Protective and pathologic immune responses in human tegumentary leishmaniasis

Frontiers in Immunology

Volumn 3, Issue OCT, 2012, Pages

  Carvalho, Lucas P ^a,b   Passos, Sara ^a,b   Schriefer, Albert ^a,b   Carvalho, Edgar M ^a,b  

^a FEDERAL UNIVERSITY OF BAHIA   (Brazil)

^b Fellow of the National Research Council   (Brazil)

Author keywords

Immune response; Leishmania braziliensis; Leishmaniasis

Indexed keywords

EID: 84874215238     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00301     Document Type: Review

References (103)

1. Acestor, N., Masina, S., Ives, A., Walker, J., Saravia, N. G., and Fasel, N. (2006). Resistance to oxidative stress is associated with metastasis in mucocuta-neous leishmaniasis. J. Infect. Dis. 194,1160-1167.
2. Afonso, L., Borges, V. M., Cruz, H., Ribeiro-Gomes, F. L., DosReis, G. A., Dutra, A. N., Clarêncio, J., Oliveira, C. I., Barral, A., Barral-Netto, M., and Brodskyn, C. I. (2008). Interactions with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages infected with Leishmania amazonensis. J. leukoc. Biol. 84, 389-396.
3. Almeida, R. P., Brito, J., Machado, P. L., AR, D. E. J., Schriefer, A., Guimaraes, L. H., and Carvalho, E. M. (2005). Successful treatment of refractory cutaneous leishmaniasis with GM-CSF and antimonials. Am. J. Trop. Med. Hyg. 73, 79-81.
4. Andersen, E. M., Cruz-Saldarriaga, M., Llanos-Cuentas, A., Luz-Cjuno, M., Echevarria, J., Miranda-Verastegui, C., Colina, O., and Berman, J. D. (2005). Comparison of meglu-mine antimoniate and pentamidine for peruvian cutaneous leishmaniasis. Am. J. Trop. Med. Hyg., 133-137.
5. Ansari, N. A., Kumar, R., Gautam, S., Nylen, S., Singh, O. P., Sundar, S., and Sacks, D. (2011). IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J. Immunol. 186, 3977-3985.
6. Antonelli, L. R., Dutra, W. O., Almeida, R. P., Bacellar, O., Carvalho, E. M., and Gollob, K. J. (2005). Activated inflammatory T cells correlate with lesion size in human cutaneous leishmaniasis. Immunol. Lett. 101, 226-230.
7. Arevalo, J., Ramirez, L., Adaui, V., Zimic, M., Tulliano, G., Miranda-Verastegui, C., Lazo, M., Loayza-Muro, R., De Doncker, S., Maurer, A., Chappuis, F., Dujardin, J. C., and Llanos-Cuentas, A. (2007). Influence of Leishmania (Viannia) species on the response to antimonial treatment in patients with American tegumen-tary leishmaniasis. J. Infect. Dis. 195, 1846-1851.
8. Aseffa, A., Gumy, A., Launois, P., Mac-Donald, H. R., Louis, J. A., and Tacchini-Cottier, F. (2002). The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4+CD25+ T cells.J. Immunol. 169, 3232-3241.
9. Azeredo-Coutinho, R. B., Mendonca, S. C., Callahan, H., Portal, A. C., and Max, G. (2007). Sensitivity of Leishmania braziliensis promastig-otes to meglumine antimoniate (glu-cantime) is higher than that of other Leishmania species and correlates with response to therapy in American tegumentary leishmaniasis. J. Parasitol. 93, 688-693.
10. Azulay, R. D., and Azulay Júnior, D. R. (1995). Immune-clinical-pathologic spectrum of leishmaniasis. Int. J. Dermatol. 34, 303-307.
11. Bacellar, O., Faria, D., Nascimento, M., Cardoso, T. M., Gollob, K. J., Dutra, W. O., Scott, P., and Carvalho, E. M. (2009). Interleukin 17 production among patients with American cutaneous leishmaniasis. J. Infect. Dis. 200,75-78.
12. Bacellar, O., Lessa, H., Schriefer, A., Machado, P., Ribeiro de Jesus, A., Dutra, W. O., Gollob, K. J., and Carvalho, E. M. (2002). Up-regulation of Th1-type responses in mucosal leishmaniasis patients. Infect. Immun. 70, 6734-6740.
13. Badaro, R., Falcoff, E., Badaro, F. S., Carvalho, E. M., Pedral-Sampaio, D., Barral, A., Carvalho, J. S., Barral-Netto, M., Brandely, M., Silva, L., Bina, J. C., Teixeira, R., Falcoff, R., Rocha, H., Ho, J. L., and Johnson, W. D. (1990). Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. N. Engl. J.Med. 322,16-21.
14. Bafica, A., Oliveira, F., Freitas, L. A., Nascimento, E. G., and Barral, A. (2003). American cutaneous leishmaniasis unresponsive to antimonial drugs: successful treatment using combination of N-methilglucamine antimoniate plus pentoxifylline. Int. J. Dermatol. 42, 203-207.
15. Barral, A., Barral-Netto, M., Yong, E. C., Brownell, C. E., Twardzik, D. R., and Reed, S. G. (1993). Transforming growth factor beta as a virulence mechanism for Leishmania braziliensis. Proc. Natl. Acad. Sci. U.S.A. 90, 3442-3446.
16. Barral, A., Guerreiro, J., Bomfim, G., Correia, D., Barral-Netto, M., and Carvalho, E. M. (1995). Lym-phadenopathy as the first sign of human cutaneous infection by Leishmania braziliensis. Am. J. Trop. Med. Hyg. 53, 256-259.
17. Boaventura, V. S., Santos, C. S., Cardoso, C. R., de Andrade, J., Dos Santos, W. L., Clarencio, J., Silva, J. S., Borges, V. M., Barral-Netto, M., Brodskyn, C. I., and Barral, A. (2010). Human mucosal leishmaniasis: neutrophils infiltrate areas of tissue damage that express high levels of Th17-related cytokines. Eur. J. Immunol. 40, 2830-2836.
18. Bosque, F., Milon, G., Valderrama, L., and Saravia, N. G. (1998). Permissiveness of human monocytes and monocyte-derived macrophages to infection by promastigotes of Leishmania (Viannia) panamensis. J. Parasitol. 84, 1250-1256.
19. Bourreau, E., Ronet, C., Darsissac, E., Lise, M. C., Marie, D. S., Clity, E., Tacchini-Cottier, F., Couppie, P., and Launois, P. (2009). In leishmaniasis due to Leishmania guya-nensis infection, distinct intralesional interleukin-10 and Foxp3 mRNA expression are associated with unre-sponsiveness to treatment. J. Infect. Dis. 199,576-579.
20. Brodskyn, C. I., Barral, A., Boaventura, V., Carvalho, E., and Barral-Netto, M. (1997). Parasite-driven in vitro human lymphocyte cyto-toxicity against autologous infected macrophages from mucosal leishmaniasis. J. Immunol. 159, 4467-4473.
21. Campanelli, A. P., Brodskyn, C. I., Boaventura, V., Silva, C., Roselino, A. M., Costa, J., Saldanha, A. C., de Freitas, L. A. R., de Oliveira, C. I., Barral-Netto, M., Silvaa, J. S., and Barralc, A. (2010). Chemokines and chemokine receptors coordinate the inflammatory immune response in human cutaneous leishmaniasis. Hum. Immunol. 71, 1220-1227.
22. Campanelli, A. P., Roselino, A. M., Cavassani, K. A., Pereira, M. S., Mor-tara, R. A., Brodskyn, C. I., Goncalves, H. S., Belkaid, Y., Barral-Netto, M., Barral, A., and Silva, J. S. (2006). CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells. J. Infect. Dis. 193, 1313-1322.
23. Carvalho, E. M., Bacellar, O., Brownell, C., Regis, T., Coffman, R. L., and Reed, S. G. (1994a). Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis.J. Immunol. 152, 5949-5956.
24. Carvalho, E. M., Barral, A., Costa, J. M., Bittencourt, A., and Marsden, P. (1994b). Clinical and immunopatho-logical aspects of disseminated cutaneous leishmaniasis. Acta Trop. 56, 315-325.
25. Carvalho, L. P., Passos, S., Bacellar, O., Lessa, M., Almeida, R. P., Magal-haes, A., Dutra, W. O., Gollob, K. J., Machado, P., and de Jesus, A. R. (2007). Differential immune regulation of activated T cells between cutaneous and mucosal leishmaniasis as a model for pathogenesis. Parasite Immunol. 29,251-258.
26. Carvalho, L. P., Pearce, E. J., and Scott, P. (2008). Functional dichotomy of dendritic cells following interaction with Leishmania braziliensis: infected cells produce high levels of TNF-alpha, whereas bystander dendritic cells are activated to promote T cell responses. J. Immunol. 181, 6473-6480.
27. Castellucci, L., Jamieson, S. E., Miller, E. N., Menezes, E., Oliveira, J., Magal-haes, A., Guimaraes, L. H., Lessa, M., de Jesus, A. R., Carvalho, E. M., and Blackwell, J. M. (2011). CXCR1 and SLC11A1 polymorphisms affect susceptibility to cutaneous leishmaniasis in Brazil: a case-control and family-based study. BMCMed. Genet. 11,10. doi: 10.1186/1471-2350-11-10
28. Castellucci, L., Menezes, E., Oliveira, J., Magalhaes, A., Guimaraes, L. H., Lessa, M., Ribeiro, S., Reale, J., Noronha, E. F., Wilson, M. E., Dug-gal, P., Beaty, T. H., Jeronimo, S., Jamieson, S. E., Bales, A., Blackwell, J. M., de Jesus, A. R., and Carvalho, E. M. (2006). IL6-174 G/C promoter polymorphism influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil. J. Infect. Dis. 194,519-527.
29. Charmoy, M., Auderset, F., Allenbach, C., and Tacchini-Cottier, F. (2010). The prominent role of neutrophils during the initial phase of infection by Leishmania parasites. J. Biomed. Biotechnol. 2010,719361.
30. Charmoy, M., Megnekou, R., Allen-bach, C., Zweifel, C., Perez, C., Monnat, K., Breton, M., Ronet, C., Launois, P., and Tacchini-Cottier, F. (2007). Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection. J. Leukoc. Biol. 82, 288-299.
31. Costa, J. M., Marsden, P. D., Llanos-Cuentas, E. A., Netto, E. M., Carvalho, E. M., Barral,A., Rosa, A. C., Cuba, C. C., Magalhaes, A. V., and Barreto, A. C. (1986). Disseminated cutaneous leishmaniasis in a field clinic in Bahia, Brazil: a report of eight cases. J. Trop. Med.Hyg. 89,319-323.
32. Croan, D. G., Morrison, D. A., and Ellis, J. T. (1997). Evolution of the genus Leishmania revealed by comparison of DNA and RNA polymerase gene sequences. Mol Biochem. Parasitol. 89,149-159.
33. Cupolillo, E., Brahim, L. R., Toaldo, C. B., de Oliveira-Neto, M. P., de Brito, M. E., Falqueto, A., de Farias Naiff, M., and Grimaldi, G. Jr. (2003). Genetic polymorphism and molecular epidemiology of Leishmania (Viannia) braziliensis from different hosts and geographic areas in Brazil. J. Clin. Microbiol. 41, 3126-3132.
34. Daboul, M. W. (2010). Role of neutrophils in cutaneous leishmaniasis. East. Mediterr. Health J. 16, 1055-1058.
35. Da-Cruz, A. M., Bittar, R., Mattos, M., Oliveira-Neto, M. P., Nogueira, R., Pinho-Ribeiro, V., Azeredo-Coutinho, R. B., and Coutinho, S. G. (2002). T-cell-mediated immune responses in patients with cutaneous or mucosal leishmaniasis: long-term evaluation after therapy. Clin. Diagn. Lab. Immunol. 9,251-256.
36. Das Gupta, S., Ghosh, D. K., and Majumder, H. K. (1991). A cloned kinetoplast DNA mini-circle fragment from a Leishmania spp. specific for post-kala-azar dermal leishmaniasis strains. Parasitology 102(Pt 2), 187-191.
37. De Trez, C., Brait, M., Leo, O., Aebis-cher, T., Torrentera, F. A., Carlier, Y., and Muraille, E. (2004). Myd88-dependent in vivo maturation of splenic dendritic cells induced by Leishmania donovani and other Leishmania species. Infect. Immun. 72,824-832.
38. Fadok, V. A., McDonald, P. P., Bratton, D. L., and Henson, P. M. (1998). Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochem. Soc. Trans. 26, 653-656.
39. Faria, D. R., Gollob, K. J., Barbosa, J. Jr., Schriefer, A., Machado, P. R., Lessa, H., Carvalho, L. P., Romano-Silva, M. A., de Jesus, A. R., Carvalho, E. M., and Dutra, W. O. (2005). Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cyto-toxic responses observed in mucosal leishmaniasis. Infect. Immun. 73, 7853-7859.
40. Faria, D. R., Souza, P. E., Duraes, F. V., Carvalho, E. M., Gollob, K. J., Machado, P. R., and Dutra, W. O. (2009). Recruitment of CD8+ T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis. Parasite Immunol. 31, 432-439.
41. Favali, C., Tavares, N., Clarencio, J., Barral, A., Barral-Netto, M., and Brodskyn, C. (2007). Leishmania amazonensis infection impairs differentiation and function of human dendritic cells. J. Leukoc. Biol. 82, 1401-1406.
42. Follador, I., Araujo, C., Bacellar, O., Araujo, C. B., Carvalho, L. P., Almeida, R. P., and Carvalho, E. M. (2002). Epidemiologic and immuno-logic findings for the subclinical form of Leishmania braziliensis infection. Clin. Infect. Dis. 34, E54-E58.
43. Forget, G., Gregory, D. J., and Olivier, M. (2005). Proteasome-mediated degradation of STAT1alphafollowing infection of macrophages with Leishmania donovani. J. Biol. Chem. 280, 30542-30549.
44. Gaur, U., Roberts, S. C., Dalvi, R. P., Corraliza, I., Ullman, B., and Wilson, M. E. (2007). An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis. J. Immunol. 179, 8446-8453.
45. Gaze, S. T., Dutra, W. O., Lessa, M., Lessa, H., Guimaraes, L. H., Jesus, A. R., Carvalho, L. P., Machado, P., Carvalho, E. M., and Gollob, K. J. (2006). Mucosal leishmaniasis patients display an activated inflammatory T-cell phenotype associated with a nonbal-anced monocyte population. Scand. J. Immunol. 63, 70-78.
46. Giudice, A., Camada, I., Leopoldo, P. T., Pereira, J. M., Riley, L. W., Wilson, M. E., Ho, J. L., de Jesus, A. R., Carvalho, E. M., and Almeida, R. P. (2007). Resistance of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis to nitric oxide correlates with disease severity in Tegumentary Leishmaniasis. BMC Infect. Dis. 7, 7. doi: 10.1186/1471-2334-7-7
47. Giudice, A., Vendrame, C., Bezerra, C., Carvalho, L. P., Delavechia, T., Carvalho, E. M., and Bacellar, O. (2012). Macrophages participate in host protection and the disease pathology associated with Leishmania braziliensis infection. BMC Infect. Dis. 12, 75. doi: 10.1186/1471-2334-12-75
48. Gomes, R. F., Macedo, A. M., Pena, S. D., and Melo, M. N. (1995). Leishmania (Viannia) braziliensis: genetic relationships between strains isolated from different areas of Brazil as revealed by DNA fingerprinting and RAPD. Exp. Parasitol. 80, 681-687.
49. Griewank, K., Gazeau, C., Eichhorn, A., and von Stebut, E. (2010). Miltefosine efficiently eliminates Leishmania major amastigotes from infected murine dendritic cells without altering their immune functions. Antimicrob. Agents Chemother. 54, 652-659.
50. Guerra, J. A. O., Barbosa, M. G. V., Paes, M. G., Sousa, R. T., Silva., P. G., Silva, M. J., Macião, A. R., Carvalho, R. S., Coelha, L. I. A. R. C., and Ferreira, L. C. L. (2011). Mucosal Leishmaniasis -clinical and epidemiological aspects of 234 cases treated in a tertiary reference center in the Brazilian Amazon. J. Community Med. Health Educ. 1, 1-2.
51. Hadighi, R., Mohebali, M., Boucher, P., Hajjaran, H., Khamesipour, A., and Ouellette, M. (2006). Unrespon-siveness to glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites. PLoS Med. 3, e162. doi: 10.1371/journal.pmed.0030162
52. Hunter, C. A., Subauste, C. S., Van Cleave, V. H., and Remington, J. S. (1994). Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha. Infect. Immun. 62,2818-2824.
53. Iniesta, V., Gomez-Nieto, L. C., and Corraliza, I. (2001). The inhibition of arginase by N(omega)-hydroxy-L-arginine controls the growth of Leishmania inside macrophages. J. Exp. Med. 193,777-784.
54. Ishikawa, E. A., Silveira, F. T., Magalhaes, A. L., Guerra junior, R. B., Melo, M. N., Gomes, R., Silveira, T. G., and Shaw, J. J. (2002). Genetic variation in populations of Leishmania species in Brazil. Trans. R. Soc. Trop. Med. Hyg. 96(Suppl. 1), S111-S121.
55. Ives, A., Ronet, C., Prevel, F., Ruzzante, G., Fuertes-Marraco, S., Schutz, F., Zangger, H., Revaz-Breton, M., Lye, L. F., Hickerson, S. M., Beverley, S. M., Acha-Orbea, H., Launois, P., Fasel, N., and Masina, S. (2011). Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science 331, 775-778.
56. Ji, J., Masterson, J., Sun, J., and Soong, L. (2005). CD4+CD25+ regulatory T cells restrain pathogenic responses during Leishmania amazonensis infection. J. Immunol. 174, 7147-7153.
57. Kahl, L. P., Byram, J. E., David, J. R., Comerford, S. A., and Von Lichten-berg, F. (1991). Leishmania (Viannia) braziliensis: comparative pathology of golden hamsters infected with isolates from cutaneous and mucosal lesions of patients residing in Tres Bracos, Bahia, Brazil. Am. J. Trop. Med. Hyg. 44,218-232.
58. Leopoldo, P. T., Machado, P. R., Almeida, R. P., Schriefer, A., Giudice, A., de Jesus, A. R., Ho, J. L., Guimaraes, L. H., Bacellar, O., and Carvalho, E. M. (2006). Differential effects of antigens from L. braziliensis isolates from disseminated and cutaneous leishmaniasis on in vitro cytokine production. BMC Infect. Dis. 6, 75. doi: 10.1186/1471-2334-6-75
59. Lessa, H. A., Machado, P., Lima, F., Cruz, A. A., Bacellar, O., Guerreiro, J., and Carvalho, E. M. (2001). Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am. J. Trop. Med. Hyg. 65, 87-89.
60. Lieke, T., Nylen, S., Eidsmo, L., Schmetz, C., Berg, L., and Akuffo, H. (2011).The interplay between Leishmania promastigotes and human Natural Killer cells in vitro leads to direct lysis of Leishmania by NK cells and modulation of NK cell activity by Leishmania promastigotes. Parasitology 138, 1898-1909.
61. Llanos-Cuentas, A., Tulliano, G., Araujo-Castillo, R., Miranda-Ver-astegui, C., Santamaria-Castrellon, G., Ramirez, L., Lazo, M., De Don-cker, S., Boelaert, M., Robays, J., Dujardin, J. C., Arevalo, J., and Chap-puis, F. (2008). Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru. Clin. Infect. Dis. 46,223-231.
62. Lopez Kostka, S., Dinges, S., Griewank, K., Iwakura, Y., Udey, M. C., and von Stebut,E. (2009). IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice. J. Immunol. 182,3039-3046.
63. Maasho, K., Sanchez, F., Schurr, E., Hailu, A., and Akuffo, H. (1998). Indications of the protective role of natural killer cells in human cutaneous leishmaniasis in an area of endemicity. Infect. Immun. 66, 2698-2704.
64. Machado, P., Araujo, C., Da Silva, A. T., Almeida, R. P., D'Oliveira, A. Jr., Bittencourt, A., and Carvalho, E. M. (2002). Failure of early treatment of cutaneous leishmaniasis in preventing the development of an ulcer. Clin. Infect. Dis. 34, E69-E73.
65. Machado, P. R., Lessa, H., Lessa, M., Guimaraes, L. H., Bang, H., Ho, J. L., and Carvalho, E. M. (2007). Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Clin. Infect. Dis. 44, 788-793.
66. Machado, P. R., Rosa, M. E., Costa, D., Mignac, M., Silva, J. S., Schriefer, A., Teixeira, M. M., Bacellar, O., and Carvalho, E. M. (2011). Reappraisal of the immunopathogene-sis of disseminated leishmaniasis: in situ and systemic immune response. Trans. R. Soc. Trop. Med. Hyg. 105, 438-444.
67. Marovich, M. A., McDowell, M. A., Thomas, E. K., and Nut-man, T. B. (2000). IL-12p70 production by Leishmania major-harboring human dendritic cells is a CD40/CD40 ligand-dependent process.J. Immunol. 164,5858-5865.
68. Martinez, F. O., Helming, L., and Gordon, S. (2009). Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451-483.
69. McDowell, M. A., Marovich, M., Lira, R., Braun, M., and Sacks, D. (2002). Leishmania priming of human dendritic cells for CD40 ligand-induced interleukin-12p70 secretion is strain and species dependent. Infect. Immun. 70, 3994-4001.
70. Mendez, S., Reckling, S. K., Piccirillo, C. A., Sacks, D., and Belkaid, Y. (2004). Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J. Exp. Med. 200,201-210.
71. Mosser, D. M., and Zhang, X. (2008). Activation of murine macrophages. Curr. Protoc. Immunol. Chapter 14, Unit 14.2.
72. Murray, H. W., Berman, J. D., Davies, C. R., and Saravia, N. G. (2005) Advances in leishmaniasis. Lancet 366, 1561-1577.
73. Nathan, C. (2006). Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173-182.
74. Novais, F. O., Santiago, R. C., Bafica, A., Khouri, R., Afonso, L., Borges, V. M., Brodskyn, C., Barral-Netto, M., Barral, A., and de Oliveira, C. I. (2009). Neutrophils and macrophages cooperate in host resistance against Leishmania brazilien-sis infection. J. Immunol. 183, 8088-8098.
75. Novoa, R., Bacellar, O., Nascimento, M., Cardoso, T. M., Ramasawmy, R., Oliveira, W. N., Schriefer, A., and Carvalho, E. M. (2011). IL-17 and regulatory cytokines (IL-10 and IL-27) in L. braziliensis infection. Parasite Immunol. 33, 132-136.
76. Nylen, S., Maasho, K., Soderstrom, K., Ilg, T., and Akuffo, H. (2003). Live Leishmania promastigotes can directly activate primary human natural killer cells to produce interferon-gamma. Clin. Exp. Immunol. 131, 457-467.
77. Nylen, S., and Sacks, D. (2007). Interleukin-10 and the pathogene-sis of human visceral leishmaniasis. Trends Immunol. 28, 378-384.
78. Pinheiro, N. F. Jr., Hermida, M. D., Macedo, M. P., Mengel, J., Bafica, A., and dos-Santos, W. L. (2006). Leishmania infection impairs beta 1-integrin function and chemokine receptor expression in mononuclear phagocytes. Infect. Immun. 74, 3912-3921.
79. Pitta, M. G., Romano, A., Cabantous, S., Henri, S., Hammad, A., Kouriba, B., Argiro, L., el Kheir, M., Bucheton, B., Mary, C., El-Safi, S. H., and Dessein, A. (2009). IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani. J. Clin. Invest. 119, 2379-2387.
80. Powrie, F., Correa-Oliveira, R., Mauze, S., and Coffman, R. L. (1994). Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J. Exp. Med. 179, 589-600.
81. Revest, M., Donaghy, L., Cabillic, E, Guiguen, C., and Gangneux, J. P. (2008). Comparison of the immunomodulatory effects of L. donovani and L. major excreted-secreted antigens, particulate and soluble extracts and viable parasites on human dendritic cells. Vaccine 26, 6119-6123.
82. Rocha, P. N., Almeida, R. P., Bacellar, O., de Jesus, A. R., Filho, D. C., Filho, A. C., Barral, A., Coffman, R. L., and Carvalho, E. M. (1999). Down-regulation of Th1 type of response in early human American cutaneous leishmaniasis. J. Infect. Dis. 180,1731-1734.
83. Sacks, D., and Kamhawi, S. (2001). Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu. Rev. Microbiol. 55, 453-483.
84. Saldanha, A. C., Romero, G. A., Merchan-Hamann, E., Magalhaes, A. V., and Macedo Vde, O. (1999). A comparative study between sodium stibogluconate BP 88R and meglu-mine antimoniate in the treatment of cutaneous leishmaniasis. I. The efficacy and safety. Rev. Soc. Bras. Med. Trop. 32, 383-387.
85. Samant, M., Sahasrabuddhe, A. A., Singh, N., Gupta, S. K., Sundar, S., and Dube, A. (2007). Proteophos-phoglycan is differentially expressed in sodium stibogluconate-sensitive and resistant Indian clinical isolates of Leishmania donovani. Parasitology 134(Pt9), 1175-1184.
86. Sanabria, M. X., Vargas-Inchaustegui, D. A., Xin, L., and Soong, L. (2008). Role of natural killer cells in modulating dendritic cell responses to Leishmania amazonensis infection. Infect. Immun. 76, 5100- 5109.
87. Saravia, N. G., Segura, I., Holguin, A. F., Santrich, C., Valderrama, L., and Ocampo, C. (1998). Epidemi-ologic, genetic, and clinical associations among phenotypically distinct populations of Leishmania (Viannia) in Colombia. Am. J. Trop. Med. Hyg. 59, 86-94.
88. Saravia, N. G., Weigle, K., Navas, C., Segura, I., Valderrama, L., Valencia, A. Z., Escorcia, B., and McMahon-Pratt, D. (2002). Heterogeneity, geographic distribution, and pathogenicity of serodemes of Leishmania viannia in Colombia. Am. J. Trop. Med. Hyg. 66, 738-744.
89. Savill, J. (2000). Apoptosis in resolution of inflammation. Kidney Blood Press. Res. 23,173-174.
90. Schriefer, A., Guimaraes, L. H., Machado, P. R., Lessa, M., Lessa, H. A., Lago, E., Ritt, G., Goes-Neto, A., Schriefer, A. L., Riley, L. W., and Carvalho, E. M. (2009). Geographic clustering of leishmaniasis in northeastern Brazil. Emerg. Infect. Dis. 15, 871-876.
91. Schriefer, A., Schriefer, A. L., Goes-Neto, A., Guimaraes, L. H., Carvalho, L. P., Almeida, R. P., Machado, P. R., Lessa, H. A., de Jesus, A. R., Riley, L. W., and Carvalho, E. M. (2004). Multiclonal Leishmania braziliensis population structure and its clinical implication in a region of endemicity for American tegumen-tary leishmaniasis. Infect. Immun. 72, 508-514.
92. Shaw, J. J. (1994). Taxonomy of the genus Leishmania: present and future trends and their implications. Mem. Inst. Oswaldo Cruz 89, 471-478.
93. Thomaz-Soccol, V., Lanotte, G., Rioux, J. A., Pratlong, F., Martini-Dumas, A., and Serres, E. (1993a). Monophyletic origin of the genus Leishmania Ross, 1903. Ann. Parasitol Hum. Comp. 68, 107-108.
94. Thomaz-Soccol, V., Lanotte, G., Rioux, J. A., Pratlong, F., Martini-Dumas, A., and Serres, E. (1993b). Phylogenetic taxonomy of New World Leishmania. Ann. Parasitol Hum. Comp. 68, 104-106.
95. Turetz, M. L., Machado, P. R., Ko, A. I., Alves, F., Bittencourt, A., Almeida, R. P., Mobashery, N., Johnson, W. D. Jr., and Carvalho, E. M. (2002). Disseminated leishmaniasis: a new and emerging form of leishmaniasis observed in northeastern Brazil. J. Infect. Dis. 186, 1829-1834.
96. Unger, A., O'Neal, S., Machado, P. R., Guimaraes, L. H., Morgan, D. J., Schriefer, A., Bacellar, O., Glesby, M. J., and Carvalho, E. M. (2009). Association of treatment of American cutaneous leishmaniasis prior to ulcer development with high rate of failure in northeastern Brazil. Am. J. Trop. Med. Hyg. 80, 574-579.
97. Vargas-Inchaustegui, D. A., Xin, L., and Soong, L. (2008). Leishmania braziliensis infection induces dendritic cell activation, ISG15 transcription, and the generation of protective immune responses. J. Immunol. 180, 7537-7545.
98. Vendrame, C. M., Carvalho, M. D., Rios, F. J., Manuli, E. R., Petitto-Assis, F., and Goto, H. (2007). Effect of insulin-like growth factor-I on Leishmania amazonen-sis promastigote arginase activation and reciprocal inhibition of NOS2 pathway in macrophage in vitro. Scand. J. Immunol. 66, 287-296.
99. Voll, R. E., Herrmann, M., Roth, E. A., Stach, C., Kalden, J. R., and Girkon-taite, I. (1997). Immunosuppressive effects of apoptotic cells. Nature 390, 350-351.
100. Walker, J., Acestor, N., Gongora, R., Quadroni, M., Segura, I., Fasel, N., and Saravia, N. G. (2006). Comparative protein profiling identifies elongation factor-1beta and trypare-doxin peroxidase as factors associated with metastasis in Leishmania guya-nensis. Mol. Biochem. Parasitol. 145, 254-264.
101. Wanasen, N., and Soong, L. (2008). L-arginine metabolism and its impacts on host immunity against Leishmania infection. Immunol. Res. 41, 15-25.
102. Wang, Z. E., Reiner, S. L., Hatam, E, Heinzel, E P., Bouvier, J., Turck, C. W., and Locksley, R. M. (1993). Targeted activation of CD8 cells and infection of beta 2-microglobulin-deficient mice fail to confirm a primary protective role for CD8 cells in experimental leishmaniasis. J. Immunol. 151, 2077-2086.
103. Xu, D., Liu, H., Komai-Koma, M., Campbell, C., McSharry, C., Alexander, J., and Liew, E Y. (2003). CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J. Immunol. 170, 394-399.