Chapter 35 : Intracellular Pathogenesis of

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This chapter reviews what is known about the strategies used by yeasts to survive within human and animal murine macrophages, how murine macrophages become activated, and the mechanisms by which activated murine macrophages kill yeasts. The interaction of with dendritic cells (DC) is also discussed, as are the different roles that murine macrophages and DC may play in the development of cell-mediated immunity to . Recent studies demonstrate that the ligand on the surface of yeasts and conidia that is recognized by murine macrophages CD18 receptors is heat shock protein 60 (hsp60). Once inside the phagosome, must avoid the microbicidal armamentarium of the murine macrophages that consists of the generation of toxic oxygen molecules (respiratory burst) and lysosomal hydrolases (phagolysosomal fusion [PL fusion]). Intracellular pathogens have evolved numerous strategies to avoid these murine macrophages defense mechanisms, including inhibition of phagolysosomal fusion (PL) (e.g., ), escaping from the phagocytic vacuole into the cytoplasm (e.g., ), and initiating phagocytosis without stimulating the respiratory burst (e.g., Toxoplasma gondii). The intracellular replication of yeasts in human monocytes and murine macrophages occurs at a similar rate even though murine macrophages have lost their myeloperoxidase and are unable to make toxic oxygen metabolites distal to HO. In contrast to our knowledge of murine immunology, the cytokines required to activate human murine macrophages fungistatic or fungicidal activity against remain obscure.

Citation: Newman S. 2006. Intracellular Pathogenesis of , p 527-536. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch35
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Image of Figure 1.
Figure 1.

Differential response of human and murine Mϕ to yeasts. Upon ingestion of yeasts, the respiratory burst of murine Mϕ is not stimulated, but PL fusion does occur. In contrast, there is production of toxic oxygen radicals by human Mϕ, but minimal PL fusion. Further, murine Mϕ are activated by IFN-γ to inhibit the intracellular replication of yeasts, whereas IFN-γ does not activate human Mϕ. In both human and murine Mϕ, the intraphagosomal pH is maintained at 6.5.

Citation: Newman S. 2006. Intracellular Pathogenesis of , p 527-536. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch35
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Image of Figure 2.
Figure 2.

Differential recognition and response of human Mϕ and DC to yeasts. Mϕ utilize the CD18 receptor family to recognize the ligand Hsp60 on the surface of yeasts. Upon ingestion of the yeasts, PL fusion is blocked and the yeasts replicate. In contrast, DC use the VLA-5 receptor to recognize cyclophilin A on the surface of yeasts. Upon ingestion of the yeasts, PL fusion takes place and the yeasts are killed and degraded.

Citation: Newman S. 2006. Intracellular Pathogenesis of , p 527-536. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch35
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1. Ajello, L. 1971. Distribution of Histoplasma capsulatum in the United States, p. 103–122. In L. Ajello, E. W. Chick, and M. F. Furcolow (ed.), Histoplasmosis. Charles C Thomas, Springfield, Ill.
2. Allendoerfer, R.,, G. P. Biovin, and, G. S. Deepe, Jr. 1997. Modulation of immune responses in murine pulmonary histoplasmosis. J. Infect. Dis. 175: 905914.
3. Allendoerfer, R., and, G. S. Deepe, Jr. 1998. Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J. Immunol. 160: 60726082.
4. Allendoerfer, R.,, D. M. Magee,, G. S. Deepe, Jr., and, J. R. Graybill. 1993. Transfer of protective immunity in murine histoplasmosis by a CD4 + T-cell clone. Infect. Immun. 61: 714718.
5. Banchereau, J., and, R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245252.
6. Batanghari, J. W.,, G. S. Deepe, Jr.,, E. Di Cera, and, W. E. Goldman. 1998. Histoplasma acquisition of calcium and expression of CBP1 during intracellular parasitism. Mol. Microbiol. 27: 531539.
7. Batanghari, J. W., and, W. E. Goldman. 1997. Calcium dependence and binding in cultures of Histoplasma capsulatum. Infect. Immun. 65: 52575261.
8. Bates, G. W., and, J. Wernicke. 1971. The kinetics and mechanism of iron (III) exchange between chelates and transferrin. J. Biol. Chem. 246: 36793686.
9. Baughman, R. P.,, C. K. Kim,, A. Vinegar,, D. E. Hendricks,, D. J. Schmidt, and, W. E. Bullock. 1986. The pathogenesis of experimental pulmonary histoplasmosis. Correlative studies of histopathology, bronchoalveolar lavage, and respiratory function. Am. Rev. Respir. Dis. 134: 771776.
10. Berry, C. L. 1969. The production of disseminated histoplasmosis in the mouse: the effects of changes in reticuloendothelial function. J. Pathol. 97: 441457.
11. Brummer, E.,, N. Kurita,, S. Yosihida,, K. Nishimura, and, M. Miyaji. 1991. Fungistatic activity of human neutrophils against Histoplasma capsulatum: correlation with phagocytosis. J. Infect. Dis. 164: 158162.
12. Bullock, W. E., and, S. D. Wright. 1987. Role of the adherence-promoting receptors, CR3, LFA-1, and p150,95, in binding of Histoplasma capsulatum by human macrophages. J. Exp. Med. 165: 195210.
13. Burt, W. R. 1982. Identification of coprogen B and its breakdown products from Histoplasma capsulatum. Infect. Immun. 35: 990996.
14. Burt, W. R.,, A. L. Underwood, and, G. L. Appleton. 1981. Hydroxamic acid from Histoplasma capsulatum that displays growth factor activity. Appl. Environ. Microbiol. 42: 560563.
15. Byrd, T. F., and, M. A. Horwitz. 1989. Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. J. Clin. Investig. 83: 14571465.
16. Deepe, G. S., and, W. E. Bullock. 1992. Histoplasmosis: a granulomatous inflammatory response, p. 943–958. In J. I. Gallin, I. M. Goldstein, and R. Snyderman (ed.), Inflammation: Basic Principles and Clinical Correlates. Raven Press, New York, N.Y.
17. Deepe, G. S., Jr. 1988. Protective immunity in murine histoplasmosis: functional comparison of adoptively transferred T-cell clones and splenic T cells. Infect. Immun. 56: 23502355.
18. Deepe, G. S., Jr.,, R. Gibbons, and, E. Woodward. 1999. Neutralization of endogenous granulocyte-macrophage colony-stimulating factor subverts the protective immune response to Histoplasma capsulatum. J. Immunol. 163: 49854993.
19. Deepe, G. S., Jr., and, R. A. Seder. 1998. Molecular and cellular determinants of immunity to Histoplasma capsulatum. Res. Immunol. 149:397–406; discussion 509–510.
20. DeMonbruen, W. A. 1934. The cultivation and characteristics of Darling’s Histoplasma capsulatum. Am. J. Trop. Med. 14: 93125.
21. De Sanchez, S. B., and, L. M. Carbonell. 1975. Immunological studies on Histoplasma capsulatum. Infect. Immun. 11: 387394.
22. Eissenberg, L. G., and, W. E. Goldman. 1987. Histoplasma capsulatum fails to trigger release of super-oxide from macrophages. Infect. Immun. 55: 2934.
23. Eissenberg, L. G.,, W. E. Goldman, and, P. H. Schlesinger. 1993. Histoplasma capsulatum modulates the acidification of phagolysosomes. J. Exp. Med. 177: 16051611.
24. Eissenberg, L. G.,, P. H. Schlesinger, and, W. E. Goldman. 1988. Phagosome-lysosome fusion in P388D1 macrophages infected with Histoplasma capsulatum. J. Leukoc. Biol. 43: 483491.
25. Ennis, H. L., and, M. Lubin. 1964. Cycloheximide: aspects of inhibition of protein synthesis in mammalian cells. Science 146: 14741476.
26. Fleischmann, J.,, B. Wu-Hsieh, and, D. H. Howard. 1990. The intracellular fate of Histoplasma capsulatum in human macrophages is unaffected by recombinant human interferon-gamma. J. Infect. Dis. 161: 143145.
27. Frydman, J., and, F. Hartl. 1994. Molecular chaperone of Hsp70 and Hsp60 in protein folding, p. 251–283. In R. I. Morimoto, A. Tissieres, and C. Georgopoulos (ed.), The Biology of Heat Shock Protein and Molecular Chaperones. Cold Spring Harbor Laboratory Press, Plain View, N.Y.
28. Gildea, L. A.,, G. M. Ciraolo,, R. E. Morris, and, S. L. Newman. 2005. Human dendritic cell activity against Histoplasma capsulatum is mediated by phagolysosomal fusion. Infect. Immun. 73: 68036811.
29. Gildea, L. A.,, R. E. Morris, and, S. L. Newman. 2001. Histoplasma capsulatum yeasts are phagocytosed via very late antigen-5, killed, and processed for antigen presentation by human dendritic cells. J. Immunol. 166: 10491056.
30. Gomez, A. M.,, W. E. Bullock,, C. L. Taylor, and, G. S. Deepe, Jr. 1988. Role of L3T4 + T cells in host defense against Histoplasma capsulatum. Infect. Immun. 56: 16851691.
31. Gomez, F. J.,, R. Allendoerfer, and, G. S. Deepe, Jr. 1995. Vaccination with recombinant heat shock protein 60 from Histoplasma capsulatum protects mice against pulmonary histoplasmosis. Infect. Immun. 63: 25872595.
32. Hallberg, R. L. 1990. A mitochondrial chaperonin: genetic, biochemical, and molecular characteristics. Semin. Cell Biol. 1: 3745.
33. Howard, D. H. 1981. Comparative sensitivity of Histoplasma capsulatum conidiospores and blastospores to oxidative antifungal systems. Infect. Immun. 32: 381387.
34. Howard, D. H. 1960. Effect of Mycostatin and Fungizone on the growth of Histoplasma capsulatum in tissue culture. J. Bacteriol. 79: 442449.
35. Howard, D. H. 1973. Further studies on the inhibition of Histoplasma capsulatum within macrophages from immunized animals. Infect. Immun. 8: 577581.
36. Howard, D. H. 1964. Intracellular behavior of Histoplasma capsulatum. J. Bacteriol. 87: 3338.
37. Howard, D. H. 1965. Intracellular growth of Histoplasma capsulatum. J. Bacteriol. 89: 518523.
38. Howard, D. H. 1959. Observation on tissue cultures of mouse peritoneal exudates inoculated with Histoplasma capsulatum. J. Bacteriol. 78: 6978.
39. Howard, D. H.,, V. Otto, and, R. K. Gupta. 1971. Lymphocyte-mediated cellular immunity in histoplasmosis. Infect. Immun. 4: 605610.
40. Howard, D. H.,, R. Rafie,, A. Tiwari, and, K. F. Faull. 2000. The hydroxamate siderophores of Histoplasma capsulatum. Infect. Immun. 68: 23382343.
41. Howell, A. 1939. Studies on Histoplasma capsulatum and similar form species. 1. Morphology and development. Mycologia 31: 191216.
42. Kimberlin, C. L.,, A. R. Hariri,, H. O. Hempel, and, N. L. Goodman. 1981. Interactions between Histoplasma capsulatum and macrophages from normal and treated mice: comparison of the mycelial and yeast phases in alveolar and peritoneal macrophages. Infect. Immun. 34: 610.
43. Konecny, P.,, A. J. Stagg,, H. Jebbari,, N. English,, R. N. Davidson, and, S. C. Knight. 1999. Murine dendritic cells internalize Leishmania major promastigotes, produce IL-12 p40 and stimulate primary T cell proliferation in vitro. Eur. J. Immunol. 29: 18031811.
44. Krogstad, D. J., and, P. H. Schlesinger. 1987. Acid-vesicle function, intracellular pathogens, and the action of chloroquine against Plasmodium falciparum. N. Engl. J. Med. 317: 542549.
45. Kubota, H.,, G. Hynes, and, K. Willison. 1995. The chap-eronin containing t-complex polypeptide 1 (TCP-1). Multisubunit machinery assisting in protein folding and assembly in the eukaryotic cytosol. Eur. J. Biochem. 230: 316.
46. Kugler, S.,, B. Young,, V. L. Miller, and, W. E. Goldman. 2000. Monitoring phase-specific gene expression in Histoplasma capsulatum with telomeric GFP fusion plasmids. Cell. Microbiol. 2: 537547.
47. Lane, T. E.,, G. C. Otero,, B. A. Wu-Hsieh, and, D. H. Howard. 1994. Expression of inducible nitric oxide synthase by stimulated macrophages correlates with their antihistoplasma activity. Infect. Immun. 62: 14781479.
48. Lane, T. E.,, B. A. Wu-Hsieh, and, D. H. Howard. 1994. Antihistoplasma effect of activated mouse splenic macrophages involves production of reactive nitrogen intermediates. Infect. Immun. 62: 19401945.
49. Lane, T. E.,, B. A. Wu-Hsieh, and, D. H. Howard. 1993. Gamma interferon cooperates with lipopolysaccharide to activate mouse splenic macrophages to an antihisto-plasma state. Infect. Immun. 61: 14681473.
50. Lane, T. E.,, B. A. Wu-Hsieh, and, D. H. Howard. 1991. Iron limitation and the gamma interferon-mediated anti-histoplasma state of murine macrophages. Infect. Immun. 59: 22742278.
51. Long, K. H.,, F. J. Gomez,, R. E. Morris, and, S. L. Newman. 2003. Identification of heat shock protein 60 as the ligand on Histoplasma capsulatum that mediates binding to CD18 receptors on human macrophages. J. Immunol. 170: 487494.
52. Maresca, B., and, G. S. Kobayashi. 1989. Dimorphism in Histoplasma capsulatum: a model for the study of cell differentiation in pathogenic fungi. Microbiol. Rev. 53: 186209.
53. Marth, T., and, B. L. Kelsall. 1997. Regulation of interleukin-12 by complement receptor 3 signaling. J. Exp. Med. 185: 19871995.
54. Murray, H. W., and, D. M. Cartelli. 1983. Killing of intracellular Leishmania donovani by human mononuclear phagocytes. Evidence for oxygen-dependent and -independent leishmanicidal activity. J. Clin. Investig. 72: 3244.
55. Murray, H. W.,, B. Y. Rubin,, S. M. Carriero,, A. M. Harris, and, E. A. Jaffee. 1985. Human mononuclear phagocyte antiprotozoal mechanisms: oxygen-dependent vs oxygen-independent activity against intracellular Toxoplasma gondii. J. Immunol. 134: 19821988.
56. Newman, S. L. 2001. Cell-mediated immunity to Histoplasma capsulatum. Semin. Respir. Infect. 16: 102108.
57. Newman, S. L.,, C. Bucher,, J. Rhodes, and, W. E. Bullock. 1990. Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. Cellular cytoskeleton requirement for attachment and ingestion. J. Clin. Investig. 85: 223230.
58. Newman, S. L., and, L. Gootee. 1992. Colony-stimulating factors activate human macrophages to inhibit intracellular growth of Histoplasma capsulatum yeasts. Infect. Immun. 60: 45934597.
59. Newman, S. L.,, L. Gootee,, G. Brunner, and, G. S. Deepe, Jr. 1994. Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis. J. Clin. Investig. 93: 14221429.
60. Newman, S. L.,, L. Gootee,, C. Bucher, and, W. E. Bullock. 1991. Inhibition of intracellular growth of Histoplasma capsulatum yeast cells by cytokine-activated human monocytes and macrophages. Infect. Immun. 59: 737741.
61. Newman, S. L.,, L. Gootee, and, J. E. Gabay. 1993. Human neutrophil-mediated fungistasis against Histoplasma capsulatum. Localization of fungistatic activity to the azurophil granules. J. Clin. Investig. 92: 624631.
62. Newman, S. L.,, L. Gootee,, J. E. Gabay, and, M. E. Selsted. 2000. Identification of constituents of human neutrophil azurophil granules that mediate fungistasis against Histoplasma capsulatum. Infect. Immun. 68: 56685672.
63. Newman, S. L.,, L. Gootee,, J. Hilty, and, R. E. Morris. 2006. Human macrophages do not require phagosome acidification to mediate fungistatic/fungicidal activity against Histoplasma capsulatum. J. Immunol. 176: 18061813.
64. Newman, S. L.,, L. Gootee,, C. Kidd,, G. M. Ciraolo, and, R. Morris. 1997. Activation of human macrophage fungistatic activity against Histoplasma capsulatum upon adherence to type 1 collagen matrices. J. Immunol. 158: 17791786.
65. Newman, S. L.,, L. Gootee,, R. Morris, and, W. E. Bullock. 1992. Digestion of Histoplasma capsulatum yeasts by human macrophages. J. Immunol. 149: 574580. (Erratum, 149: 3127.)
66. Nogueira, N.,, S. Chaplan,, M. Reesink,, J. Tydings, and, Z. A. Cohn. 1982. Trypanosoma cruzi : induction of microbicidal activity in human mononuclear phagocytes. J. Immunol. 128: 21422146.
67. Pabst, M. J.,, H. B. Hedegaard, and, R. B. Johnston, Jr. 1982. Cultured human monocytes require exposure to bacterial products to maintain an optimal oxygen radical response. J. Immunol. 128: 123128.
68. Patel, J. B.,, J. W. Batanghari, and, W. E. Goldman. 1998. Probing the yeast phase-specific expression of the CBP1 gene in Histoplasma capsulatum. J. Bacteriol. 180: 17861792.
69. Princiotto, J. V., and, E. J. Zapolski. 1975. Difference between the two iron-binding sites of transferrin. Nature 255: 8788.
70. Procknow, J. J.,, M. I. Page, and, C. G. Loosli. 1960. Early pathogenesis of experimental histoplasmosis. Arch. Pathol. 69: 413426.
71. Rothermel, C. D.,, B. Y. Rubin,, E. A. Jaffe, and, H. W. Murray. 1986. Oxygen-independent inhibition of intracellular Chlamydia psittaci growth by human monocytes and interferon-gamma-activated macrophages. J. Immunol. 137: 689692.
72. Salvin, S. B. 1955/56. Acquired resistance in experimental histoplasmosis. Trans. N. Y. Acad. Sci. 18: 462468.
73. Sanchez-Madrid, F.,, J. A. Nagy,, E. Robbins,, P. Simon, and, T. A. Springer. 1983. A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule. J. Exp. Med. 158: 17851803.
74. Sasada, M.,, A. Kubo,, T. Nishimura,, T. Kakita,, T. Moriguchi,, K. Yamamoto, and, H. Uchino. 1987. Candidacidal activity of monocyte-derived human macrophages: relationship between Candida killing and oxygen radical generation by human macrophages. J. Leukoc. Biol. 41: 289294.
75. Schaffner, A.,, C. E. Davis,, T. Schaffner,, M. Markert,, H. Douglas, and, A. I. Braude. 1986. In vitro susceptibility of fungi to killing by neutrophil granulocytes discriminates between primary pathogenicity and opportunism. J. Clin. Investig. 78: 511524.
76. Schnur, R. A., and, S. L. Newman. 1990. The respiratory burst response to Histoplasma capsulatum by human neutrophils. Evidence for intracellular trapping of superoxide anion. J. Immunol. 144: 47654772.
77. Sebghati, T. S.,, J. T. Engle, and, W. E. Goldman. 2000. Intracellular parasitism by Histoplasma capsulatum: fungal virulence and calcium dependence. Science 290: 13681372.
78. Siegel, M. R., and, H. D. Sisler. 1964. Site of action of cycloheximide in cells of Saccharomyces pastorianus. II. The nature of inhibition of protein synthesis in a cell free system. Biochim. Biophys. Acta 87: 8389.
79. Smith, J. G.,, D. M. Magee,, D. M. Williams, and, J. R. Graybill. 1990. Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum. J. Infect. Dis. 162: 13491353.
80. Strasser, J. E.,, S. L. Newman,, G. M. Ciraolo,, R. E. Morris,, M. L. Howell, and, G. E. Dean. 1999. Regulation of the macrophage vacuolar ATPase and phagosomelysosome fusion by Histoplasma capsulatum. J. Immunol. 162: 61486154.
81. Taylor, M. L.,, M. E. Espinosa-Schoelly,, R. Iturbe,, B. Rico,, J. Casasola, and, F. Goodsaid. 1989. Evaluation of phagolysosome fusion in acridine orange stained macrophages infected with Histoplasma capsulatum. Clin. Exp. Immunol. 75: 466470.
82. Timmerman, M. M., and, J. P. Woods. 1999. Ferric reduction is a potential iron acquisition mechanism for Histoplasma capsulatum. Infect. Immun. 67: 64036408.
83. Timmerman, M. M., and, J. P. Woods. 2001. Potential role for extracellular glutathione-dependent ferric reductase in utilization of environmental and host ferric compounds by Histoplasma capsulatum. Infect. Immun. 69: 76717678.
84. Wheat, J. 1994. Histoplasmosis and coccidioidomycosis in individuals with AIDS. A clinical review. Infect. Dis. Clin. North Am. 8: 467482.
85. Williams, D. M.,, J. R. Graybill, and, D. J. Drutz. 1981. Adoptive transfer of immunity to Histoplasma capsulatum in athymic nude mice. Sabouraudia 19: 3948.
86. Wolf, J. E.,, A. L. Abegg,, S. J. Travis,, G. S. Kobayashi, and, J. R. Little. 1989. Effects of Histoplasma capsulatum on murine macrophage functions: inhibition of macrophage priming, oxidative burst, and antifungal activities. Infect. Immun. 57: 513519.
87. Wolf, J. E.,, V. Kerchberger,, G. S. Kobayashi, and, J. R. Little. 1987. Modulation of the macrophage oxidative burst by Histoplasma capsulatum. J. Immunol. 138: 582586.
88. Wu-Hsieh, B A., and, D. H. Howard. 1987. Inhibition of the intracellular growth of Histoplasma capsulatum by recombinant murine gamma interferon. Infect. Immun. 55: 10141016.
89. Wu-Hsieh, B A.,, G. S. Lee,, M. Franco, and, F. M. Hofman. 1992. Early activation of splenic macrophages by tumor necrosis factor alpha is important in determining the outcome of experimental histoplasmosis in mice. Infect. Immun. 60: 42304238. (Erratum, 60: 5324.)
90. Zhou, P.,, G. Miller, and, R. A. Seder. 1998. Factors involved in regulating primary and secondary immunity to infection with Histoplasma capsulatum: TNF-alpha plays a critical role in maintaining secondary immunity in the absence of IFN-gamma. J. Immunol. 160: 13591368.
91. Zhou, P.,, M. C. Sieve,, J. Bennett,, K. J. Kwon-Chung,, R. P. Tewari,, R. T. Gazzinelli,, A. Sher, and, R. A. Seder. 1995. IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma. J. Immunol. 155: 785795.
92. Zhou, P.,, M. C. Sieve,, R. P. Tewari, and, R. A. Seder. 1997. Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum. Infect. Immun. 65: 936942.

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