Cell membrane Complex Enzyme Eukaryotic cell or cell component Microbe-host cell complex Microorganism or its component Other Other -- ion Pathway or action Protein Protein or gene Protein or gene complex Protein or protein complex Bacterial membrane or virus envelope Cell membrane Cytoplasm Eukaryotic cell or cell component Extracellular Golgi Golgi membrane Intercellular Intracellular Mitochondria Nucleocapsid/Cytoplasm Organelle Organelle -- Cell membrane Organelle -- Endoplasmic reticulum Organelle -- ER Organelle -- Golgi Organelle -- Golgi membrane Organelle -- Nucleus Organelle -- Phagolysosome Organelle -- Phagosome Organelle -- Ribosome Other Phagolysosome Phagosome Chaperone Defense, immunity protein Enzyme Enzyme activator Enzyme inhibitor Genomic S segment Infection Ligand binding or carrier Motor Nucleic acid binding Other Signal transducer Toxicity Transcription factor binding Transcription regulation Transporter Unknown IC Inferred by Curator IDA Inferred from Direct Assay IEA Inferred from Electronic Annotation IEP Inferred from Expression Pattern IGI Inferred from Genetic Interaction IMP Inferred from Mutant Phenotype IPI Inferred from Physical Interaction ISS Inferred from Sequence or Structural Similarity NAS Non-traceable Author Statement ND No biological Data available RCA inferred from Reviewed Computational Analysis TAS Traceable Author Statement NR Not Recorded Telepnev M, Golovliov I, Grundstrom T, Tarnvik A, Sjostedt A Cellular microbiology Francisella tularensis inhibits Toll-like receptor-mediated activation of intracellular signalling and secretion of TNF-alpha and IL-1 from murine macrophages 2003 12542469 PubMed Golovliov I, Ericsson M, Sandstrom G, Tarnvik A, Sjostedt A Infection and immunity Identification of proteins of Francisella tularensis induced during growth in macrophages and cloning of the gene encoding a prominently induced 23-kilodalton protein 1997 9169749 PubMed Reilly TJ, Baron GS, Nano FE, Kuhlenschmidt MS The Journal of biological chemistry Characterization and sequencing of a respiratory burst-inhibiting acid phosphatase from Francisella tularensis 19963 8631917 PubMed Baron GS, Reilly TJ, Nano FE FEMS microbiology letters The respiratory burst-inhibiting acid phosphatase AcpA is not essential for the intramacrophage growth or virulence of Francisella novicida 19991 10418134 PubMed Fortier AH, Leiby DA, Narayanan RB, Asafoadjei E, Crawford RM, Nacy CA, Meltzer MS Infection and immunity Growth of Francisella tularensis LVS in macrophages: the acidic intracellular compartment provides essential iron required for growth 1995 7890413 PubMed Sandstrom G, Lofgren S, Tarnvik A Infection and immunity A capsule-deficient mutant of Francisella tularensis LVS exhibits enhanced sensitivity to killing by serum but diminished sensitivity to killing by polymorphonuclear leukocytes 1988 3356465 PubMed Pavlovich NV, Sorokin VM, Blagorodova NS Zhurnal mikrobiologii, epidemiologii, i immunobiologii [The resistance of Francisella tularensis to the bactericidal action of normal serum as a criterion for evaluating the virulence of the bacterium] 1996 8820667 PubMed Sjostedt A, Tarnvik A, Sandstrom G Infection and immunity The T-cell-stimulating 17-kilodalton protein of Francisella tularensis LVS is a lipoprotein 1991 1879938 PubMed Sjostedt A, Kuoppa K, Johansson T, Sandstrom G Microbial pathogenesis The 17 kDa lipoprotein and encoding gene of Francisella tularensis LVS are conserved in strains of Francisella tularensis 1992 1291846 PubMed Sjostedt A, Eriksson U, Berglund L, Tarnvik A Journal of clinical microbiology Detection of Francisella tularensis in ulcers of patients with tularemia by PCR 1997 9114378 PubMed Cowley SC, Gray CJ, Nano FE FEMS microbiology letters Isolation and characterization of Francisella novicida mutants defective in lipopolysaccharide biosynthesis 20001 10612732 PubMed Vinogradov E, Perry MB, Conlan JW European journal of biochemistry / FEBS Structural analysis of Francisella tularensis lipopolysaccharide 2002 12473106 PubMed Ancuta P, Pedron T, Girard R, Sandstrom G, Chaby R Infection and immunity Inability of the Francisella tularensis lipopolysaccharide to mimic or to antagonize the induction of cell activation by endotoxins 1996 8675305 PubMed Sandstrom G, Sjostedt A, Johansson T, Kuoppa K, Williams JC FEMS microbiology immunology Immunogenicity and toxicity of lipopolysaccharide from Francisella tularensis LVS 1992 1419118 PubMed Bhatnagar NB, Elkins KL, Fortier AH Infection and immunity Heat stress alters the virulence of a rifampin-resistant mutant of Francisella tularensis LVS 1995 7806352 PubMed Lai XH, Golovliov I, Sjostedt A Infection and immunity Francisella tularensis induces cytopathogenicity and apoptosis in murine macrophages via a mechanism that requires intracellular bacterial multiplication 2001 11402018 PubMed Sjostedt A Current opinion in microbiology Virulence determinants and protective antigens of Francisella tularensis 2003 12615222 PubMed Gerasimov VN, Dolotov VI, Stepanov AV, Urakov NN Vestnik Rossi inverted question marksko inverted question mark akademii meditsinskikh nauk / Rossi inverted question markskaia akademiia meditsinskikh nauk [Morphology, ultrastructure and populational features of bacteria francisella] 1997 9289274 PubMed Francisella tularensis. Cell envelope Function: . Francisella tularensis was isolated as the agent of a plague-like disease in a ground squirrel in Tulare County, California, in 1911.F. tularensis is a highly virulent facultative intracellular bacterium and the etiological agent of tularemia. The disease is characterized by ulceroglandular infection, pneumonia, and typhoidal symptoms in some cases.F. tularensis is one of the most infectious bacteria known, and in humans, inoculation or inhalation of a few cells can cause severe disease. In addition, tularemia is one of the most common laboratory-acquired diseases. Because of its high infectivity, together with an ease of dissemination and ability to cause severe disease and death, F. tularensis is designated as a category A agent (i.e.a likely biological weapon).Little is known about how it survives within host cells, since, unlike many other facultative intracellular bacteria, it produces no toxins and harbors no secretion systems.The cell envelope of F.tularensis has considerable interest because of its unusual biological and structural properties.(Gerasimov et al., 1997)(Sjostedt, 2003)(Lai et al., 2001)(Bhatnagar et al., 1995) Unique lipopolysaccharide (LPS) Function: . The lipopolysaccharide (LPS) of F. tularensis shows an unusual low toxicity in vitro and in vivo. Its ability to elicit release of interleukin 1 and tumor necrosis factor from mononuclear cells is 1000-fold less than Escherichia coli LPS. The LPS contains a beta-GlcN-(1-6)-GlcN lipid A backbone, but has a number of unusual structural features; it apparently has no substituent at O-1 of the reducing end GlcN residue in the lipid part in the major part of the population, no substituents at O-3 and O-4 of beta-GlcN, and no substituent at O-4 of the Kdo residue.(Sandstrom et al., 1992)(Ancuta et al., 1996)(Vinogradov et al., 2002) LPS. O-antigen. Protection function Function: . The O-specific polysaccharide (O-antigen region) of LPS protects the bacterial cell from complement mediated killing by serum. O-antigen is required to mask determinants within the core and lipid A region involved in activation of both the classical and alternative complement pathways. Furthermore, although O-antigen activates the alternative pathway, the steric hindrance of longer O-side chains is involved in protecting the membrane from the complement attack complex.(Cowley et al., 2000) 17-kDa membrane lipoprotein Function: . The 17-kDa lipoprotein, a major membrane protein of F. tularensis, and the encoding gene has no significant similarity to prokaryotic or eukaryotic sequences.(Sjostedt et al., 1997)(Sjostedt et al., 1992)(Sjostedt et al., 1991) Lipoprotein. Recognition by T cells Function: . A 17-kDa membrane lipoprotein of F. tularensis is recognized by T cells from humans vaccinated with F. tularensis. The 17-kDa lipoprotein is recognized not only by T cells but also by serum antibodies of F. tularensis-primed individuals.(Sjostedt et al., 1992)(Sjostedt et al., 1991) Lipid containing capsule Function: . The capsule contains 50-70% (w/w) lipids, the other components have not been identified.(Sjostedt, 2003) Capsule. Protection function Function: . The capsule protects against serum-mediated lysis but its possession may not be advantageous intracellularly.(Pavlovich et al., 1996)(Sandstrom et al., 1988) Fully virulent F. tularensis cells Function: . The capsule, lipopolysaccharide and 17-kDa membrane lipoprotein appear to be a necessary components for expression of F.tularensis virulence.(Cowley et al., 2000)(Sjostedt et al., 1997)(Sjostedt et al., 1992)(Gerasimov et al., 1997)(Sjostedt, 2003)(Pavlovich et al., 1996) F. tularensis as intracellular pathogen Function: . It is clear that F. tularensis is an intracellular pathogen, replicating mainly in macrophages. The growth rate in macrophages is apparently similar to the growth rate in laboratory media.(Fortier et al., 1995) Acid phosphatase (AcpA) Function: . The acid phosphatase (AcpA) of intracellular pathogen F. tularensis is a factor that enhances intracellular survival. The deduced amino acid sequence of AcpA has no similarity to any known phosphatases and lacks acid phosphatase (RHGXRXP) and protein tyrosine phosphatase (PTPase) ((I/V)HCXAGXXR(S/T)G) signature motifs.(Baron et al., 1999)(Reilly et al., 1996) AcpA. Respiratory burst inhibition Function: . The Francisella acid phosphatase (AcpA) is reported to be a potent inhibitor of the respiratory burst. The mechanism by which AcpA inhibits the respiratory burst is unknown. It is possible that AcpA may cooperate with other proteins, such as catalase and superoxide dismutase, to protect Francisella from the damaging effects of the respiratory burst.(Baron et al., 1999)(Reilly et al., 1996) F. tularensis. Survival in macrophages Function: . The intracellular pathogen F. tularensis may enhance their survival in phagocytic cells (macrophages) by inhibition of the respiratory burst using tartrate-resistant, non-specific acid phosphatase (AcpA).(Baron et al., 1999)(Reilly et al., 1996) F. tularensis. Replication within endosomes Function: . It has been suggested that F. tularensis cells replicate within acidified endosomes in macrophages. It is possible that these acid conditions liberate ferric ions from transferrin. Thus, intracellular localization in an acidic vesicle which facilitates the availability of iron essential for Francisella growth is a survival tactic of this bacterium, and iron depletion is one mechanism that macrophages use to inhibit its growth.(Fortier et al., 1995) F. tularensis. Cytoplasmic 23-kDa protein Function: Enzyme inhibitor. A 23-kDa protein of F. tularensis is upregulated during intracellular growth in murine macrophages or after exposure of extracellular bacteria to hydrogen peroxide. Thus, this protein seems to play an important role in the ability of several F. tularensis subspecies to multiply intracellularly. The deduced amino acid sequence of this 23-kDa protein has no significant similarity to any previously characterized protein.(Golovliov et al., 1997) NF-kB and MAPK pathways inhibition Function: Enzyme inhibitor. F. tularensis is capable of manipulating the antimicrobial effector mechanisms of macrophages. The abrogation by F. tularensis of the antimicrobial response of macrophages is dependent on the expression of a 23 kDa protein. The bacterium completely inhibits the release of proinflammatory cytokines by targeting the nuclear factor (NF)-kB system and mitogen-activated protein kinase (MAPK) pathways.(Telepnev et al., 2003) F. tularensis. Multiplication in macrophages Function: Enzyme inhibitor. The presence of the 23 kDa protein is sufficient for the rapid intracellular multiplication of F. tularensis.Some demonstrations verified the crucial role of the 23 kDa protein for intracellular parasitism because the mutant lacking its expression showed impaired intracellular multiplication.(Telepnev et al., 2003) Host cell apoptosis Function: . The intracellular growth of F. tularensis in murine macrophages is associated with cytopathogenicity in murine macrophages, but the underlying mechanism remains unclear.The signaling required to induce apoptosis is triggered by the presence of relatively high numbers of F. tularensis in the logarithmic growth phase inside the host cellsApoptosis can be demonstrated in the infected cells. The first signs of apoptosis are observed at 18 h of infection and this is the probable reason for loss of membrane integrity seen at 24 h.Despite this host cell apoptosis, no decrease in bacterial numbers is observed.(Lai et al., 2001)