Distinct Leishmania braziliensis Isolates Induce Different Paces of Chemokine Expression Patterns
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感染与免疫杂志 2005年第2期
Centro de Pesquisas Gonalo Moniz-Fiocruz
Faculdade de Medicina, Universidade Federal da Bahia-UFBA
Immunology Investigation Institute, Salvador
Núcleo de Medicina Tropical, Universidade Federal do Ceará-UFC, Fortaleza
Departamento de Imunologia, Faculdade de Medicina de Ribeiro Preto, Universidad de So Paulo, Ribeiro Preto, Brazil
ABSTRACT
Inflammatory events during Leishmania braziliensis infection in mice were investigated. Large lesions were directly correlated with the inflammatory reaction but not with parasite burden. Different L. braziliensis strains induce different paces of chemokine expression patterns, leading to diverse cell recruitment and differential inflammatory responses.
TEXT
Chemokines have been implicated in inflammatory responses against numerous infectious agents, including Leishmania (5, 17, 18, 20). Leishmania braziliensis is the main agent of cutaneous leishmaniasis (CL) in Brazil; it causes single self-limited cutaneous ulcers and highly destructive mucosal leishmaniasis (10). In this study, using a murine model, we compared L. braziliensis strains isolated from two states in Brazil, namely, Ceará and Bahia, located in northeastern Brazil. CL caused by L. braziliensis is endemic in both states. In Ceará, the cutaneous lesion is accompanied and sometimes preceded by an impressive enlargement of the regional lymph nodes; the term "bubonic leishmaniasis" has been coined to describe this manifestation (23). Bubonic leishmaniasis is restricted to L. braziliensis infection in Ceará; however, localized lymphadenopathy has been observed in CL patients from Bahia (2, 3).
Mice were infected with 106 stationary-phase forms of L. braziliensis (6). In preliminary experiments, the isolates obtained from CL patients from Ceará (MHOM/BR/94/H3227 [H3227]and MHOM/BR/94/H3456) and from Bahia (MHOM/BR/00/BA711, MHOM/BR/00/BA774, MHOM/BR/00/BA775, and MHOM/BR/01/BA788 [BA788]) showed significant differences in pathogenicity (Fig. 1, inset). Further experiments were performed with two of these L. braziliensis isolates, H3227 and BA788. The lesions caused by H3227 were larger and persisted longer than those caused by BA788 (Fig. 1). Lesion size differences did not appear to be due to diverse parasite loads, since parasite numbers were not significantly different between H3227- and BA788-infected mice at 15 days postinfection (p.i.) (mean and standard error of the mean, 7.29 x 105 ± 5.28 x 105 and 2.64 x 105 ± 1.20 x 105, respectively), when lesion sizes were different. Lesions from H3227-infected mice exhibited an inflammatory infiltrate consisting mainly of polymorphonuclear leukocytes and macrophages at 3 days p.i., and these histopathological features persisted at 15 days p.i. Sections from BA788-infected mice showed a less intense and more transient leukocyte infiltrate.
In order to explore the role of the parasite in the histopathological differences observed, we evaluated cell recruitment induced by H3227 and BA788 by using the air pouch model (14, 15). Responses induced by H3227 were three times higher than those induced by BA788 (Fig. 2A); these responses were correlated with a more intense exudate of leukocytes observed in the lesions of H3227-infected mice. H3227 was able to induce more influx of all cell types, attracting mainly more neutrophils and macrophages than BA788 (Fig. 2B). These data reinforce a role of the parasite in the differences observed in the inflammatory processes induced by the two L. braziliensis isolates used here.
RNA was extracted from lesions for reverse transcription-PCR analysis of chemokine expression at 6 h, 3 days, and 15 days p.i (12, 16). The sequences of the primers used are shown in Table 1. The expression of CCL2/MCP-1, CCL3/MIP-1, and CXCL1/KC was upregulated at 6 h p.i. on H3227-induced lesions and only at 3 days p.i. in BA788-infected mice (Fig. 3A). In addition, CCL2/MCP-1, CCL3/MIP-1, XCL1/lymphotactin-1, CXCL1/KC, and CCL11/eotaxin expression was more strongly induced by H3227 than by BA788. CXCL10/IP-10 was the only chemokine that appeared to be more strongly expressed by BA788 than by H3227. Regarding chemokine receptor expression, H3227 showed significantly higher expression of all chemokine receptors studied here than did BA788 (Fig. 3B). CCR5 was slightly upregulated in BA788-infected mice. Immunohistochemical analysis for the presence of CCL2/MCP-1 and CXCL10/IP-10 proteins in lesions induced by H3227 and BA788 confirmed the results obtained by mRNA expression analysis (Fig. 3C).
Lesions from patients with CL show a significant increase in the expression of CCL2/MCP-1 and CCL3/MIP-1 (20), and in vitro infection with Leishmania induces CCL2/MCP-1 and CXCL1/KC/GRO- expression in mouse and human macrophages (1, 19). CCL2/MCP-1 and CCL3/MIP-1 are potent chemoattractants for monocytes (9, 13). CXCL1/KC recruits neutrophils and is a dominant chemokine in murine inflammatory responses (4). The earlier expression of CCL2/MCP-1, CCL3/MIP-1, and CXCL1/KC in more severe lesions may explain the significant and early accumulation of neutrophils and macrophages at the H3227 infection site and suggests that these chemokines can be factors regulating the differential inflammatory responses which develop upon infection with the two L. braziliensis isolates used here.
H3227 induced XCL1/lymphotactin-1 and, to a lesser extent, CXCL10/IP-10. XCL1/lymphotactin-1 is chemotactic for NK, CD4+, and CD8+ T cells in vitro and in vivo (8, 11), and CXCL10/IP-10 activates NK cells in vivo (25). Furthermore, XCL1/lymphotactin-1, CCL3/MIP-1, CCL4/MIP-1, and CCL5/RANTES are associated with a Th1 immune response (7, 22). Interestingly, CXCL10/IP-10 was the only chemokine that was more strongly expressed in lesions induced by the less pathogenic strain BA788, and its expression was correlated with the earlier production of gamma interferon in the draining lymph nodes and with the larger number of NK cells in the lesions of BA788-infected mice (6). NK cells produce gamma interferon and may contribute to resistance to L. braziliensis, as previously shown for L. major (21). Therefore, it is possible that XCL1/lymphotactin-1 and CXCL10/IP-10 are involved in resistance to L. braziliensis infection in BALB/c mice. Lesions caused by L. braziliensis H3227 exhibited a higher level of chemokine receptor expression than did those caused by L. braziliensis BA788. BA788 was unable to promote the strong expression of chemokine receptors, a result which was correlated with its reduced capacity to induce leukocyte recruitment. CCR5 was slightly upregulated in BA788-infected mice at 3 days p.i. and was stimulated by CCL3/MIP-1, which was expressed during the same time period. A low level of expression of CCR5 in lesions was correlated with a lower level of expression of IL-10 in the draining lymph nodes (6), as IL-10 selectively upregulates CCR5 expression in monocytes (24).
Studies with murine macrophages showed that chemokine induction after Leishmania infection was dependent on the parasite strain used. Indeed, CCL2/MCP-1 was predominantly induced by avirulent L. major. In contrast, virulent parasites induced considerably less CCL2/MCP-1 (19). Therefore, it appears that Leishmania virulence is linked to the modulation of chemokine expression by macrophages. The kinetics of chemokine induction seem to be more important than parasite multiplication, and this fact may be related to structural differences between the two isolates used here. Of note, results from an analysis by random amplification of polymorphic DNA showed that strains H3227 and BA788 of L. braziliensis are genetically diverse (6).
Collectively, the findings presented here indicate that two L. braziliensis isolates, albeit at similar parasite burdens, induced chemokine expression patterns at different paces and/or intensities, leading to diverse cell recruitment and differential inflammatory responses; these features might ultimately be implicated in disease presentations.
ACKNOWLEDGMENTS
We thank Cristiane M. Milanezi and Jorge L. Tolentino for technical assistance.
This work was supported by grants from FAPESB, CAPES (PROCAD 0018/01-5), and CNPq. M.J.T. and C.R.T. received fellowships from CAPES. J.S.d.S., C.I.B., M.B.-N., and A.B. are senior investigators from CNPq. J.D.F. and B.B.A. received scientific initiation fellowships from CNPq.
REFERENCES
1. Badolato, R., D. L. Sacks, D. Savoia, and T. Musso. 1996. Leishmania major: infection of human monocytes induces expression of IL-8 and MCAF. Exp. Parasitol. 82:21-26.
2. Barral, A., M. Barral-Netto, R. Almeida, A. R. De Jesus, G. Grimaldi, Jr., E. M. Netto, I. Santos, O. Bacellar, and E. M. Carvalho. 1992. Lymphadenopathy associated with Leishmania braziliensis cutaneous infection. Am. J. Trop. Med. Hyg. 47:587-592.
3. Barral, A., J. Guerreiro, G. Bomfim, D. Correia, M. Barral-Netto, and E. M. Carvalho. 1995. Lymphadenopathy as the first sign of human cutaneous infection by Leishmania braziliensis. Am. J. Trop. Med. Hyg. 53:256-259.
4. Bozic, C. R., L. F. J. Kolakowski, N. P. Gerard, C. Garcia-Rodriguez, C. von Uexkull-Guldenband, M. J. Conklyn, R. Breslow, H. J. Showell, and C. Gerard. 1995. Expression and biologic characterization of the murine chemokine KC. J. Immunol. 154:6048-6057.
5. Burgmann, H., U. Hollenstein, C. Wenisch, F. Thalhammer, S. Looareesuwan, and W. Graninger. 1995. Serum concentrations of MIP-1 and interleukin-8 in patients suffering from acute Plasmodium falciparum malaria. Clin. Immunol. Immunopathol. 76:32-36.
6. de Oliveira, C. I., M. J. Teixeira, C. R. Teixeira, J. R. de Jesus, A. B. Rosato, J. S. da Silva, C. Brodskyn, M. Barral-Netto, and A. Barral. 2004. Leishmania braziliensis isolates differing at the genome level display distinctive features in BALB/c mice. Microbes Infect. 6:977-984.
7. Dorner, B. G., A. Scheffold, M. S. Rolph, M. B. Huser, S. H. E. Kaufmann, A. Radbruch, I. E. A. Flesch, and R. A. Kroczek. 2002. MIP-1, MIP-1, RANTES, and ATAC/lymphotactin function together with IFN- as type 1 cytokines. Proc. Natl. Acad. Sci. USA 99:6181-6186.
8. Emtage, P. C., Z. Xing, Y. Wan, A. Zlotnik, F. L. Graham, and J. Gauldie. 2002. Adenoviral-mediated gene transfer of lymphotactin to the lungs of mice and rats results in infiltration and direct accumulation of CD4+, CD8+, and NK cells. J. Interferon Cytokine Res. 22:573-582.
9. Fahey, T. J. I., K. J. Tracey, P. Tekamp-Olson, L. S. Cousens, W. G. Jones, G. T. Shires, A. Cerami, and B. Sherry. 1992. Macrophage inflammatory protein 1 modulates macrophage function. J. Immunol. 148:2764-2769.
10. Gontijo, B., and M. L. de Carvalho. 2003. American cutaneous leishmaniasis. Rev. Soc. Bras. Med. Trop. 36:71-80.
11. Hedrick, J. A., V. Saylor, D. Figueroa, L. Mizoue, Y. Xu, S. Menon, J. Abrams, T. Handel, and A. Zlotnik. 1997. Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo. J. Immunol. 158:1533-1540.
12. Kawakami, K., M. Tohyama, X. Qifeng, and A. Saito. 1997. Expression of cytokines and chemokines inducible in the lungs of mice infected with Cryptococcus neoformans: effects of interleukin-12. Infect. Immun. 65:1307-1312.
13. Leonard, E. J., and T. Yoshimura. 1990. Human monocyte chemoattractant protein-1 (MCP-1). Immunol. Today 11:97-101.
14. Matte, C., and M. Olivier. 2002. Leishmania-induced cellular recruitment during the early inflammatory response: modulation of proinflammatory mediators. J. Infect. Dis. 185:673-681.
15. Muller, K., G. van Zandbergen, B. Hansen, H. Laufs, N. Jahnke, W. Solbach, and T. Laskay. 2001. Chemokines, natural killer cells and granulocytes in the early course of Leishmania major infection in mice. Med. Microbiol. Immunol. 190:73-76.
16. Neumann, B., K. Emmanuilidis, M. Stadler, and B. Holzmann. 1998. Distinct functions of interferon- for chemokine expression in models of acute lung inflammation. Immunology 95:512-521.
17. Olszewski, M. A., G. B. Huffnagle, T. R. Traynor, R. A. McDonald, D. N. Cook, and G. B. Toews. 2001. Regulatory effects of macrophage inflammatory protein 1/CCL3 on the development of immunity to Cryptococcus neoformans depend on expression of early inflammatory cytokines. Infect. Immun. 69:6256-6263.
18. Park, M. K., K. F. Hoffmann, A. W. Cheever, D. Amichay, T. A. Wynn, and J. M. Farber. 2001. Patterns of chemokine expression in models of Schistosoma mansoni inflammation and infection reveal relationships between type 1 and type 2 responses and chemokines in vivo. Infect. Immun. 69:6755-6768.
19. Racoosin, E. L., and S. M. Beverley. 1997. Leishmania major: promastigotes induce expression of a subset of chemokine genes in murine macrophages. Exp. Parasitol. 85:283-295.
20. Ritter, U., H. Moll, T. Laskay, E. Brocker, O. Velazco, I. Becker, and R. Gillitzer. 1996. Differential expression of chemokines in patients with localized and diffuse cutaneous American leishmaniasis. J. Infect. Dis. 173:699-709.
21. Scharton, T. M., and P. Scott. 1993. Natural killer cells are a source of interferon- that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med. 178:567-577.
22. Schrum, S., P. Probst, B. Fleischer, and P. F. Zipfel. 1996. Synthesis of the CC-chemokines MIP-1, MIP-1, and RANTES is associated with a type 1 immune response. J. Immunol. 157:3598-3604.
23. Sousa, A. Q., M. E. Parise, M. L. Pompeu, J. M. Coelho Filho, I. A. B. Vasconcelos, J. W. O. Lima, E. G. Oliveira, A. W. Vasconcelos, J. R. David, and J. H. Maguire. 1995. Bubonic leishmaniasis: a common manifestation of Leishmania (Viannia) braziliensis infection in Ceará, Brazil. Am. J. Trop. Med. Hyg. 53:380-385.
24. Sozzani, S., S. Ghezzi, G. Iannolo, W. Luini, A. Borsatti, N. Polentarutti, A. Sica, M. Locati, C. Mackay, T. N. Wells, P. Biswas, E. Vicenzi, G. Poli, and A. Mantovani. 1998. Interleukin 10 increases CCR5 expression and HIV infection in human monocytes. J. Exp. Med. 187:439-444.
25. Vester, B., K. Muller, W. Solbach, and T. Laskay. 1999. Early gene expression of NK cell-activating chemokines in mice resistant to Leishmania major. Infect. Immun. 67:3155-3159.(Maria Jania Teixeira, Jul)
Faculdade de Medicina, Universidade Federal da Bahia-UFBA
Immunology Investigation Institute, Salvador
Núcleo de Medicina Tropical, Universidade Federal do Ceará-UFC, Fortaleza
Departamento de Imunologia, Faculdade de Medicina de Ribeiro Preto, Universidad de So Paulo, Ribeiro Preto, Brazil
ABSTRACT
Inflammatory events during Leishmania braziliensis infection in mice were investigated. Large lesions were directly correlated with the inflammatory reaction but not with parasite burden. Different L. braziliensis strains induce different paces of chemokine expression patterns, leading to diverse cell recruitment and differential inflammatory responses.
TEXT
Chemokines have been implicated in inflammatory responses against numerous infectious agents, including Leishmania (5, 17, 18, 20). Leishmania braziliensis is the main agent of cutaneous leishmaniasis (CL) in Brazil; it causes single self-limited cutaneous ulcers and highly destructive mucosal leishmaniasis (10). In this study, using a murine model, we compared L. braziliensis strains isolated from two states in Brazil, namely, Ceará and Bahia, located in northeastern Brazil. CL caused by L. braziliensis is endemic in both states. In Ceará, the cutaneous lesion is accompanied and sometimes preceded by an impressive enlargement of the regional lymph nodes; the term "bubonic leishmaniasis" has been coined to describe this manifestation (23). Bubonic leishmaniasis is restricted to L. braziliensis infection in Ceará; however, localized lymphadenopathy has been observed in CL patients from Bahia (2, 3).
Mice were infected with 106 stationary-phase forms of L. braziliensis (6). In preliminary experiments, the isolates obtained from CL patients from Ceará (MHOM/BR/94/H3227 [H3227]and MHOM/BR/94/H3456) and from Bahia (MHOM/BR/00/BA711, MHOM/BR/00/BA774, MHOM/BR/00/BA775, and MHOM/BR/01/BA788 [BA788]) showed significant differences in pathogenicity (Fig. 1, inset). Further experiments were performed with two of these L. braziliensis isolates, H3227 and BA788. The lesions caused by H3227 were larger and persisted longer than those caused by BA788 (Fig. 1). Lesion size differences did not appear to be due to diverse parasite loads, since parasite numbers were not significantly different between H3227- and BA788-infected mice at 15 days postinfection (p.i.) (mean and standard error of the mean, 7.29 x 105 ± 5.28 x 105 and 2.64 x 105 ± 1.20 x 105, respectively), when lesion sizes were different. Lesions from H3227-infected mice exhibited an inflammatory infiltrate consisting mainly of polymorphonuclear leukocytes and macrophages at 3 days p.i., and these histopathological features persisted at 15 days p.i. Sections from BA788-infected mice showed a less intense and more transient leukocyte infiltrate.
In order to explore the role of the parasite in the histopathological differences observed, we evaluated cell recruitment induced by H3227 and BA788 by using the air pouch model (14, 15). Responses induced by H3227 were three times higher than those induced by BA788 (Fig. 2A); these responses were correlated with a more intense exudate of leukocytes observed in the lesions of H3227-infected mice. H3227 was able to induce more influx of all cell types, attracting mainly more neutrophils and macrophages than BA788 (Fig. 2B). These data reinforce a role of the parasite in the differences observed in the inflammatory processes induced by the two L. braziliensis isolates used here.
RNA was extracted from lesions for reverse transcription-PCR analysis of chemokine expression at 6 h, 3 days, and 15 days p.i (12, 16). The sequences of the primers used are shown in Table 1. The expression of CCL2/MCP-1, CCL3/MIP-1, and CXCL1/KC was upregulated at 6 h p.i. on H3227-induced lesions and only at 3 days p.i. in BA788-infected mice (Fig. 3A). In addition, CCL2/MCP-1, CCL3/MIP-1, XCL1/lymphotactin-1, CXCL1/KC, and CCL11/eotaxin expression was more strongly induced by H3227 than by BA788. CXCL10/IP-10 was the only chemokine that appeared to be more strongly expressed by BA788 than by H3227. Regarding chemokine receptor expression, H3227 showed significantly higher expression of all chemokine receptors studied here than did BA788 (Fig. 3B). CCR5 was slightly upregulated in BA788-infected mice. Immunohistochemical analysis for the presence of CCL2/MCP-1 and CXCL10/IP-10 proteins in lesions induced by H3227 and BA788 confirmed the results obtained by mRNA expression analysis (Fig. 3C).
Lesions from patients with CL show a significant increase in the expression of CCL2/MCP-1 and CCL3/MIP-1 (20), and in vitro infection with Leishmania induces CCL2/MCP-1 and CXCL1/KC/GRO- expression in mouse and human macrophages (1, 19). CCL2/MCP-1 and CCL3/MIP-1 are potent chemoattractants for monocytes (9, 13). CXCL1/KC recruits neutrophils and is a dominant chemokine in murine inflammatory responses (4). The earlier expression of CCL2/MCP-1, CCL3/MIP-1, and CXCL1/KC in more severe lesions may explain the significant and early accumulation of neutrophils and macrophages at the H3227 infection site and suggests that these chemokines can be factors regulating the differential inflammatory responses which develop upon infection with the two L. braziliensis isolates used here.
H3227 induced XCL1/lymphotactin-1 and, to a lesser extent, CXCL10/IP-10. XCL1/lymphotactin-1 is chemotactic for NK, CD4+, and CD8+ T cells in vitro and in vivo (8, 11), and CXCL10/IP-10 activates NK cells in vivo (25). Furthermore, XCL1/lymphotactin-1, CCL3/MIP-1, CCL4/MIP-1, and CCL5/RANTES are associated with a Th1 immune response (7, 22). Interestingly, CXCL10/IP-10 was the only chemokine that was more strongly expressed in lesions induced by the less pathogenic strain BA788, and its expression was correlated with the earlier production of gamma interferon in the draining lymph nodes and with the larger number of NK cells in the lesions of BA788-infected mice (6). NK cells produce gamma interferon and may contribute to resistance to L. braziliensis, as previously shown for L. major (21). Therefore, it is possible that XCL1/lymphotactin-1 and CXCL10/IP-10 are involved in resistance to L. braziliensis infection in BALB/c mice. Lesions caused by L. braziliensis H3227 exhibited a higher level of chemokine receptor expression than did those caused by L. braziliensis BA788. BA788 was unable to promote the strong expression of chemokine receptors, a result which was correlated with its reduced capacity to induce leukocyte recruitment. CCR5 was slightly upregulated in BA788-infected mice at 3 days p.i. and was stimulated by CCL3/MIP-1, which was expressed during the same time period. A low level of expression of CCR5 in lesions was correlated with a lower level of expression of IL-10 in the draining lymph nodes (6), as IL-10 selectively upregulates CCR5 expression in monocytes (24).
Studies with murine macrophages showed that chemokine induction after Leishmania infection was dependent on the parasite strain used. Indeed, CCL2/MCP-1 was predominantly induced by avirulent L. major. In contrast, virulent parasites induced considerably less CCL2/MCP-1 (19). Therefore, it appears that Leishmania virulence is linked to the modulation of chemokine expression by macrophages. The kinetics of chemokine induction seem to be more important than parasite multiplication, and this fact may be related to structural differences between the two isolates used here. Of note, results from an analysis by random amplification of polymorphic DNA showed that strains H3227 and BA788 of L. braziliensis are genetically diverse (6).
Collectively, the findings presented here indicate that two L. braziliensis isolates, albeit at similar parasite burdens, induced chemokine expression patterns at different paces and/or intensities, leading to diverse cell recruitment and differential inflammatory responses; these features might ultimately be implicated in disease presentations.
ACKNOWLEDGMENTS
We thank Cristiane M. Milanezi and Jorge L. Tolentino for technical assistance.
This work was supported by grants from FAPESB, CAPES (PROCAD 0018/01-5), and CNPq. M.J.T. and C.R.T. received fellowships from CAPES. J.S.d.S., C.I.B., M.B.-N., and A.B. are senior investigators from CNPq. J.D.F. and B.B.A. received scientific initiation fellowships from CNPq.
REFERENCES
1. Badolato, R., D. L. Sacks, D. Savoia, and T. Musso. 1996. Leishmania major: infection of human monocytes induces expression of IL-8 and MCAF. Exp. Parasitol. 82:21-26.
2. Barral, A., M. Barral-Netto, R. Almeida, A. R. De Jesus, G. Grimaldi, Jr., E. M. Netto, I. Santos, O. Bacellar, and E. M. Carvalho. 1992. Lymphadenopathy associated with Leishmania braziliensis cutaneous infection. Am. J. Trop. Med. Hyg. 47:587-592.
3. Barral, A., J. Guerreiro, G. Bomfim, D. Correia, M. Barral-Netto, and E. M. Carvalho. 1995. Lymphadenopathy as the first sign of human cutaneous infection by Leishmania braziliensis. Am. J. Trop. Med. Hyg. 53:256-259.
4. Bozic, C. R., L. F. J. Kolakowski, N. P. Gerard, C. Garcia-Rodriguez, C. von Uexkull-Guldenband, M. J. Conklyn, R. Breslow, H. J. Showell, and C. Gerard. 1995. Expression and biologic characterization of the murine chemokine KC. J. Immunol. 154:6048-6057.
5. Burgmann, H., U. Hollenstein, C. Wenisch, F. Thalhammer, S. Looareesuwan, and W. Graninger. 1995. Serum concentrations of MIP-1 and interleukin-8 in patients suffering from acute Plasmodium falciparum malaria. Clin. Immunol. Immunopathol. 76:32-36.
6. de Oliveira, C. I., M. J. Teixeira, C. R. Teixeira, J. R. de Jesus, A. B. Rosato, J. S. da Silva, C. Brodskyn, M. Barral-Netto, and A. Barral. 2004. Leishmania braziliensis isolates differing at the genome level display distinctive features in BALB/c mice. Microbes Infect. 6:977-984.
7. Dorner, B. G., A. Scheffold, M. S. Rolph, M. B. Huser, S. H. E. Kaufmann, A. Radbruch, I. E. A. Flesch, and R. A. Kroczek. 2002. MIP-1, MIP-1, RANTES, and ATAC/lymphotactin function together with IFN- as type 1 cytokines. Proc. Natl. Acad. Sci. USA 99:6181-6186.
8. Emtage, P. C., Z. Xing, Y. Wan, A. Zlotnik, F. L. Graham, and J. Gauldie. 2002. Adenoviral-mediated gene transfer of lymphotactin to the lungs of mice and rats results in infiltration and direct accumulation of CD4+, CD8+, and NK cells. J. Interferon Cytokine Res. 22:573-582.
9. Fahey, T. J. I., K. J. Tracey, P. Tekamp-Olson, L. S. Cousens, W. G. Jones, G. T. Shires, A. Cerami, and B. Sherry. 1992. Macrophage inflammatory protein 1 modulates macrophage function. J. Immunol. 148:2764-2769.
10. Gontijo, B., and M. L. de Carvalho. 2003. American cutaneous leishmaniasis. Rev. Soc. Bras. Med. Trop. 36:71-80.
11. Hedrick, J. A., V. Saylor, D. Figueroa, L. Mizoue, Y. Xu, S. Menon, J. Abrams, T. Handel, and A. Zlotnik. 1997. Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo. J. Immunol. 158:1533-1540.
12. Kawakami, K., M. Tohyama, X. Qifeng, and A. Saito. 1997. Expression of cytokines and chemokines inducible in the lungs of mice infected with Cryptococcus neoformans: effects of interleukin-12. Infect. Immun. 65:1307-1312.
13. Leonard, E. J., and T. Yoshimura. 1990. Human monocyte chemoattractant protein-1 (MCP-1). Immunol. Today 11:97-101.
14. Matte, C., and M. Olivier. 2002. Leishmania-induced cellular recruitment during the early inflammatory response: modulation of proinflammatory mediators. J. Infect. Dis. 185:673-681.
15. Muller, K., G. van Zandbergen, B. Hansen, H. Laufs, N. Jahnke, W. Solbach, and T. Laskay. 2001. Chemokines, natural killer cells and granulocytes in the early course of Leishmania major infection in mice. Med. Microbiol. Immunol. 190:73-76.
16. Neumann, B., K. Emmanuilidis, M. Stadler, and B. Holzmann. 1998. Distinct functions of interferon- for chemokine expression in models of acute lung inflammation. Immunology 95:512-521.
17. Olszewski, M. A., G. B. Huffnagle, T. R. Traynor, R. A. McDonald, D. N. Cook, and G. B. Toews. 2001. Regulatory effects of macrophage inflammatory protein 1/CCL3 on the development of immunity to Cryptococcus neoformans depend on expression of early inflammatory cytokines. Infect. Immun. 69:6256-6263.
18. Park, M. K., K. F. Hoffmann, A. W. Cheever, D. Amichay, T. A. Wynn, and J. M. Farber. 2001. Patterns of chemokine expression in models of Schistosoma mansoni inflammation and infection reveal relationships between type 1 and type 2 responses and chemokines in vivo. Infect. Immun. 69:6755-6768.
19. Racoosin, E. L., and S. M. Beverley. 1997. Leishmania major: promastigotes induce expression of a subset of chemokine genes in murine macrophages. Exp. Parasitol. 85:283-295.
20. Ritter, U., H. Moll, T. Laskay, E. Brocker, O. Velazco, I. Becker, and R. Gillitzer. 1996. Differential expression of chemokines in patients with localized and diffuse cutaneous American leishmaniasis. J. Infect. Dis. 173:699-709.
21. Scharton, T. M., and P. Scott. 1993. Natural killer cells are a source of interferon- that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med. 178:567-577.
22. Schrum, S., P. Probst, B. Fleischer, and P. F. Zipfel. 1996. Synthesis of the CC-chemokines MIP-1, MIP-1, and RANTES is associated with a type 1 immune response. J. Immunol. 157:3598-3604.
23. Sousa, A. Q., M. E. Parise, M. L. Pompeu, J. M. Coelho Filho, I. A. B. Vasconcelos, J. W. O. Lima, E. G. Oliveira, A. W. Vasconcelos, J. R. David, and J. H. Maguire. 1995. Bubonic leishmaniasis: a common manifestation of Leishmania (Viannia) braziliensis infection in Ceará, Brazil. Am. J. Trop. Med. Hyg. 53:380-385.
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