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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
gallium disrupts iron uptake by intracellular and extracellular francisella strains and exhibits therapeutic efficacy in a murine pulmonary infection model.francisella tularensis requires iron (fe) for growth, but the biologic sources of fe for this organism are largely unknown. we found that francisella sp. growing in broth culture or within human macrophages can acquire fe from the two major host fe-binding proteins, lactoferrin (lf) and transferrin (tf). fe acquisition is a potential target for novel therapies. gallium (ga) is a transition metal that interferes with cellular fe metabolism by competing with fe for uptake/utilization. growth of ei ...201019917753
an outbreak of holarctica-type tularemia in pediatric patients.holarctica-type tularemia is endemic in the northern hemisphere. despite recurrent epidemics tularemia is not well known in children and the pediatric cases are often misdiagnosed.201019918211
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
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
francisella tularensis blue-gray phase variation involves structural modifications of lipopolysaccharide o-antigen, core and lipid a and affects intramacrophage survival and vaccine efficacy.francisella tularensis is a cdc category a biological agent and a potential bioterrorist threat. there is no licensed vaccine against tularemia in the united states. a long-standing issue with potential francisella vaccines is strain phase variation to a gray form that lacks protective capability in animal models. comparisons of the parental strain (lvs) and a gray variant (lvsg) have identified lipopolysaccharide (lps) alterations as a primary change. the lps of the f. tularensis variant strain ...201021687776
the role of the francisella tularensis pathogenicity island in type vi secretion, intracellular survival, and modulation of host cell signaling.francisella tularensis is a highly virulent gram-negative intracellular bacterium that causes the zoonotic disease tularemia. essential for its virulence is the ability to multiply within host cells, in particular monocytic cells. the bacterium has developed intricate means to subvert host immune mechanisms and thereby facilitate its intracellular survival by preventing phagolysosomal fusion followed by escape into the cytosol, where it multiplies. moreover, it targets and manipulates numerous h ...201021687753
the francisella intracellular life cycle: toward molecular mechanisms of intracellular survival and proliferation.the tularemia-causing bacterium francisella tularensis is a facultative intracellular organism with a complex intracellular lifecycle that ensures its survival and proliferation in a variety of mammalian cell types, including professional phagocytes. because this cycle is essential to francisella pathogenesis and virulence, much research has focused on deciphering the mechanisms of its intracellular survival and replication and characterizing both bacterial and host determinants of the bacterium ...201021687806
an outbreak of disease caused by francisella sp. in nile tilapia oreochromis niloticus at a recirculation fish farm in the uk.this study details the first diagnosis of francisella sp. in tilapia in the united kingdom. losses of tilapia fry at a recirculation fish farm in england were investigated, giving a presumptive positive diagnosis of infection with francisella sp. by histopathological examination. most fish sampled showed moderate to marked pathology of the major organs, with lesions being present in most tissues. the most obvious host response was granuloma formulation. a subsequent follow-up visit provided furt ...201021387995
francisella tularensis metabolism and its relation to virulence.francisella tularensis is a gram-negative bacterium capable of causing the zoonotic disease tularaemia in a large number of mammalian species and in arthropods. f. tularensis is a facultative intracellular bacterium that infects and replicates in vivo mainly inside macrophages. during its systemic dissemination, f. tularensis must cope with very different life conditions (such as survival in different target organs or tissues and/or survival in the blood streamôçª) and may thus encounter a broad ...201021687763
detection of francisella piscicida in atlantic cod (gadus morhua l) by the loop-mediated isothermal amplification (lamp) reaction.the loop-mediated isothermal amplification (lamp) reaction was evaluated for its speed and sensitivity in detecting the presence of francisella piscicida, the causative agent of francisellosis in atlantic cod (gadus morhua). four primer sets, consisting of two outer and two inner, were designed from the groel gene of the pathogen. the lamp reaction was optimised at 63 degrees c for 1h using bacterial genomic dna as the template and the products were visualised under ultra-violet light and analys ...201019398357
[tularemia: a decade in the province of soria (spain)].tularemia is a zoonotic disease that has been regularly reported in spain since 1997. this study analyzes suspected, probable, and confirmed cases of tularemia in the province of soria, and compares them with tularemia cases recorded in the autonomous community of castilla y léon, which, with the exception of 1 sporadic case, occurred in 2 epidemic outbreaks in 1997/1998 and 2007/2008.201019419798
characterization of francisella tularensis strains, comparing their carbon source utilization.thirteen francisella tularensis strains were isolated from 22 seropositive brown hares (lepus europaeus) originating from different parts of hungary, and further two from a patas monkey (erythrocebus patas) and vervet monkey (chlorocebus aethiops). the isolates were identified as f. tularensis ssp. holarctica on the basis of culture, morphological and biochemical characteristics. the identification was verified by polymerase chain reaction and the sequencing of the partial 16s rrna gene. utiliza ...201019538455
the role of birds in dissemination of francisella tularensis: first direct molecular evidence for bird-to-human transmission.during a recent large tularemia outbreak in bulgaria we found several cases that were remote from the main focus. one case had an unusual mode of transmission. a hunter acquired tularemia through a nail scratch from a buzzard (buteo buteo) and consequently developed a typical ulceroglandular form of the disease. the diagnosis was confirmed by serological methods and successful cultivation. comparative strain typing was performed by high-resolution multi-locus variable-number tandem repeat analys ...201019664305
diversity of francisella species in environmental samples from martha's vineyard, massachusetts.we determined whether francisella spp. are present in water, sediment, and soil from an active tularemia natural focus on martha's vineyard, massachusetts, during a multiyear outbreak of pneumonic tularemia. environmental samples were tested by polymerase chain reaction (pcr) targeting francisella species 16s rrna gene and succinate dehydrogenase a (sdha) sequences; evidence of the agent of tularemia was sought by amplification of francisella tularensis-specific sequences for the insertion eleme ...201019669828
tularemia.tularemia is a potentially fatal multi-systemic disease of humans and other animals caused by the bacterial pathogen francisella tularensis. the disease can be transmitted by ticks, biting flies, water exposure, food, and aerosols and occurs around the northern hemisphere including north america, europe, and asia. there are several defined species and subspecies, including f. tularensis subsp. tularensis (jellison type a) which is pathogenic for rabbits and occurs in north america, f. tularensis ...201019713053
a possible novel francisella genomic species isolated from blood and urine of a patient with severe illness.two identical isolates were recovered in pure culture from the blood and urine of a patient suffering from severe septicaemia associated with obstructive pyelonephritis secondary to lithotripsy. preliminary phenotypic and genotypic characterizations based on serological, biochemical and sequence analyses following pcr amplification of selected gene regions indicate that this organism represents a potential new francisella genomic species.201019709068
francisella novicida forms in vitro biofilms mediated by an orphan response regulator.francisella tularensis is associated with water and waterways and infects many species of animals, insects, and protists. the mechanism francisella utilizes to persist in the environment and in tick vectors is currently unknown. we have demonstrated for the first time that francisella novicida, a model organism of f. tularensis, forms a biofilm in vitro. selected f. novicida transposon mutants were tested for their ability to form biofilm compared to the wildtype f. novicida strain. mutation of ...201019763680
survival of secondary lethal systemic francisella lvs challenge depends largely on interferon gamma.although survival of primary infection with the live vaccine strain (lvs) of francisella tularensis depends on interferon gamma (ifn-gamma), the relative importance of ifn-gamma to secondary protective immunity in vivo has not been clearly established. here we examine the role of ifn-gamma in t cell priming and expression of vaccine-induced protection against lethal intraperitoneal challenge of mice. large amounts of ifn-gamma were detected between days 3 and 7 in the sera of lvs-immunized mice, ...201019781659
description of francisella hispaniensis sp. nov., isolated from human blood, reclassification of francisella novicida (larson et al. 1955) olsufiev et al. 1959 as francisella tularensis subsp. novicida comb. nov. and emended description of the genus francisella.strain fhsp1t, isolated from human blood in spain in 2003, was studied for its taxonomic allocation. by 16s rrna and reca gene sequencing, the strain was shown to belong to the genus francisella. in the 16s rrna gene sequence, francisella sp. fhsp1t shared similarity of more than 99% with strains of francisella tularensis subspecies and francisella novicida u112t, 98% with francisella piscicida gm2212t and 98.4% with francisella philomiragia atcc 25015t. in the reca gene sequence, francisella sp ...201019783615
aged mice display an altered pulmonary host response to francisella tularensis live vaccine strain (lvs) infections.aging is a complex phenomenon that has been shown to affect many organ systems including the innate and adaptive immune systems. the current study was designed to examine the potential effect of immunosenescence on the pulmonary immune response using a francisella tularensis live vaccine strain (lvs) inhalation infection model. f. tularensis is a gram-negative intracellular pathogen that can cause a severe pneumonia. in this study both young (8-12 week old) and aged (20-24 month old) mice were i ...201019825409
development of real-time pcr assays for the specific detection of francisella tularensis ssp. tularensis, holarctica and mediaasiatica.real-time polymerase chain reaction (pcr) assays were developed to detect francisella tularensis (ft), the causative agent of tularaemia in humans. two real-time pcrs (ftt0376 and ftt0523) were designed in genetic sequences identified by the insignia genome comparison tool (http://insignia.cbcb.umd.edu/) as being unique to pathogenic subspecies of f. tularensis. both pcrs identified all pathogenic f. tularensis subspecies but did not cross react with avirulent francisella philomiragia or f. tula ...201019833196
the presence of cd14 overcomes evasion of innate immune responses by virulent francisella tularensis in human dendritic cells in vitro and pulmonary cells in vivo.francisella tularensis is a gram-negative bacterium that causes acute, lethal disease following inhalation. we have previously shown that viable f. tularensis fails to stimulate secretion of proinflammatory cytokines following infection of human dendritic cells (hdc) in vitro and pulmonary cells in vivo. here we demonstrate that the presence of the cd14 receptor is critical for detection of virulent f. tularensis strain schus4 by dendritic cells, monocytes, and pulmonary cells. addition of solub ...201019841074
acid phosphatases do not contribute to the pathogenesis of type a francisella tularensis.the intracellular pathogen francisella tularensis is the causative agent of tularemia, a zoonosis that can affect humans with potentially lethal consequences. essential to francisella virulence is its ability to survive and proliferate within phagocytes through phagosomal escape and cytosolic replication. francisella spp. encode a variety of acid phosphatases, whose roles in phagosomal escape and virulence have been documented yet remain controversial. here we have examined in the highly virulen ...201019858304
cell biology and molecular ecology of francisella tularensis.francisella tularensis is a highly infectious intracellular bacterium that causes the fulminating disease tularemia, which can be transmitted between mammals by arthropod vectors. genomic studies have shown that the f. tularensis has been undergoing genomic decay with the most virulent strains having the lowest number of functional genes. entry of f. tularensis into macrophages is mediated by looping phagocytosis and is associated with signalling through syk tyrosine kinase. within macrophages a ...201019863554
utilization of an unstable plasmid and the i-scei endonuclease to generate routine markerless deletion mutants in francisella tularensis.we engineered an efficient system to make francisella tularensis deletion mutations using an unstable, poorly maintained plasmid to enhance the likelihood of homologous recombination. for counterselection, we adapted a strategy using i-scei, which causes a double-stranded break in the integrated suicide vector, forcing a second recombination to mediate allelic replacement.201019879904
phagosomal retention of francisella tularensis results in tirap/mal-independent tlr2 signaling.tlr2 plays a central role in the activation of innate immunity in response to ft, the causative agent of tularemia. we reported previously that ft lvs elicited strong, dose-dependent nf-kappab reporter activity in tlr2-expressing human embryo kidney 293 t cells and that ft lvs-induced murine macrophage proinflammatory cytokine gene and protein expression is tlr2-dependent. we demonstrated further that ft can signal through tlr2 from within the phagosome and that phagosomal retention of ft leads ...201019889726
regulation of apoptosis and anti-apoptosis signalling by francisella tularensis.francisella tularensis induces apoptosis within macrophages but the temporal and spatial modulation through activation of caspase-1, caspase-3, and the anti-apoptosis nuclear transcription factor b (nf-kappab) is not known. whether escape of the bacteria into the cytosol is sufficient and/or essential for activation of nf-kappab is not known. our results show that f. tularensis subsp. novicida induces sustained nuclear translocation of nf-kappab at early time points after infection of human mono ...201019925880
restricted cytosolic growth of francisella tularensis subsp. tularensis by ifn-gamma activation of macrophages.the intracellular bacterium francisella tularensis ensures its survival and proliferation within phagocytes of the infected host through phagosomal escape and cytosolic replication, to cause the disease tularemia. the cytokine interferon-gamma (ifn-gamma) is important in controlling primary infections in vivo, and in vitro intracellular proliferation of francisella in macrophages, but its actual effects on the intracellular cycle of the bacterium are ambiguous. here, we have performed an extensi ...201019926654
contributions of francisella tularensis subsp. novicida chitinases and sec secretion system to biofilm formation on chitin.francisella tularensis, the zoonotic cause of tularemia, can infect numerous mammals and other eukaryotes. although studying f. tularensis pathogenesis is essential to comprehending disease, mammalian infection is just one step in the ecology of francisella species. f. tularensis has been isolated from aquatic environments and arthropod vectors, environments in which chitin could serve as a potential carbon source and as a surface for attachment and growth. we show that f. tularensis subsp. novi ...201019948864
mechanisms of bacterial virulence in pulmonary infections.to consider the relevance to severe human lung infections of recently discovered virulence mechanisms of staphylococcus aureus and francisella tularensis.201019956071
a novel brain heart infusion broth supports the study of common francisella tularensis serotypes.francisella tularensis schu s4, lvs and u112 have become model organisms for the study of francisella pathogenesis, and represent a cross section of the different f. tularensis subspecies. both schu s4 and lvs are fastidious organisms, requiring medium fortified with supplements and nutrients for enhanced growth. chamberlains defined medium, tryptone soy broth supplemented with cysteine (tsbc), and cation-adjusted mueller-hinton broth (camhb) supplemented with 2% isovitalex are typically used in ...201020005265
identification, cloning, expression, and purification of francisella lpp3: an immunogenic lipoprotein.the severe and fatal human disease, tularemia, results from infection with the gram-negative pathogen francisella tularensis. identification of surface outer membrane proteins, specifically lipoproteins, has been of interest for vaccine development and understanding the initiation of disease. we sought to identify francisella live vaccine strain lipoproteins that could be a component of a subunit vaccine and have adjuvant properties as tlr2 agonists. we have identified a membrane lipoprotein of ...201020006480
a rapid multiplex assay for nucleic acid-based diagnostics.we have developed a rapid (under 4 hours), multiplex, nucleic acid assay, adapted to a microsphere array detection platform. we call this assay multiplex oligonucleotide ligation-pcr (mol-pcr). unlike other ligation-based assays that require multiple steps, our protocol consists of a single tube reaction, followed by hybridization to a luminex microsphere array for detection. we demonstrate the ability of this assay to simultaneously detect diverse nucleic acid signatures (e.g., unique sequences ...201020006656
francisella tularensis t-cell antigen identification using humanized hla-dr4 transgenic mice.there is no licensed vaccine against the intracellular pathogen francisella tularensis. the use of conventional mouse strains to screen protective vaccine antigens may be problematic, given the differences in the major histocompatibility complex (mhc) binding properties between murine and human antigen-presenting cells. we used engineered humanized mice that lack endogenous mhc class ii alleles but that express a human hla allele (hla-dr4 transgenic [tg] mice) to identify potential subunit vacci ...201020016043
differential ability of novel attenuated targeted deletion mutants of francisella tularensis subspecies tularensis strain schu s4 to protect mice against aerosol challenge with virulent bacteria: effects of host background and route of immunization.francisella tularensis subspecies tularensis is a highly virulent facultative intracellular pathogen of humans and a potential biological weapon. a live vaccine strain, f. tularensis lvs, was developed more than 50 years ago by pragmatic attenuation of a strain of the less virulent holarctica subspecies. lvs was demonstrated to be highly effective in human volunteers who were exposed to intradermal challenge with fully virulent subsp. tularensis, but was less effective against aerosol exposure. ...201020018266
the genome of the amoeba symbiont "candidatus amoebophilus asiaticus" reveals common mechanisms for host cell interaction among amoeba-associated bacteria.protozoa play host for many intracellular bacteria and are important for the adaptation of pathogenic bacteria to eukaryotic cells. we analyzed the genome sequence of "candidatus amoebophilus asiaticus," an obligate intracellular amoeba symbiont belonging to the bacteroidetes. the genome has a size of 1.89 mbp, encodes 1,557 proteins, and shows massive proliferation of is elements (24% of all genes), although the genome seems to be evolutionarily relatively stable. the genome does not encode pat ...201020023027
a tolc mutant of francisella tularensis is hypercytotoxic compared to the wild type and elicits increased proinflammatory responses from host cells.the highly infectious bacterium francisella tularensis is a facultative intracellular pathogen and the causative agent of tularemia. tolc, which is an outer membrane protein involved in drug efflux and type i protein secretion, is required for the virulence of the f. tularensis live vaccine strain (lvs) in mice. here, we show that an lvs deltatolc mutant colonizes livers, spleens, and lungs of mice infected intradermally or intranasally, but it is present at lower numbers in these organs than in ...201020028804
inhibition of acpa phosphatase activity with ascorbate attenuates francisella tularensis intramacrophage survival.acid phosphatase activity in the highly infectious intracellular pathogen francisella tularensis is directly related with the ability of these bacteria to survive inside host cells. pharmacological inactivation of acid phosphatases could potentially help in the treatment of tularemia or even be utilized to neutralize the infection. in the present work, we report inhibitory compounds for three of the four major acid phosphatases produced by f. tularensis schu4: acpa, acpb, and acpc. the inhibitor ...201020028980
real-time pcr for diagnosis of oculoglandular tularemia. 201020031067
the unraveling panoply of francisella tularensis virulence attributes.francisella tularensis is a highly infectious gram-negative bacterium causing the zoonotic disease tularemia. this facultative intracellular pathogen multiplies in vivo mainly inside macrophages, but has the capacity to infect and survive in many other cell types, including other phagocytic and nonphagocytic cells. in vitro, f. tularensis escapes rapidly from the phagosomal compartment and replicates in the cytoplasm of infected cells. an impressive number of novel genes related to f. tularensis ...201020034843
modulation of hepatic ppar expression during ft lvs lps-induced protection from francisella tularensis lvs infection.it has been shown previously that administration of francisella tularensis (ft) live vaccine strain (lvs) lipopolysaccharide (lps) protects mice against subsequent challenge with ft lvs and blunts the pro-inflammatory cytokine response.201020082697
identification of ciprofloxacin resistance by simpleprobe, high resolution melt and pyrosequencing nucleic acid analysis in biothreat agents: bacillus anthracis, yersinia pestis and francisella tularensis.the potential for genetic modification of biological warfare agents makes rapid identification of antibiotic resistant strains critical for the implementation of suitable infection control measures. the fluorinated quinolone, ciprofloxacin, is an antibiotic effective for treating bacterial infections by inhibiting the enzyme activity of the dna type ii topoisomerases dna gyrase and topoisomerase iv. the genes that encode the subunits of dna gyrase (gyra and gyrb) and topo iv (par c and pare) con ...201020100564
insect infection model for campylobacter jejuni reveals that o-methyl phosphoramidate has insecticidal activity.galleria mellonella (wax moth) larvae have elsewhere been shown to be susceptible to pathogens such as francisella tularensis, burkholderia mallei, and pseudomonas aeruginosa. we report that the larvae are rapidly killed by campylobacter jejuni at 37c. three strains of c. jejuni tested, 11168h (human diarrheal isolate), g1 (human guillain-barré syndrome isolate), and 81-176 (human diarrheal isolate), were equally effective at killing g. mellonella larvae. a panel of defined mutants of c. jejuni ...201020113177
investigating an airborne tularemia outbreak, germany.in november 2005, an outbreak of tularemia occurred among 39 participants in a hare hunt in hesse, germany. previously reported tularemia outbreaks in germany dated back to the 1950s. we conducted a retrospective cohort study among participants and investigated the environment to identify risk factors for infection. ten participants had serologic evidence of acute francisella tularensis infection; 1 other participant died before laboratory confirmation was obtained. presence within 5 meters of t ...201020113553
[rabbit fever--a neck tumor].twenty-two-year-old previously healthy male is referred to the ent clinic with a neck tumour. the patient was an animal caretaker. ultrasonic examination showed a lymph gland conglomerate on the left side of the neck. primary serologic examination was negative and the lymph tumour was removed. the biopsy showed necrotic lymphadenitis. three weeks after the first consultation the patient tests positive for f. tularensis. the patient was treated with ciprofloxacin 750 mg x 2 by the oral route for ...201020122334
[a case of tularemia in a danish hunter]."rabbit fever" (francisella tularensis) is a rare infection in denmark. it was first described in denmark in 1987. it is most likely to affect people who come into close contact with infected animals or ticks, such as hunters, butchers and veterinarians. the diagnosis should be suspected in such persons presenting with fever, headache, lethargy, lymphadenitis and bite wounds. we present a danish case describing the diagnosis and treatment of a hunter infected with t. tularensis.201020122335
toll-like receptor 3 agonist protection against experimental francisella tularensis respiratory tract infection.we investigated whether toll-like receptor 3 (tlr3) stimulation would protect the host from inhaled francisella tularensis. tlr3 is expressed by respiratory epithelial cells and macrophages and can be activated by a synthetic double-stranded rna ligand called polyinosine-polycytosine [poly(i:c)]. thus, we evaluated poly(i:c) as a novel treatment against inhaled f. tularensis. in vivo, balb/c mice intranasally (i.n.) treated with poly(i:c) (100 microg/mouse) 1 h before or after schu 4 or lvs (100 ...201020123717
groel and lipopolysaccharide from francisella tularensis live vaccine strain synergistically activate human macrophages.francisella tularensis, the causative agent of tularemia, interacts with host cells of innate immunity in an atypical manner. for most gram-negative bacteria, the release of lipopolysaccharide (lps) from their outer membranes stimulates an inflammatory response. when lps from the attenuated live vaccine strain (lvs) or the highly virulent schu s4 strain of f. tularensis was incubated with human umbilical vein endothelial cells, neither species of lps induced expression of the adhesion molecule e ...201020123721
identification of trkh, encoding a potassium uptake protein required for francisella tularensis systemic dissemination in mice.francisella tularensis is a highly infectious bacterium causing the zoonotic disease tularaemia. during its infectious cycle, f. tularensis is not only exposed to the intracellular environment of macrophages but also resides transiently in extracellular compartments, in particular during its systemic dissemination. the screening of a bank of f. tularensis lvs transposon insertion mutants on chemically defined medium (cdm) led us to identify a gene, designated trkh, encoding a homolog of the pota ...201020126460
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
francisella tularensis deltapyrf mutants show that replication in nonmacrophages is sufficient for pathogenesis in vivo.the pathogenesis of francisella tularensis has been associated with this bacterium's ability to replicate within macrophages. f. tularensis can also invade and replicate in a variety of nonphagocytic host cells, including lung and kidney epithelial cells and hepatocytes. as uracil biosynthesis is a central metabolic pathway usually necessary for pathogens, we characterized deltapyrf mutants of both f. tularensis lvs and schu s4 to investigate the role of these mutants in intracellular growth. as ...201020385757
indoleamine 2,3-dioxygenase 1 is a lung-specific innate immune defense mechanism that inhibits growth of francisella tularensis tryptophan auxotrophs.upon microbial challenge, organs at various anatomic sites of the body employ different innate immune mechanisms to defend against potential infections. accordingly, microbial pathogens evolved to subvert these organ-specific host immune mechanisms to survive and grow in infected organs. francisella tularensis is a bacterium capable of infecting multiple organs and thus encounters a myriad of organ-specific defense mechanisms. this suggests that f. tularensis may possess specific factors that ai ...201020385761
lung cd4-cd8- double-negative t cells are prominent producers of il-17a and ifn-gamma during primary respiratory murine infection with francisella tularensis live vaccine strain.for several intracellular infections, pulmonary vaccination provides measurably better protection against pulmonary challenge. the unique factors that contribute to pulmonary immune responses are not well characterized. in this study, we show that cd4(-)cd8(-) double negative (dn) t cells are a major responding t cell subset in the lungs of mice during pulmonary francisella tularensis live vaccine strain (lvs) infection. dn t cells were a minor (<2%) subset in spleens and lungs of mice during su ...201020393138
antimicrobial and antibiofilm activity of cathelicidins and short, synthetic peptides against francisella.francisella infects the lungs causing pneumonic tularemia. focusing on the lung's host defense, we have examined antimicrobial peptides as part of the innate immune response to francisella infection. interest in antimicrobial peptides, such as the cathelicidins, has grown due their potential therapeutic applications and the increasing problem of bacterial resistance to commonly used antibiotics. only one human cathelicidin, ll-37, has been characterized. helical cathelicidins have also been disc ...201020399752
sensing cytoplasmic danger signals by the inflammasome.introduction: the innate immune system depends on molecules collectively known as pattern recognition receptors (prrs) to survey the extracellular space and the cytoplasm for the presence of dangerous pathogens, pathogen-derived molecules, or even self-derived molecular danger signals, which arise from tissue damage. absent in melanoma 2 (aim2) is a newly discovered prr involved in the sensing of dangerous cytosolic dna produced by infection with dna viruses. discussion: remarkably, recent studi ...201020401524
[tularaemia - an overview of the current knowledge].francisella tularensis belongs to the family francisellaceae. it is the aetiological agent of a zoonosis called tularaemia, spread throughout the northern hemisphere. currently, several subspecies of f. tularensis may be distinguished with various pathogenicity and geographical distribution. in human medicine, only sporadic infections or local epidemics are reported. given the fact that f. tularensis is highly pathogenic for humans and is easily spread by aerosol, water or food, it may be exploi ...201020401834
[detection of francisella tularensis by blood culture].francisella tularensis, from the family francisellaceae, is the aetiological agent of a zoonosis called tularaemia, spread throughout the northern hemisphere. the infectious dose is extremely low (10 cfu/ml) and the infection causes severe diseases or even death if untreated. the transmission to humans is always related to animals, either by a direct contact or by a contact with the environment contaminated by them. clinical symptoms of the disease can vary depending on the point of entry of the ...201020401835
mass mortality of giant abalone haliotis gigantea caused by a francisella sp. bacterium.in february 2005, a mass mortality of giant abalone haliotis (nordotis) gigantea gmelin, 1791 occurred on a private abalone farm in shimane prefecture, japan. the cumulative mortality rate reached about 84%. in histological observations, bacteria-like spherical particles were found in affected animals, suggesting a bacterial infection. many of the bacteria-like particles were found in the cells that were presumably host phagocytes. dna was extracted from the hemolymph of a diseased abalone and a ...201020402232
[identifying bacteria using a matrix-assisted laser desorption ionization time-of-flight (maldi-tof) mass spectrometer. comparison with routine methods used in clinical microbiology laboratories].the methods routinely used for bacterial identification in clinical microbiology laboratory, although miniaturized and automated, are still based on the same basic principles as classical identification methods. nevertheless, technological advances are emerging which could modify these routine methods. we report a comparative study between conventional identification methods and mass spectrometry maldi-tof (ms maldi-tof) for bacterial identification in the clinical microbiology laboratory.201020409613
azithromycin effectiveness against intracellular infections of francisella.macrolide antibiotics are commonly administered for bacterial respiratory illnesses. azithromycin (az) is especially noted for extremely high intracellular concentrations achieved within macrophages which is far greater than the serum concentration. clinical strains of type b francisella (f.) tularensis have been reported to be resistant to az, however our laboratory francisella strains were found to be sensitive. we hypothesized that different strains/species of francisella (including type a) m ...201020416090
virulence differences among francisella tularensis subsp. tularensis clades in mice.francisella tularensis subspecies tularensis (type a) and holarctica (type b) are of clinical importance in causing tularemia. molecular typing methods have further separated type a strains into three genetically distinct clades, a1a, a1b and a2. epidemiological analyses of human infections in the united states suggest that a1b infections are associated with a significantly higher mortality rate as compared to infections caused by a1a, a2 and type b. to determine if genetic differences as define ...201020419133
ecological niche modeling of francisella tularensis subspecies and clades in the united states.two subspecies of francisella tularensis are recognized: f. tularensis subsp. tularensis (type a) and f. tularensis subsp. holartica (type b). type a has been subdivided further into a1a, a1b, and a2, which differ geographically and clinically. the aim of this work was to determine whether or not differences among subspecies and clades translate into distinct ecological niches. we used 223 isolates from humans and wildlife representing all six genotypes (type a, b, a1, a2, a1a, or a1b). ecologic ...201020439975
cloning, expression, purification, crystallization and preliminary x-ray diffraction analysis of macrophage growth locus a (mgla) protein from francisella tularensis.francisella tularensis, a potential bioweapon, causes a rare infectious disease called tularemia in humans and animals. the macrophage growth locus a (mgla) protein from f. tularensis associates with rna polymerase to positively regulate the expression of multiple virulence factors that are required for its survival and replication within macrophages. the mgla protein was overproduced in escherichia coli, purified and crystallized. the crystals diffracted to 7.5 a resolution at the advanced phot ...201020445258
absent in melanoma 2 is required for innate immune recognition of francisella tularensis.macrophages respond to cytosolic nucleic acids by activating cysteine protease caspase-1 within a complex called the inflammasome. subsequent cleavage and secretion of proinflammatory cytokines il-1beta and il-18 are critical for innate immunity. here, we show that macrophages from mice lacking absent in melanoma 2 (aim2) cannot sense cytosolic double-stranded dna and fail to trigger inflammasome assembly. caspase-1 activation in response to intracellular pathogen francisella tularensis also req ...201020457908
tularemia of european brown hare (lepus europaeus): a pathological, histopathological, and immunohistochemical study.the european brown hare (lepus europaeus) plays an important role in the ecology of tularemia, and it may serve as a significant source of human infection. the aim of the present study was to examine the lesions induced by francisella tularensis in 50 cases of naturally infected seropositive european brown hares. gross pathological examination revealed scant to numerous grayish-white foci with diameters of 0.1 to 1.0 cm in single organs (24 cases) or multiple organs (20 cases) in 44 of 50 cases ...201020466857
differentiation of bacteria using fatty acid profiles from gas chromatography-tandem mass spectrometry.fatty acids are essential components in cell membranes of bacteria, and they determine the different structures of lipids and lipid a. therefore, fatty acids are good targets for development of rapid and reliable methods for differentiation of bacteria.201020474059
directed screen of francisella novicida virulence determinants using drosophila melanogaster.francisella tularensis is a highly virulent, facultative intracellular human pathogen whose virulence mechanisms are not well understood. occasional outbreaks of tularemia and the potential use of f. tularensis as a bioterrorist agent warrant better knowledge about the pathogenicity of this bacterium. thus far, genome-wide in vivo screens for virulence factors have been performed in mice, all however restricted by the necessity to apply competition-based, negative-selection assays. we wanted to ...201020479082
development of a real-time pcr assay for identification and quantification of the fish pathogen francisella noatunensis subsp. orientalis.members of the genus francisella are small gram-negative facultative intracellular bacteria that cause francisellosis in a wide variety of fish species worldwide. f. noatunensis subsp. orientalis has been recently described as a warm-water pathogen of tilapia oreochromis spp. in this study, a quantitative real-time polymerase chain reaction (qpcr) taqman probe assay was developed to rapidly and accurately detect and quantify f. noatunensis subsp. orientalis from fish tissue. the target region of ...201020481087
molecular bases of proliferation of francisella tularensis in arthropod vectors.arthropod vectors are important vehicles for transmission of francisella tularensis between mammals, but very little is known about the f. tularensis-arthropod vector interaction. drosophila melanogaster has been recently developed as an arthropod vector model for f. tularensis. we have shown that intracellular trafficking of f. tularensis within human monocytes-derived macrophages and d. melanogaster-derived s2 cells is very similar. within both evolutionarily distant host cells, the francisell ...201020482589
molecular complexity orchestrates modulation of phagosome biogenesis and escape to the cytosol of macrophages by francisella tularensis.upon entry of francisella tularensis to macrophages, the francisella-containing phagosome (fcp) is trafficked into an acidified late endosome-like phagosome with limited fusion to the lysosomes followed by rapid escape into the cytosol where the organism replicates. although the francisella pathogenicity island (fpi), which encodes a type vi-like secretion apparatus, is required for modulation of phagosome biogenesis and escape into the cytosol, the mechanisms involved are not known. to decipher ...201020482590
involvement of the aim2, nlrc4, and nlrp3 inflammasomes in caspase-1 activation by listeria monocytogenes.infection with listeria monocytogenes can cause meningitis and septicemia in newborn, elderly, or immunocompromised individuals. pregnant women are particularly susceptible to listeria, leading to a potentially fatal infection. cytosolic listeria activates the proinflammatory caspase-1 and induces the processing and secretion of interleukins il-1beta and il-18 as well as caspase-1-dependent pyroptosis. this study elucidates the role of various inflammasome components of host macrophages in the p ...201020490635
j774 macrophage-like cell line cytokine and chemokine patterns are modulated by francisella tularensis lvs strain infection.mutual interactions were investigated between intracellular parasitic bacterium francisella tularensis (f.t.; highly virulent bacterium responsible for tularemia, replicating within the host macrophages) and murine macrophage-like cell line j774. recombinant murine lymphokine inf-gamma and/or lps derived from e. coli were determined to stimulate in vitro antimicrobial activity of macrophage-like j774 cell line against the live vaccine strain (lvs) of f.t. through their ability to produce proinfl ...201020490763
mir-155 induction by f. novicida but not the virulent f. tularensis results in ship down-regulation and enhanced pro-inflammatory cytokine response.the intracellular gram-negative bacterium francisella tularensis causes the disease tularemia and is known for its ability to subvert host immune responses. previous work from our laboratory identified the pi3k/akt pathway and ship as critical modulators of host resistance to francisella. here, we show that ship expression is strongly down-regulated in monocytes and macrophages following infection with f. tularensis novicida (f.n.). to account for this negative regulation we explored the possibi ...200920041145
attenuation of the fish pathogen francisella sp. by mutation of the iglc* gene.fish francisellosis is an emergent disease caused by gram-negative facultative intracellular bacteria of the genus francisella. different strains of the bacterium have caused high mortalities in warmwater and coldwater fish species. francisella sp. isolates from fish have been found to share more than 97% identity to the human pathogen francisella tularensis upon 16s ribosomal rna sequence comparison. homologue genes of the f. tularensis intracellular growth locus (igla*, iglb*, iglc*, and igld* ...200920043398
pathological and microbiological studies of japanese hare (lepus brachyurus angustidens) naturally infected with francisella tularensis subsp. holarctica.an adult male hare (lepus brachyurus angustidens) was discovered in a moribund condition in the bush in the mountains of aomori prefecture in japan. upon gross inspection, many ticks were found on the neck and the external ear regions, and more than half the ticks contained blood in the intestine. the skin around the tick bite wounds was alopecic and mildly thickened. at necropsy, enlargement of the cervical lymph nodes and spleen were observed. histologically, acute necrotizing splenitis, lymph ...200920046031
the francisella tularensis pathogenicity island encodes a secretion system that is required for phagosome escape and virulence.francisella tularensis causes the human disease tularemia. f. tularensis is able to survive and replicate within macrophages, a trait that has been correlated with its high virulence, but it is unclear the exact mechanism(s) this organism uses to escape killing within this hostile environment. f. tularensis virulence is dependent upon the francisella pathogenicity island (fpi), a cluster of genes that we show here shares homology with type vi secretion gene clusters in vibrio cholerae and pseudo ...200920054881
[the lipoolygosaccharide o-antigen of francisella tularensis]. 200920063802
assessment of low-molecular-weight antioxidants in francisella tularensis infected hosts: comparison of two rodents with different susceptibility to tularemia.bacterium francisella tularensis is the causative agent of tularemia disease. it is a zoonosis accompanied with high mortality when untreated. small rodents and hares, in particular, are natural reservoirs of tularemia. despite physiological similarity of common hosts, tularemia exerts different mortality rates. the pathogenesis of tularemia is still not fully understood. the main pathway is associated with proliferation in macrophages after activation by reactive oxygen species in phagosomes.200920027169
genome sequence of the endosymbiont rickettsia peacockii and comparison with virulent rickettsia rickettsii: identification of virulence factors.rickettsia peacockii, also known as the east side agent, is a non-pathogenic obligate intracellular bacterium found as an endosymbiont in dermacentor andersoni ticks in the western usa and canada. its presence in ticks is correlated with reduced prevalence of rickettsia rickettsii, the agent of rocky mountain spotted fever. it has been proposed that a virulent sfg rickettsia underwent changes to become the east side agent. we determined the genome sequence of r. peacockii and provide a compariso ...200920027221
a real-time pcr array for hierarchical identification of francisella isolates.a robust, rapid and flexible real-time pcr assay for hierarchical genetic typing of clinical and environmental isolates of francisella is presented. typing markers were found by multiple genome and gene comparisons, from which 23 canonical single nucleotide polymorphisms (cansnps) and 11 canonical insertion-deletion mutations (canindels) were selected to provide phylogenetic guidelines for classification from genus to isolate level. the specificity of the developed assay, which uses 68 wells of ...200920027310
kinetic characterization and phosphoregulation of the francisella tularensis 1-deoxy-d-xylulose 5-phosphate reductoisomerase (mep synthase).deliberate and natural outbreaks of infectious disease underscore the necessity of effective vaccines and antimicrobial/antiviral therapeutics. the prevalence of antibiotic resistant strains and the ease by which antibiotic resistant bacteria can be intentionally engineered further highlights the need for continued development of novel antibiotics against new bacterial targets. isoprenes are a class of molecules fundamentally involved in a variety of crucial biological functions. mammalian cells ...200920011597
tick-borne agents in rodents, china, 2004-2006.a total of 705 rodents from 6 provinces and autonomous regions of mainland people's republic of china were tested by pcrs for tick-borne agents (anaplasma phagocytophilum, borrelia burgdorferi sensu lato, spotted fever group rickettsiae, and francisella tularensis). infection rates were 5.5%, 6.7%, 9.1% and 5.0%, respectively. eighteen (2.6%) rodents of 10 species were positive for 2 or 3 agents. sequence analysis of pcr products confirmed the presence and genotypes of detected agents. these fin ...200919961668
landscape epidemiology of tularemia outbreaks in sweden.summer outbreaks of tularemia that occurred from 1995 through 2005 in 2 locations in sweden affected 441 persons. we performed an epidemiologic investigation of these outbreaks using a novel strategy, involving high-resolution genotyping of francisella tularensis isolates obtained from 136 patients (using 18 genetic markers developed from 6 f. tularensis genome sequences) and interviews with the patients. strong spatial associations were found between f. tularensis subpopulations and the places ...200919961673
identification of francisella tularensis cluster in central and western europe.we conducted a molecular analysis of francisella tularensis strains isolated in switzerland and identified a specific subpopulation belonging to a cluster of f. tularensis subsp. holarctica that is widely dispersed in central and western continental europe. this subpopulation was present before the tularemia epidemics on the iberian peninsula.200919961699
[pandora's box: pathogens in ixodes ricinus ticks in central europe].among the various species of hard ticks, ixodes ricinus is the most frequently found tick throughout europe. as with other ixodid ticks, the developmental cycle runs through three stages. in each stage a blood meal is required in order to develop to the next stage. ixodes ricinus has been found to feed on more than 300 different vertebrate species. usually, larval ticks feed on small mammals such as mice and become infected with various microorganisms and viruses, of which some are substantial p ...200919998007
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