Skip to main content Accessibility help
  • Print publication year: 2004
  • Online publication date: August 2009

10 - Human Susceptibility to Visceral Leishmaniasis (Leishmania donovani) and to Schistosomiasis (Schistosoma mansoni) Is Controlled by Major Genetic Loci

    • By A. Dessein, Immunology and Genetics of Parasitic Diseases, INSERM, U. 399, Marseille, France, B. Bucheton, Immunology and Genetics of Parasitic Diseases, INSERM, U. 399, Marseille, France, L. Argiro, Immunology and Genetics of Parasitic Diseases, INSERM, U. 399, Marseille, France, N. M. A. Elwali, Institute of Nuclear Medicine and Molecular Biology, University of Gezira, Wad Medani, Sudan, V. Rodrigues, Laboratory of Immunology, University of Medicine, Triangulo Miniero, Uberaba, Brazil, C. Chevillard, Immunology and Genetics of Parasitic Diseases, INSERM, U. 399, Marseille, France, S. Marquet, Immunology and Genetics of Parasitic Diseases, INSERM, U. 399, Marseille, France, H. Dessein, Immunology and Genetics of Parasitic Diseases, INSERM, U. 399, Marseille, France, S. H. El-Safi, Institute for Tropical Medicine, PO Box 1304, Khartoum, Sudan, L. Abel, Laboratory of Human Genetics of Infectious Diseases, INSERM, U. 550, Paris, France
  • Edited by Krishna R. Dronamraju, Foundation for Genetic Research, Houston, Texas
  • Publisher: Cambridge University Press
  • DOI:
  • pp 241-262



Visceral leishmaniasis (VL) is caused by protozoan parasites of the Leishmania genus that are transmitted to humans by infected sandflies (Figure 10.1a). Parasites rapidly invade host phagocytes and multiply inside phagolysosomes. Clinical disease is primarily due to the uncontrolled multiplication of the parasite in many organs including the spleen and the liver; clinical symptoms include recurrent fever, considerable splenomegaly, hepatomegaly, and adenopathy (1). Death is certain if the patient is left untreated. Violent outbreaks of VL have occurred in regions of eastern Africa (2) (Kenya, Sudan) and in India (Bihar). VL is endemic in South America and in the Mediterranean basin. VL is caused by three Leishmania species: Leishmania donovani, L. chagasi/infantum, and L. archibaldi (L. donovani being the most pathogenic) (3). To identify the principal risk factors in VL, we carried out a five-year longitudinal study on 1,600 subjects from a village located on the Sudanese–Ethiopian border. The study was initiated in 1995 when the number of VL cases had just begun to rise in the village (4). Within five years, 28% of the population had been affected by VL. Most of these VL patients were treated and cured. Unfortunately, a small percentage either failed to respond to treatment or were not treated because of the difficulties involved in reaching them during the rainy season.

Related content

Powered by UNSILO
Dessein, A J, Chevillard, C, Marquet, S, Henri, S, Hillaire, D, Dessein, H. 2001. Genetics of parasitic infections. Drug Metab. Dispos. 29(4 Pt 2): 484–8
Seaman, J, Mercer, A J, Sondorp, E. 1996. The epidemic of visceral leishmaniasis in western Upper Nile, southern Sudan: Course and impact from 1984 to 1994. Int. J. Epidemiol. 25(4): 862–71
Desjeux P. The increase in risk factors for leishmaniasis worldwide. 2001. Trans. R. Soc. Trop. Med. Hyg. 95: 239–43
El-Safi, S H, Bucheton, B, Kheir, M M, Musa, H A, El-Obeid, M, Hammad, A, and Dessein, A. 2002. Epidemiology of visceral leishmaniasis in Atbara River area, Eastern Sudan: The outbreak of Barbar El Fugara village (1996–1997). Microb. Infect. 14: 1439–47
Bucheton B, El-Safi S H, Hammad A, Kheir M M, Eudes N, Mergani A, and Dessein A. 2002. Anti-Leishmania antibodies in an outbreak of visceral leishmaniasis in Eastern Sudan: High antibody responses occur in resistant subjects and are not predictive of disease. Trans. R. Trop. Med. Hyg. (in press)
Lambert, J, and 7 colleagues. 2002. The sand fly fauna in the visceral leishmaniasis focus of Gedaref (Atbara River area, Eastern Sudan). Ann. Trop. Med. Parasitol. 96(6): 631–6
Bucheton, B, Kheir, M M, El-Safi, S H, Hammad, A, Mergani, A, Mary, C, Abel, L, and Dessein, A. 2002. The interplay between environmental and host factors during an outbreak of visceral leishmaniasis in Eastern Sudan. Microb. Infect. 14: 1449–57
Bradley, D J, Taylor, B A, Blackwell, J, Evans, E P, Freeman, J. 1979. Regulation of Leishmania populations within the host. III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse. Clin. Exp. Immunol. 37(1): 7–14
Blackwell, J M. 1996. Genetic susceptibility to leishmanial infections: Studies in mice and man. Parasitology 112(Suppl): S67–S74
Vidal, S and 9 colleagues. 1995. The Ity/Lsh/Bcg locus: Natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J. Exp. Med. 182(3): 655–66
Blackwell, J, Freeman, J, Bradley, D. 1980. Influence of H-2 complex on acquired resistance to Leishmania donovani infection in mice. Nature 283(5742): 72–4
Searle, S, Bright, N A, Roach, T I, Atkinson, P G, Barton, C H, Meloen, R H, and colleagues. 1998. Localisation of Nramp1 in macrophages: Modulation with activation and infection. J. Cell. Sci. 111(Pt 19): 2855–66
Biggs, T E, Baker, S T, Botham, M S, Dhital, A, Barton, C H, Perry, V H. 2001. Nramp1 modulates iron homoeostasis in vivo and in vitro: Evidence for a role in cellular iron release involving de-acidification of intracellular vesicles. Eur. J. Immunol. 31(7): 2060–70
Blackwell, J M, Goswami, T, Evans, C A, Sibthorpe, D, Papo, N, White, J K, and 5 colleagues. 2001. SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol. 3(12): 773–84
Liu, J, Fujiwara, T M, Buu, N T, Sanchez, F O, Cellier, M, Paradis, A J, and colleagues. 1995. Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene. Am. J. Hum. Genet. 56(4): 845–53
Bellamy, R, Ruwende, C, Corrah, T, McAdam, K P, Whittle, H C, Hill, A V. 1998. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N. Engl. J. Med. 338(10): 640–4
Abel, L, Sanchez, F O, Oberti, J, Thuc, N V, Hoa, L V, Lap, V D, and colleagues. 1998. Susceptibility to leprosy is linked to the human NRAMP1 gene. J. Infect. Dis. 177(1): 133–45
Greenwood, C M, Fujiwara, T M, Boothroyd, L J, Miller, M A, Frappier, D, Fanning, E A, and colleagues. 2000. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am. J. Hum. Genet. 67(2): 405–16
Searle, S, Blackwell, J M. 1999. Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J. Med. Genet. 36(4): 295–9
Bucheton, B, Abel, L, Kheir, M M, Mirghani, A, El-Safi, S, Chevillard, C, Dessein, A. 2003. Genetic control of visceral leishmaniasis in a Sudanese population: Candidate gene testing indicates a linkage to the NRAMP1 gene. Genes. Immun. 4: 104–109
Abel, L, Muller-Myhsok, B. 1998. Robustness and power of the maximum-likelihood-binomial and maximum-likelihood-score methods, in multipoint linkage analysis of affected-sibship data. Am. J. Hum. Genet. 63(2): 638–47
Xu, J, Meyers, D A, Ober, C, Blumenthal, M N, Mellen, B, Barnes, K C, and 9 colleagues. 2001. Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: Collaborative study on the genetics of asthma. Am. J. Hum. Genet. 68(6): 1437–46
Lichtenberg, F. 1962. Host response to eggs of S. mansoni. I. Granuloma formation in the unsensitized laboratory mouse. Am. J. Pathol. 41: 711–31
Warren, K S, Domingo, E O, Cowan, R B. 1967. Granuloma formation around schistosome eggs as a manifestation of delayed hypersensitivity. Am. J. Pathol. 51(5): 735–56
Butterworth, A E, Capron, M, Cordingley, J S, Dalton, P R, Dunne, D W, Kariuki, H C, and 9 colleagues. 1985. Immunity after treatment of human schistosomiasis mansoni. II. Identification of resistant individuals, and analysis of their immune responses. Trans. R. Soc. Trop. Med. Hyg. 79(3): 393–408
Dessein, A J, Begley, M, Demeure, C, Caillol, D, Fueri, J, dos Reis, M G, and 3 colleagues. 1988. Human resistance to Schistosoma mansoni is associated with IgG reactivity to a 37-kDa larval surface antigen. J. Immunol. 140(8): 2727–36
Abel, L, Dessein, A. 1991. Genetic predisposition to high infections in an endemic area of Schistosoma mansoni [editorial]. Rev. Soc. Bras. Med. Trop. 24(1): 1–3
Dessein, A J, Couissinier, P, Demeure, C, Rihet, P, Kohlstaedt, S, Carneiro-Carvalho, D, and 4 colleagues. 1992. Environmental, genetic and immunological factors in human resistance to Schistosoma mansoni. Immunol. Invest. 21(5): 423–53
Hagan, P, Blumenthal, U J, Dunn, D, Simpson, A J, Wilkins, H A. 1991. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature 349(6306): 243–5
Rihet, P, Demeure, C E, Bourgois, A, Prata, A, Dessein, A J. 1991. Evidence for an association between human resistance to Schistosoma mansoni and high anti-larval IgE levels. Eur. J. Immunol. 21(11): 2679–86
Couissinier, P, Dessein, A J. 1995. Schistosoma-specific helper T cell from subjects resistant to infection by Schistosoma mansoni are ThO/2. Euro. J. Immunol. 25: 2295–302
Rodriguez, V, Piper, K, Couissinier-Paris, P, Bacelar, O, Dessein, H, Dessein, A J. 1999. Genetic control of Schistosome infections by SM1 locus of the 5q31-q33 region is linked to differentition of type 2 helper T lymphocytes. Infect. Immun.67, 4689–92
Rihet, P, Demeure, C E, Dessein, A J, Bourgois, A. 1992. Strong serum inhibition of specific IgE correlated to competing IgG4, revealed by a new methodology in subjects from a S. mansoni endemic area. Eur. J. Immunol. 22(8): 2063–70
Demeure, C E, Rihet, P, Abel, L, Ouattara, M, Bourgois, A, Dessein, A J. 1993. Resistance to Schistosoma mansoni in humans: Influence of the IgE/IgG4 balance and IgG2 in immunity to reinfection after chemotherapy. J. Infect. Dis. 168(4): 1000–8
Abel, L, Demenais, F, Prata, A, Souza, A E, Dessein, A. 1991. Evidence for the segregation of a major gene in human susceptibility/resistance to infection by Schistosoma mansoni [see comments]. Am. J. Hum. Genet. 48(5): 959–70
Marquet, S, Abel, L, Hillaire, D, Dessein, H, Kalil, J, Feingold, J, and 2 colleagues. 1996. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nat. Genet. 14(2): 181–4
Muller-Myhsok, B, Stelma, F F, Guisse-Sow, F, Muntau, B, Thye, T, Burchard, G D, and 2 colleagues. 1997. Further evidence suggesting the presence of a locus, on human chromosome 5q31-q33, influencing the intensity of infection with Schistosoma mansoni [letter; comment]. Am. J. Hum. Genet. 61(2): 452–4
Marsh, D G, Neely, J D, Breazeale, D R, Ghosh, B, Freidhoff, L R, Ehrlich-Kautzky, E, and colleagues. 1994. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 264(5162): 1152–6
Martinez, F D, Solomon, S, Holberg, C J, Graves, P E, Baldini, M, Erickson, R P. 1998. Linkage of circulating eosinophils markers on chromosome 5q. Am. J. Respir. Crit. Care Med. 158: 1739–44
Rioux, J D, Stone, V A, Daly, M J, Cargill, M, Green, T, Nguyen, H, and colleagues. 1998. Familial eosinophiliz maps to the cytokine gene cluster on human chromosomal region 5q31-q33. Am. J. Hum. Genet. 63: 1086–94
Warren, K S. 1977. Modulation of immunopathology and disease in schistosomiasis. Am. J. Trop. Med. Hyg. 26(6 Pt 2): 113–9
Chensue, S W, Warmington, K S, Ruth, J, Lincoln, P M, Kunkel, S L. 1994. Cross-regulatory role of interferon-gam ma (IFN-gamma), IL-4 and IL-10 in schistosome egg granuloma formation: The in vivo regulation of activity and inflammation. Clin. Exp. Immunol. 98(3): 395–400
Wynn, T A, Morawetz, R, Scharton-Kersten, T, Hieny, S, Morse, H C 3rd, Kuhn, R, and colleagues. 1997. Analysis of granuloma formation in double cytokine-deficient mice reveals a central role for IL-10 in polarizing both T helper cell 1- and T helper cell 2-type cytokine responses in vivo. J. Immunol. 159(10): 5014–23
Grimaud, J A, Borojevic, R. 1977. Chronic human schistosomiasis mansoni. Pathology of the Disse's space. Lab. Invest. 36(3): 268–73
Gressner, A M, Bachem, M G. 1995. Molecular mechanisms of liver fibrogenesis – A homage to the role of activated fat-storing cells. Digestion 56(5): 335–46
Poli, G. 2000. Pathogenesis of liver fibrosis: Role of oxidative stress. Mol. Aspects Med. 21(3): 49–98
Hoffmann, K F, Cheever, A W, Wynn, T A. 2000. IL-10 and the dangers of immune polarization: Excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J. Immunol. 164(12): 6406–16
Jimenez, S A, Freundlich, B, Rosenbloom, J. 1984. Selective inhibition of human diploid fibroblast collagen synthesis by interferons. J. Clin. Invest. 74(3): 1112–6
Duncan, M R, Berman, B. 1985. Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation. J. Exp. Med. 162(2): 516–27
Czaja, M J, Weiner, F R, Eghbali, M, Giambrone, M A, Eghbali, M, Zern, M A. 1987. Differential effects of gamma-interferon on collagen and fibronectin gene expression. J. Biol. Chem. 262(27): 13,348–51
Czaja, M J, Weiner, F R, Takahashi, S, Giambrone, M A, Meide, P H, Schellekens, H, and 2 colleagues. 1989. Gamma-interferon treatment inhibits collagen deposition in murine schistosomiasis. Hepatology 10(5): 795–800
Rockey, D C, Chung, J J. 1994. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: Implications for treatment of hepatic fibrosis. J. Invest. Med. 42(4): 660–70
Mallat, A, Preaux, A M, Blazejewski, S, Rosenbaum, J, Dhumeaux, D, Mavier, P. 1995. Interferon alfa and gamma inhibit proliferation and collagen synthesis of human Ito cells in culture. Hepatology 21(4): 1003–10
Roberts, A B, Sporn, M B, Assoian, R K, Smith, J M, Roche, N S, Wakefield, L M, and 2 colleagues. 1986. Transforming growth factor type beta: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl. Acad. Sci. USA 83(12): 4167–71
Tiggelman, A M, Boers, W, Linthorst, C, Sala, M, Chamuleau, R A. 1995. Collagen synthesis by human liver (myo)fibroblasts in culture: Evidence for a regulatory role of IL-1 beta, IL-4, TGF beta and IFN gamma. J. Hepatol. 23(3): 307–17
Tamai, K, Ishikawa, H, Mauviel, A, Uitto, J. 1995. Interferon-gamma coordinately upregulates matrix metalloprotease (MMP)-1 and MMP-3, but not tissue inhibitor of metalloproteases (TIMP), expression in cultured keratinocytes. J. Invest. Dermatol. 104(3): 384–90
Mohamed-Ali, Q, Elwali, N E, Abdelhameed, A A, Mergani, A, Rahoud, S, Elagib, K E, and 3 colleagues. 1999. Susceptibility to periportal (Symmers) fibrosis in human Schistosoma mansoni infections: Evidence that intensity and duration of infection, gender, and inherited factors are critical in disease progression. J. Infect. Dis. 180(4): 1298–306
Henri, S, Chevillard, C, Mergani, A, Paris, P, Gaudart, J, Camilla, C, and colleagues. 2002. Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease. J. Immunol. 169(2): 929–36
Dessein, A J, Hillaire, D, Elwali, E N M A, Marquet, S, Mohamed-Ali, Q, Mirghani, A, and colleagues. 1999. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-g receptor gene. Am. J. Hum. Genet. 68: 709–21
Salam, E A, Ishaac, S, Mahmoud, A A. 1979. Histocompatibilty-linked susceptibility for hepatosplenomegaly in human schistosomiasis mansoni. J. Immunol. 123(4): 1829–31
Abaza, H, Asser, L, el Sawy, M, Wasfy, S, Montaser, L, Hagras, M, and 3 colleagues. 1985. HLA antigens in schistosomal hepatic fibrosis patients with haematemesis. Tissue Antigens 26(5): 307–9
Abdel-Wahab, M F, Esmat, G, Narooz, S I, Yosery, A, Struewing, J P, Strickland, G T. 1990. Sonographic studies of school children in a village endemic for Schistosoma mansoni. Trans. R. Soc. Trop. Med. Hyg. 84(1): 69–73
Secor, W E, del Corral, H, dos Reis, M G, Ramos, E A, Zimon, A E, Matos, E P, and colleagues. 1996. Association of hepatosplenic schistosomiasis with HLA-DQB1*0201. J. Infect. Dis. 174(5): 1131–5
Casanova, J L, Abel, L. 2002. Genetic dissection of immunity to mycobacteria: The human model. Annu. Rev. Immunol. 20: 581–620.