Transcriptomic Profiling of Murine Macrophages During Francisella tularensis Infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE337952 | GEO | 2026/07/15
REPOSITORIES: GEO
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Project description:Francisella tularensis is a Gram-negative bacterium that causes a fatal human disease known as tularemia. The Centers for Disease Control have classified F. tularensis as Category A Tier-1 Select Agent. The virulence mechanisms of Francisella are not entirely understood. Francisella possesses very few transcription regulators, and most of these regulate the expression of genes involved in intracellular survival and virulence. The F. tularensis genome sequence analysis reveals an AraC (FTL_0689) transcriptional regulator homologous to the AraC/XylS family of transcriptional regulators. In Gram-negative bacteria, AraC activates genes required for L-arabinose utilization and catabolism. The role of the FTL_0689 regulator in F. tularensis is not known. In this study, we characterized the role of FTL_0689 in gene regulation of F. tularensis and investigated its contribution to intracellular survival and virulence. The results demonstrate that FTL_0689 in Francisella is not required for L-arabinose utilization. Instead, FTL_0689 specifically regulates the expression of the oxidative and global stress response, virulence, metabolism, and other key pathways genes required by Francisella when exposed to oxidative stress. The FTL_0689 mutant is attenuated for intramacrophage growth, and mice infected with the FTL_0689 mutant survive better than wild-type F. tularensis LVS infected mice. Based on the deletion mutant phenotype, FTL_0689 was termed osrR (oxidative stress response regulator). Altogether, this study elucidates the role of the osrR transcriptional regulator in tularemia pathogenesis.
2021-10-13 | GSE183001 | GEO
Project description:Francisella tularensis, the etiological agnet of Tularemia is a Category A select agent. Preparedness means for prompt proper antibiotic treatment are of need to prevent morbidity and mortality. While standard antimicrobial susceptibility tests are time consuming, the quantification of the changes in the expression levlels of specific mRNA markers folowing antibiotic exposure may enable a rapid determination of antimicrobial susceptibility. We submit transcriptomic data sets detailing global gene expression of F. tularensis following exposure to Doxycycline or Ciprofloxacin antibiotics.
2023-03-05 | GSE210974 | GEO
Project description:Francisella tularensis is classified as a Category A priority pathogen and causes fatal disseminated disease in humans upon inhalation of less than 50 bacteria. Although drugs are available for treatment, they are not ideal because of toxicity and delivery, and in some cases relapse upon withdrawal. We have an ongoing program in the development of novel FabI enoyl-ACP-reductase enzyme inhibitors for Francisella and other select agents. To establish ftFabI in F. tularensis as a clinically relevant drug target, we demonstrated that the enzyme is essential for growth in vitro and that ftfabI is not transcriptionally altered in the presence of exogenous fatty acids. Inhibition of ftFabI results in loss of viability that is not rescued by exogenous fatty acids supplementation. Importantly, whole-genome transcriptional profiling of F. tularensis with DNA microarrays from infected tissues revealed that ftfabI and de novo fatty acid biosynthetic genes are transcriptionally active during infection. This is the first demonstration that the FabI enoyl-ACP-reductase enzyme encoded by F. tularensis is essential and that de novo fatty acid biosynthetic components are transcriptionally active during infection in the mouse model tularemia.
2012-08-04 | GSE39871 | GEO
Project description:Francisella tularensis is classified as a Category A priority pathogen and causes fatal disseminated disease in humans upon inhalation of less than 50 bacteria. Although drugs are available for treatment, they are not ideal because of toxicity and delivery, and in some cases relapse upon withdrawal. We have an ongoing program in the development of novel FabI enoyl-ACP-reductase enzyme inhibitors for Francisella and other select agents. To establish ftFabI in F. tularensis as a clinically relevant drug target, we demonstrated that the enzyme is essential for growth in vitro and that ftfabI is not transcriptionally altered in the presence of exogenous fatty acids. Inhibition of ftFabI results in loss of viability that is not rescued by exogenous fatty acids supplementation. Importantly, whole-genome transcriptional profiling of F. tularensis with DNA microarrays from infected tissues revealed that ftfabI and de novo fatty acid biosynthetic genes are transcriptionally active during infection. This is the first demonstration that the FabI enoyl-ACP-reductase enzyme encoded by F. tularensis is essential and that de novo fatty acid biosynthetic components are transcriptionally active during infection in the mouse model tularemia. 2 C57BL/6 mice were infected with Francisella tularensis strain Schu4 via the intranasal route. Spleen tissue was harvested at 120 hours post-infection and total RNA was isolated immediately after harvest. RNA was pooled and host polyA-tailed RNA and ribosomal RNA were depleted using hybridization probes coupled to magnetic beads. The resulting sample was enriched for bacterial mRNA, and dye labeled using random hexamer primed RT and Cy3-labeled dUTPs. Labeled cDNA was hybridized in triplicate to custom whole genome cDNA microarrays and scanned using a GenePix 4000B.
2012-08-03 | E-GEOD-39871 | biostudies-arrayexpress
Project description:These samples are part of an experiment comparing the expression profiles of Francisella tularensis novicida grown in chemically defined medium and bacteria isolated 24 hours post infection of J774 macrophages to identify virulence factors
2017-05-02 | GSE75689 | GEO
Project description:Francisella tularensis, is an extremely virulent bacterium that can be transmitted naturally by blood sucking arthropods. During mammalian infection, F. tularensis infects numerous types of host cells, including erythrocytes. As erythrocytes do not undergo phagocytosis or endocytosis, it remains unknown how F. tularensis invades these cells. Furthermore, the consequence of inhabiting the intracellular space of red blood cells has not been determined. Here, we provide evidence indicating that residing within an erythrocyte enhances the ability of F. tularensis to colonize ticks following a blood meal.
2017-05-24 | GSE93233 | GEO
Project description:The highly infectious bacterium Francisella tularensis is a facultative intracellular pathogen, whose virulence requires proliferation inside host cells, including macrophages. Although some Francisella determinants of intracellular growth have been identified, much remains to be understood about the pathogenesis of this organism. In particular, how Francisella responds to its intracellular environment could provide clues about its intracellular biology and reveal pathogenic determinants based on their intracellular expression profiles. Here we have performed a global transcriptional profiling of the highly virulent F. tularensis subsp. tularensis Schu S4 strain during its intracellular cycle within primary murine macrophages. Phagocytosed bacteria rapidly responded to their intracellular environment and progressively altered their transcriptional profile over time. Differential gene expression profiles were revealed that correlated with specific intracellular locations of the bacteria. Upregulation of general and oxidative stress response genes was a hallmark of the early phagosomal and late endosomal stages, while induction of a subset of transport and metabolic genes characterized the cytosolic replication stages. Expression of the Francisella Pathogenicity Island (FPI) genes, the functions of which are associated with intracellular proliferation, increased during the intracellular cycle. Similarly, 27 chromosomal loci putatively encoding hypothetical, secreted, outer membrane proteins or transcriptional regulators were identified as upregulated during the intracellular cycle. In-frame deletion of FTT0383, the Schu S4 ortholog of fevR, of FTT0369c or FTT1676 abolished the ability of Schu S4 to either survive or proliferate intracellularly, demonstrating that bacterial factors of intracellular pathogenesis can be identified based on their intracellular expression profile. In conclusion, establishing the intracellular transcriptome of Francisella has revealed important aspects of its intracellular biology and identified novel virulence determinants of this pathogen. Keywords: Time series
2009-05-05 | GSE12663 | GEO
Project description:The facultative intracellular bacterium Francisella tularensis causes the zoonotic disease tularemia. F. tularensis resides within host macrophages in vivo and this ability is essential for pathogenesis. The transcription factor MglA is required for expression of several Francisella genes that are necessary for replication in macrophages and for virulence in mice. We hypothesized that identification of MglA-regulated genes in the Francisella genome by transcriptional profiling of wild-type and mglA mutant bacteria would lead to the discovery of new virulence factors utilized by F. tularensis. One hundred and two MglA-regulated genes were identified, the majority of which were positively regulated, including all of the Francisella Pathogenicity Island (FPI) genes. We mutated novel MglA-regulated genes and tested the mutants for their ability to replicate and to induce cytotoxicity in macrophages, and to grow in mice. Mutants in MglA-regulated genes within the FPI (pdpB and cds2), as well as outside the FPI (FTT0989, oppB, and FTT1209c), were either attenuated or hypervirulent in macrophages as compared to the wild-type strain. All of these mutants exhibited decreased fitness in vivo in competition experiments with wild-type bacteria. We have identified 5 new Francisella virulence genes and our results suggest that characterization of additional MglA-regulated genes will yield further insights into the pathogenesis of this bacterium. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs
2006-10-20 | GSE5468 | GEO
Project description:Differential expression in human peripheral blood monocytes between F. novicida-infected and uninfected, and between Francisella tularensis tularensis isolate Schu S4 and uninfected. The goal was to examine genomewide transcriptional reponses to these two strains, and identify differentially-regulated genes that may help explain the virulence of Schu S4. Keywords: Immune Response, Human Monocytes, Bacteria, Francisella
2008-08-13 | GSE12108 | GEO
Project description:The facultative intracellular bacterium Francisella tularensis causes the zoonotic disease tularemia. F. tularensis resides within host macrophages in vivo and this ability is essential for pathogenesis. The transcription factor MglA is required for expression of several Francisella genes that are necessary for replication in macrophages and for virulence in mice. We hypothesized that identification of MglA-regulated genes in the Francisella genome by transcriptional profiling of wild-type and mglA mutant bacteria would lead to the discovery of new virulence factors utilized by F. tularensis. One hundred and two MglA-regulated genes were identified, the majority of which were positively regulated, including all of the Francisella Pathogenicity Island (FPI) genes. We mutated novel MglA-regulated genes and tested the mutants for their ability to replicate and to induce cytotoxicity in macrophages, and to grow in mice. Mutants in MglA-regulated genes within the FPI (pdpB and cds2), as well as outside the FPI (FTT0989, oppB, and FTT1209c), were either attenuated or hypervirulent in macrophages as compared to the wild-type strain. All of these mutants exhibited decreased fitness in vivo in competition experiments with wild-type bacteria. We have identified 5 new Francisella virulence genes and our results suggest that characterization of additional MglA-regulated genes will yield further insights into the pathogenesis of this bacterium. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs Computed
2010-07-01 | E-GEOD-5468 | biostudies-arrayexpress