulate reactiv ...201020348422
the aim2 inflammasome is essential for host defense against cytosolic bacteria and dna viruses.inflammasomes regulate the activity of caspase-1 and the maturation of interleukin 1beta (il-1beta) and il-18. aim2 has been shown to bind dna and engage the caspase-1-activating adaptor protein asc to form a caspase-1-activating inflammasome. using aim2-deficient mice, we identify a central role for aim2 in regulating caspase-1-dependent maturation of il-1beta and il-18, as well as pyroptosis, in response to synthetic double-stranded dna. aim2 was essential for inflammasome activation in respon ...201020351692
the aim2 inflammasome is critical for innate immunity to francisella tularensis.francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1beta (il-1beta) and il-18. we elucidate here how host macrophages recognize f. tularensis and elicit this proinflammatory response. using mice deficient in the dna-sensing inflammasome component aim2, we demonstrate here that aim2 is required for sensing f. tularensis. aim2-deficient mice were extremely susceptible to f. tularensis infection, ...201020351693
tlr activation of the transcription factor xbp1 regulates innate immune responses in macrophages.sensors of pathogens, such as toll-like receptors (tlrs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. here we report that tlr4 and tlr2 specifically activated the endoplasmic reticulum (er) stress sensor kinase ire1alpha and its downstream target, the transcription factor xbp1. previously described er-stress target genes of xbp1 were not induced by tlr signaling. instead, tlr-activated xbp1 was required for optimal and sustained p ...201020351694
subpopulations of francisella tularensis ssp. tularensis and holarctica: identification and associated epidemiology.tularemia is primarily caused by two subspecies of francisella tularensis worldwide, ssp. tularensis (type a) and ssp. holarctica (type b), which were originally delineated by phenotypic differences. application of molecular typing methods to investigate population structure of f. tularensis has confirmed that categorizing the two subspecies via phenotypic characteristics corresponds with genotypic differentiation. in addition, genotyping methods have demonstrated that both subspecies, type a an ...201020353304
mycoplasma suppression of thp-1 cell tlr responses is corrected with antibiotics.mycoplasma contamination of cultured cell lines is a serious problem in research, altering cellular response to different stimuli thus compromising experimental results. we found that chronic mycoplasma contamination of thp-1 cells suppresses responses of thp-1 cells to tlr stimuli. for example, e. coli lps induced il-1 beta was suppressed by 6 fold and il-8 by 10 fold in mycoplasma positive thp-1 cells. responses to live f. novicida challenge were suppressed by 50-fold and 40-fold respectively ...201020360862
immunoproteomics analysis of the murine antibody response to vaccination with an improved francisella tularensis live vaccine strain (lvs).francisella tularensis subspecies tularensis is the causative agent of a spectrum of diseases collectively known as tularemia. an attenuated live vaccine strain (lvs) has been shown to be efficacious in humans, but safety concerns have prevented its licensure by the fda. recently, f. tularensis lvs has been produced under current good manufacturing practice (cgmp guidelines). little is known about the immunogenicity of this new vaccine preparation in comparison with extensive studies conducted w ...201020368994
the fischer 344 rat reflects human susceptibility to francisella pulmonary challenge and provides a new platform for virulence and protection studies.the pathogenesis of francisella tularensis, the causative agent of tularemia, has been primarily characterized in mice. however, the high degree of sensitivity of mice to bacterial challenge, especially with the human virulent strains of f. tularensis, limits this animal model for screening of defined attenuated vaccine candidates for protection studies.201020376351
study of matrix additives for sensitive analysis of lipid a by matrix-assisted laser desorption ionization mass spectrometry.matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof ms) has been widely used for structural characterization of bacterial endotoxins (lipid a). however, the mass spectrometric behavior of the lipid a molecule is highly dependent on the matrix. furthermore, this dependence is strongly linked to phosphorylation patterns. using lipid a from escherichia coli o116 as a model system, we have investigated the effects of different matrices and comatrix compounds on th ...201020382818
[a 23-year-old patient with sore throat and cervical lymph node enlargement: a rare presentation of tularemia].we report a case of oropharyngeal tularemia--an uncommon manifestation of this disease. there is a low prevalence of tularemia in germany. therefore the diagnosis can be confirmed only by well directed laboratory diagnostics. without correct antibiotic therapy mortality can reach 33%--depending on the subspecies of francisella tularensis. for this reason tularemia should be included into the differential-diagnostic considerations in patients with unclear lymph node enlargement.201020383480
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