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Key tissue targets responsible for anthrax-toxin-induced lethality

Nature volume 501, pages 63–68 (2013)Cite this article

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Abstract

Bacillus anthracis, the causative agent of anthrax disease, is lethal owing to the actions of two exotoxins: anthrax lethal toxin (LT) and oedema toxin (ET). The key tissue targets responsible for the lethal effects of these toxins are unknown. Here we generated cell-type-specific anthrax toxin receptor capillary morphogenesis protein-2 (CMG2)-null mice and cell-type-specific CMG2-expressing mice and challenged them with the toxins. Our results show that lethality induced by LT and ET occurs through damage to distinct cell types; whereas targeting cardiomyocytes and vascular smooth muscle cells is required for LT-induced mortality, ET-induced lethality occurs mainly through its action in hepatocytes. Notably, and in contradiction to what has been previously postulated, targeting of endothelial cells by either toxin does not seem to contribute significantly to lethality. Our findings demonstrate that B. anthracis has evolved to use LT and ET to induce host lethality by coordinately damaging two distinct vital systems.

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Figure 1: LT targeting of endothelial cells is not lethal to mice.
Figure 2: Targeting of cardiomyocytes and smooth muscle cells by LT is sufficient for lethality.
Figure 3: Mice lacking CMG2 receptor in the three major cell types of the cardiovascular system are highly resistant to LT and B. anthracis infection.
Figure 4: ET directly targets intestinal epithelial cells and hepatocytes.
Figure 5: Hepatocytes are a major target of ET-induced lethality.

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References

  1. Moayeri, M. & Leppla, S. H. Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol. Aspects Med. 30, 439–455 (2009)

    Article  CAS  Google Scholar 

  2. Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J. & Young, J. A. Identification of the cellular receptor for anthrax toxin. Nature 414, 225–229 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Scobie, H. M., Rainey, G. J., Bradley, K. A. & Young, J. A. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc. Natl Acad. Sci. USA 100, 5170–5174 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Liu, S. et al. Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo. Proc. Natl Acad. Sci. USA 106, 12424–12429 (2009)

    Article  ADS  CAS  Google Scholar 

  5. Leppla, S. H. Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc. Natl Acad. Sci. USA 79, 3162–3166 (1982)

    Article  ADS  CAS  Google Scholar 

  6. Firoved, A. M. et al. Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice. Am. J. Pathol. 167, 1309–1320 (2005)

    Article  CAS  Google Scholar 

  7. Duesbery, N. S. et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280, 734–737 (1998)

    Article  ADS  CAS  Google Scholar 

  8. Vitale, G. et al. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem. Biophys. Res. Commun. 248, 706–711 (1998)

    Article  CAS  Google Scholar 

  9. Vitale, G., Bernardi, L., Napolitani, G., Mock, M. & Montecucco, C. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem. J. 352, 739–745 (2000)

    Article  CAS  Google Scholar 

  10. Newman, Z. L. et al. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog. 6, e1000906 (2010)

    Article  Google Scholar 

  11. Levinsohn, J. L. et al. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 8, e1002638 (2012)

    Article  Google Scholar 

  12. Pezard, C., Berche, P. & Mock, M. Contribution of individual toxin components to virulence of Bacillus anthracis. Infect. Immun. 59, 3472–3477 (1991)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu, S. et al. Anthrax toxin targeting of myeloid cells through the CMG2 receptor is essential for establishment of Bacillus anthracis infections in mice. Cell Host Microbe 8, 455–462 (2010)

    Article  CAS  Google Scholar 

  14. Guichard, A., Nizet, V. & Bier, E. New insights into the biological effects of anthrax toxins: linking cellular to organismal responses. Microbes Infect. 5, 48–61 (2012)

    Google Scholar 

  15. Moayeri, M., Haines, D., Young, H. A. & Leppla, S. H. Bacillus anthracis lethal toxin induces TNF-independent hypoxia-mediated toxicity in mice. J. Clin. Invest. 112, 670–682 (2003)

    Article  CAS  Google Scholar 

  16. Moayeri, M. et al. The heart is an early target of anthrax lethal toxin in mice: a protective role for neuronal nitric oxide synthase (nNOS). PLoS Pathog. 5, e1000456 (2009)

    Article  Google Scholar 

  17. Bolcome, R. E., III et al. Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature. Proc. Natl Acad. Sci. USA 105, 2439–2444 (2008)

    Article  ADS  CAS  Google Scholar 

  18. Guichard, A. et al. Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst. Nature 467, 854–858 (2010)

    Article  ADS  CAS  Google Scholar 

  19. Warfel, J. M., Steele, A. D. & D’Agnillo, F. Anthrax lethal toxin induces endothelial barrier dysfunction. Am. J. Pathol. 166, 1871–1881 (2005)

    Article  CAS  Google Scholar 

  20. Maddugoda, M. P. et al. cAMP signaling by anthrax edema toxin induces transendothelial cell tunnels, which are resealed by MIM via Arp2/3-driven actin polymerization. Cell Host Microbe 10, 464–474 (2011)

    Article  CAS  Google Scholar 

  21. Ghosh, C. C. et al. Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax. Proc. Natl Acad. Sci. USA 109, 10024–10029 (2012)

    Article  ADS  CAS  Google Scholar 

  22. Arora, N., Klimpel, K. R., Singh, Y. & Leppla, S. H. Fusions of anthrax toxin lethal factor to the ADP-ribosylation domain of Pseudomonas exotoxin A are potent cytotoxins which are translocated to the cytosol of mammalian cells. J. Biol. Chem. 267, 15542–15548 (1992)

    CAS  PubMed  Google Scholar 

  23. Liu, S. et al. Diphthamide modification on eukaryotic elongation factor 2 is needed to assure fidelity of mRNA translation and mouse development. Proc. Natl Acad. Sci. USA 109, 13817–13822 (2012)

    Article  ADS  CAS  Google Scholar 

  24. Bradley, S. V. et al. Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1. Hum. Mol. Genet. 16, 1279–1292 (2007)

    Article  CAS  Google Scholar 

  25. Lepore, J. J. et al. High-efficiency somatic mutagenesis in smooth muscle cells and cardiac myocytes in SM22α-Cre transgenic mice. Genesis 41, 179–184 (2005)

    Article  CAS  Google Scholar 

  26. Dal Molin, F. et al. Ratio of lethal and edema factors in rabbit systemic anthrax. Toxicon 52, 824–828 (2008)

    Article  CAS  Google Scholar 

  27. Sirard, J. C., Mock, M. & Fouet, A. The three Bacillus anthracis toxin genes are coordinately regulated by bicarbonate and temperature. J. Bacteriol. 176, 5188–5192 (1994)

    Article  CAS  Google Scholar 

  28. Mabry, R. et al. Detection of anthrax toxin in the serum of animals infected with Bacillus anthracis by using engineered immunoassays. Clin. Vaccine Immunol. 13, 671–677 (2006)

    Article  CAS  Google Scholar 

  29. Jernigan, J. A. et al. Bioterrorism-related inhalational anthrax: The first 10 cases reported in the United States. Emerg. Infect. Dis. 7, 933–944 (2001)

    Article  CAS  Google Scholar 

  30. Guarner, J. et al. Pathology and pathogenesis of bioterrorism-related inhalational anthrax. Am. J. Pathol. 163, 701–709 (2003)

    Article  CAS  Google Scholar 

  31. Pomerantsev, A. P., Sitaraman, R., Galloway, C. R., Kivovich, V. & Leppla, S. H. Genome engineering in Bacillus anthracis using Cre recombinase. Infect. Immun. 74, 682–693 (2006)

    Article  CAS  Google Scholar 

  32. Hu, H., Sa, Q., Koehler, T. M., Aronson, A. I. & Zhou, D. Inactivation of Bacillus anthracis spores in murine primary macrophages. Cell. Microbiol. 8, 1634–1642 (2006)

    Article  CAS  Google Scholar 

  33. Reynolds, L. E. & Hodivala-Dilke, K. M. Primary mouse endothelial cell culture for assays of angiogenesis. Methods Mol. Med. 120, 503–509 (2006)

    PubMed  Google Scholar 

  34. Liu, S. & Leppla, S. H. Cell surface tumor endothelium marker 8 cytoplasmic tail-independent anthrax toxin binding, proteolytic processing, oligomer formation, and internalization. J. Biol. Chem. 278, 5227–5234 (2003)

    Article  CAS  Google Scholar 

  35. Alva, J. A. et al. VE-Cadherin-Cre-recombinase transgenic mouse: a tool for lineage analysis and gene deletion in endothelial cells. Dev. Dyn. 235, 759–767 (2006)

    Article  CAS  Google Scholar 

  36. Agah, R. et al. Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J. Clin. Invest. 100, 169–179 (1997)

    Article  CAS  Google Scholar 

  37. Holtwick, R. et al. Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc. Natl Acad. Sci. USA 99, 7142–7147 (2002)

    Article  ADS  CAS  Google Scholar 

  38. Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 274, 305–315 (1999)

    Article  CAS  Google Scholar 

  39. Braunstein, E. M. et al. Villin: A marker for development of the epithelial pyloric border. Dev. Dyn. 224, 90–102 (2002)

    Article  CAS  Google Scholar 

  40. Hall, B. E. et al. Conditional overexpression of TGF-β1 disrupts mouse salivary gland development and function. Lab. Invest. 90, 543–555 (2010)

    Article  CAS  Google Scholar 

  41. Pomerantsev, A. P. et al. A Bacillus anthracis strain deleted for six proteases serves as an effective host for production of recombinant proteins. Protein Expr. Purif. 80, 80–90 (2011)

    Article  CAS  Google Scholar 

  42. Liu, S., Leung, H. J. & Leppla, S. H. Characterization of the interaction between anthrax toxin and its cellular receptors. Cell. Microbiol. 9, 977–987 (2007)

    Article  CAS  Google Scholar 

  43. Gupta, P. K., Moayeri, M., Crown, D., Fattah, R. J. & Leppla, S. H. Role of N-terminal amino acids in the potency of anthrax lethal factor. PLoS ONE 3, e3130 (2008)

    Article  ADS  Google Scholar 

  44. Rosovitz, M. J. et al. Alanine scanning mutations in domain 4 of anthrax toxin protective antigen reveal residues important for binding to the cellular receptor and to a neutralizing monoclonal antibody. J. Biol. Chem. 278, 30936–30944 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, National Institutes of Health. We thank L. Feigenbaum and the staff at SAIC/NCI Frederick for generation of the founder CMG2 transgenic mice. We thank A. Kulkarni, B. Hall, B. Klaunberg, S. Anderson, I. Sastalla, C. Leysath and C. Bachran for discussions, and D. Despres for help with echocardiography.

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Authors and Affiliations

  1. Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Shihui Liu, Yi Zhang, Mahtab Moayeri, Devorah Crown, Rasem J. Fattah, Alexander N. Wein & Stephen H. Leppla

  2. Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jie Liu & Toren Finkel

  3. Pathology Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Zu-Xi Yu

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Contributions

Y.Z. maintained mouse colonies and performed animal experiments. M.M. and J.L. designed, performed experiments, analysed data and edited the paper. D.C. performed animal experiments. R.J.F. purified proteins. A.N.W. made the CMG2 transgenic construct. Z.-X.Y. performed histological analyses. T.F. was involved in scientific discussions, providing reagents, and edited the paper. S.H.L. supervised research and edited the paper. S.L. conceived and supervised the project, designed and performed experiments, analysed data and wrote the paper.

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Correspondence to Shihui Liu or Stephen H. Leppla.

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Extended data figures and tables

Extended Data Figure 1 Generation of endothelial-cell-specific CMG2-null mice.

a, Strategy for generation of endothelial-cell-specific CMG2-null mice. Diagram shows CMG2fl allele having exon 12 (encoding transmembrane domain, TM) flanked by loxP sites and the endothelial-cell-specific CMG2-null allele (CMG2(EC)−). The red arrowheads indicate loxP sites. The homozygous endothelial-cell-specific CMG2-null mice (CMG2(EC)−/−) were obtained by intercrossing of CMG2(EC)+/−mice. Other cell-type-specific CMG2-null mice were made similarly by using the corresponding cell-type-specific Cre transgenic mice. b, RT–PCR analyses of CMG2 transmembrane (TM) domain deletion in various tissues of CMG2(EC)−/− mice. Primers flanking the CMG2 transmembrane domain were used to amplify a CMG2 cDNA fragment. Endothelial cells and non-endothelial cells were isolated simultaneously from lungs pooled from three CMG2(EC)−/− mice and three CMG2fl/fl control mice. Representative of two independent experiments is shown. Expression of TEM8 and GAPDH in these samples is also shown. c, Sensitivity of endothelial cells and non-endothelial cells from CMG2fl/fl and CMG2(EC)−/− mice to PA plus FP59. Cells were treated with various concentrations of PA and FP59 (100 ng ml−1) for 48 h. Cell viability was evaluated by MTT assay, expressed as relative MTT signals to untreated cells. Error bars indicate s.d. d, Resistance of endothelial cells from CMG2(EC)−/− mice to LT. Endothelial cells from CMG2(EC)−/− and wild-type mice were treated with various concentrations of LF and PA (500 ng ml−1) for 48 h. e, PA(L687A) preferentially kills CMG2-expressing cells. Cells were treated with various concentrations of PA or PA(L687A) and 100 ng ml−1 FP59 for 48 h. PR230(TEM8) and PR230(CMG2) are engineered CHO cells expressing only TEM8 or CMG2. Note that PR230(TEM8) cells are 100-fold more resistant than PR230(CMG2) cells to PA(L687A) plus FP59. f, Sensitivity of endothelial cells and non-endothelial cells from CMG2fl/fl and CMG2(EC)−/− mice to PA(L687A) plus FP59. Cells were incubated for 48 h with various concentrations of PA(L687A) and 100 ng ml−1 FP59. Error bars indicate s.d. g, Susceptibility of CMG2(EC)−/− mice to LT. CMG2(EC)−/− mice and their littermate controls were injected intravenously with 50 μg LT (50 μg PA plus 50 μg LF), and monitored for survival. Whole-body CMG2−/− mice were included as additional controls. h, Disease progression of the LT-challenged mice in panel g. Please see Methods for disease progression scoring criteria.

Extended Data Figure 2 Generation of endothelial-cell-specific CMG2-expressing mice.

a, Strategy for generation of endothelial-cell-specific CMG2-expressing mice. In the CMG2 transgenic vector (LSL-CMG2), a loxP-stop-loxP cassette containing a promoterless eGFP and a poly(A) stop signal flanked by loxP sites was placed between the CAG promoter and CMG2 cDNA. Activation of CMG2 transgene in endothelial cells (CMG2EC) was achieved by breeding LSL-CMG2 mice with Cdh-cre mice to specifically remove the loxP-stop-loxP cassette in endothelial cells. Other cell-type-specific CMG2-expressing mice were made similarly by using the corresponding cell-type-specific Cre transgenic mice. b, c, Regained toxin sensitivity of endothelial cells from CMG2EC mice. Endothelial cells and non-endothelial cells from CMG2EC and whole-body CMG2−/− mice were incubated for 48 h with various concentrations of PA (b) or PA(L687A) (c) and 100 ng ml−1 FP59. Error bars indicate s.d.

Extended Data Figure 3 Tissue-specific deletion of CMG2 in CMG2(CM)−/− and CMG2(SM/CM)−/− mice.

a, RT–PCR analyses of CMG2 deletion in tissues of CMG2(CM )−/− and CMG2(SM/CM)−/− mice. CMG2 deletion was detected in the hearts of CMG2(CM)−/− mice and in the hearts and aorta of CMG2(SM/CM)−/− mice. The small fraction of CMG2 deletion that occurred in other tissues of the CMG2(SM/CM)−/− mice was due to the existence of varying amounts of vascular smooth muscle cells in those tissues. Representative of two independent experiments is shown. b, Resistance of smooth-muscle/cardiomyocyte-specific CMG2-null mice to LT. CMG2(SM/CM)−/− mice and their littermate CMG2(SM/CM)+/− controls were injected intravenously with 50 μg LT, and monitored for survival. Whole-body CMG2−/− mice were included as additional controls. Right panel shows the disease progression of the challenged mice. CMG2(SM/CM)−/− versus CMG2+/+ mice, P = 0.0002. Log-rank test.

Extended Data Figure 4 Fluorescence microscopic analyses of GFP expression in mouse tissues.

a, Representative fluorescence microscopy of skeletal muscle (1), aorta (vascular smooth muscle) (2), small intestine (smooth muscle) (3), liver (4), lung (5), spleen (6) and kidney (cortex) (7) from CMG2CM mice (n = 2). Scale bar, 100 μm. b, Representative fluorescence microscopy of skeletal muscle (1), liver (2), kidney (cortex) (3), spleen (4) and uterus (5) from CMG2SM/CM mice (n = 3), and uterus (6) from LSL-CMG2 mice (n = 2). Scale bar, 100 μm.

Extended Data Figure 5 Histology of heart and liver of LT- and ET-treated mice.

a, Haematoxylin and eosin staining of heart and liver from wild-type (n = 3) and CMG2−/− (n = 3) mice challenged intraperitoneally with 100 μg LT for 48 h. In heart, regions with cardiomyocyte degeneration were found in LT-treated wild-type but not CMG2−/− mice. Arrows show examples of degenerated cardiomyocytes. In liver, regions with mild to modest hepatocyte degeneration were identified in LT-treated wild-type but not CMG2−/− mice. Arrows show examples of degenerated hepatocytes with cytosol vacuolization changes. Scale bar, 50 μm. b, Haematoxylin and eosin staining of heart and liver from wild-type (n = 4) and CMG2−/− (n = 3) mice 18 h after 50 μg ET injection (intravenously). In liver, regions with hepatocyte necrotic changes were identified in ET-treated wild-type mice but not CMG2−/− mice. Arrows show necrotic regions, arrowheads indicate examples of intact hepatocytes remaining in the necrotic regions. In heart, only scattered degenerated cardiomyocytes (arrow) were found in ET-treated wild-type but not CMG2−/− mice. Scale bar, 50 μm.

Extended Data Figure 6 Endothelial-cell-specific CMG2-null mice are sensitive to B. anthracis infection.

CMG2(EC)−/− mice and their littermate heterozygous mice were subcutaneously infected with 4 × 108 Sterne spores and monitored for survival. The right panel shows the disease progression of the challenged mice. Log-rank test.

Extended Data Figure 7 LT targeting of liver does not contribute to lethality.

a, Susceptibility of the hepatocyte-specific CMG2-null mice to LT. CMG2(Hep)−/− mice and their littermate CMG2+/+ control mice were challenged intraperitoneally with 100 μg LT and monitored for survival. Whole-body CMG2−/− mice were included as additional controls. b, Selective activation of CMG2 transgene in liver of CMG2Hep mice. Representative fluorescence microscopy of the liver (1), heart (3), skeletal muscles (4), lung (5), small intestines (smooth muscle) (6), aorta (7), spleen (8) and kidney (cortex) (9) from CMG2Hep mice (n = 2), and liver (2) from LSL-CMG2 mice (n = 2). Selective loss of GFP expression in liver from CMG2Hep mice but not LSL-CMG2 mice (1 and 2) is shown. Scale bar, 100 μm. c, Susceptibility of the hepatocyte-specific CMG2-expressing mice to LT. CMG2Hep mice and various control mice as indicated were intraperitoneally challenged with two doses of 100 μg LT and monitored for survival or signs of malaise. Right panel: disease progression of the challenged mice.

Extended Data Figure 8 Oedema in ET-treated mice.

a, ET-induced footpad skin oedema in mice. Mice with various genotypes were injected with 0.25 μg ET (in 20 μl PBS) and the thicknesses of footpads were measured at 0, 8 and 20 h after injection. ET only induced modest oedema in CMG2−/− mice, but caused much higher levels of oedema in CMG2+/−, CMG2(EC)−/−, CMG2(SM/CM)−/− and CMG2(SM/CM/EC)−/− mice. The P values of the indicated groups versus CMG2+/− control group are shown. Each symbol represents one mouse. b–f, ET does not cause oedema in heart, spleen, kidney, lung and brain. Mice were challenged intravenously with 30 μg ET or PBS, and hearts (b), spleens (c), kidneys (d), brains (e) and lungs (f) were collected at 6 h or 18 h for tissue wet/dry ratio measurements. The P values of the indicated groups versus the PBS control group are shown. No significant differences were detected among the groups in b–e. In f, decreases in wet/dry ratio of lungs (dehydration) from ET-treated mice were observed. Each symbol represents one mouse. In a–e, error bars indicate s.e.; two-tailed unpaired t-test.

Extended Data Figure 9 Mice with CMG2 deletion in cardiovascular system and intestines remain sensitive to ET.

a, b, Sensitivity of CMG2(CM)−/−, CMG2(SM/CM/EC)−/−, CMG2(SM/CM/EC/IE)−/− and their littermate control mice to ET. Mice were challenged intravenously with 25 μg ET (a) or intraperitoneally with 50 μg ET (b) and survival monitored after challenge.

Extended Data Table 1 Primers used for PCR genotyping and cloning
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Liu, S., Zhang, Y., Moayeri, M. et al. Key tissue targets responsible for anthrax-toxin-induced lethality. Nature 501, 63–68 (2013). https://doi.org/10.1038/nature12510

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