Genetic diversity and susceptibility to Leishmaniasis in mouse and man

Genetic variation also appears to play an important role in modulating susceptibility to a second major parasitic disease, leishmaniasis (Box 13.4). Evidence from mouse models highlighted a role for genetic factors in susceptibility to infection (Lipoldova and Demant 2006). Among humans, studies of visceral leishmaniasis in northeastern Brazil provided evidence of familial aggregation and increased risk in siblings of affected sib pairs (Cabello et al. 1995; Peacock et al. 2001).

Variation between ethnic groups in their susceptibility to leishmaniasis has also been reported with differences in the incidence of clinical disease found between adjacent villages in which people of different ethnic origin lived (Zijlstra et al. 1994). For example, the Masalit people living in an endemic region for leishmaniasis in Sudan showed high rates of disease that was fatal unless treated, while neighbouring groups such as the Hawasa tribe did not (Blackwell et al. 2004). A further example came from a study in Dinder National Park in northern Sudan, which lies in a highly endemic area for visceral leishmaniasis (Ibrahim et al. 1999). Game wardens

Box 13.4 Leishmaniasis

Infections with many species of Leishmania cause common and often serious diseases in Central and South America, around the Mediterranean, in northern and Central Africa, the Middle East, central and western Asia, and the Indian subcontinent. These intracellular protozoan parasites are transmitted by the bite of infected female phlebotom-ine sandflies. The parasite predominantly infects macrophages, a type of immune cell found in the blood which normally engulfs and destroys infectious pathogens (Fig. 13.10). The parasites can cause cutaneous disease, which varies from self-healing skin ulcers to highly disfiguring facial mucocutane-ous lesions. Disseminated spread is seen in visceral leishmaniasis, known as kala-azar, which results in various clinical manifestations including fever, wasting, an enlarged liver and spleen, lymphaden-opathy, and blood pancytopenia. It is usually fatal unless treated and is highly infectious. Devastating epidemics have occurred, as recently as 1984 in Sudan, where death rates of up to 70% in the most affected areas were reported with an estimated 100 000 deaths, among approximately 280 000 people in the epidemic area, thought to be attributable to visceral leishmaniasis (Seaman et al. 1996). The particular type of disease that results depends on several factors, notably the individual species of Leishmania parasite injected into the blood and

Figure 13.10 Leishmania major promastigote attached to a macrophage. The human host is infected with promastigotes by the infected sandfly bite, promastigotes being a particular stage in the Leishmania parasite life cycle. The promastigotes invade skin dendritic cells and macrophages. A scanning electron micrograph showing the attachment of a promastigote to a macrophage is shown. Reproduced from Roberts et al. (2000), with permission from BMJ Publishing Group Ltd.

Figure 13.10 Leishmania major promastigote attached to a macrophage. The human host is infected with promastigotes by the infected sandfly bite, promastigotes being a particular stage in the Leishmania parasite life cycle. The promastigotes invade skin dendritic cells and macrophages. A scanning electron micrograph showing the attachment of a promastigote to a macrophage is shown. Reproduced from Roberts et al. (2000), with permission from BMJ Publishing Group Ltd.

the genetic constitution of the host. Other factors include the nutritional status of the host, the sand-fly vector, environmental and social factors, and reservoir hosts which may be human or zoonotic (Lipoldova and Demant 2006).

working in the game reserve varied in their susceptibility depending on their ethnic background. Those from the Baria tribe of southern Sudan or the Nuba tribe from western Sudan were more likely to develop visceral leishmaniasis.

Strains of laboratory mice were found to differ in their susceptibility to infection with Leishamania major and L. donovani, and have proved a very powerful approach to defining genetic susceptibility (Lipoldova and Demant 2006). For example, resistant and susceptible strains were found for L. donovani that showed markedly different rates of proliferation of the parasite in the liver. By performing breeding experiments with recombinant inbred strains, it was possible to identify a region of chromosome 1 that conferred resistance to early infection (Bradley 1977). The same genetic locus was found to control other intracellular infections such as Mycobacterium bovis (BCG), M. lepraemurium, and Salmonella typhimurium (Plant and Glynn 1974, 1976; Gros et al. 1981; Skamene et al. 1982).

Positional cloning resolved a susceptibility gene in the locus called Nramp1 (also known as Slc11a1), encoding 'natural resistance associated macrophage protein' (Vidal et al. 1993). A single G to A nucleotide substitution resulted in a glycine to aspartic acid substitution at position 169 in the protein and segregated between the resistant and susceptible mouse strains (Vidal et al. 1993). Mice homozygous for this substitution were phenotypic-ally identical to knock-out mice for Nramp1 (Vidal et al. 1995). The Nramp1 protein is found on the membranes of macrophages and neutrophils where it functions as a divalent metal pH-dependent pump, transporting Fe2+, Zn2+, and Mn2+ from within cells (Goswami et al. 2001). This prevents the parasite from replicating as these metals are needed by the parasite's metabolism as well as resulting in diverse effects promoting macrophage defence (Lipoldova and Demant 2006).

In humans, genetic variation in the Nramp1 homologue gene SLC11A1, encoding solute carrier family 11 (proton-coupled divalent metal ion transporters) member 1, at chromosome 2q35, has been associated with a number of infectious, autoimmune, and inflammatory diseases (O'Brien et al. 2008). Studies of affected families among the Masalit tribe in Sudan, a group highly susceptible to visceral leishmaniasis, have shown linkage with variation in the SLC11A1 gene (Mohamed et al. 2004), a result also found independently in a different ethnic group in Sudan (Bucheton et al. 2003b). However, fine mapping and defining specific functional variants has proved challenging. A microsatellite in the promoter region was postulated as functionally important with different (CA)n alleles associated with low and high gene expression, and was found to have contrasting associations to infectious and autoimmune disease (O'Brien et al. 2008). This microsatellite was one of several variants of SLC11A1 associated with tuberculosis in a case-control study in The Gambia (Bellamy et al. 1998). The disparity between clear cut effects on susceptibility to leishmaniasis seen in mice, and more variable data in humans, reflect the fact that while in mice the Nramp1 variant dramatically affects the function of the protein, in humans the disease associated polymorphisms identified to date appear to have a much more modest effect (Lipoldova and Demant 2006).

Sequence variation in other genomic regions may also be important. In the village of Barbar El Fugara in eastern Sudan, a devastating outbreak of kala-azar occurred between 1995 and 2002. Antibody studies show nearly everyone was exposed and over a quarter of people developed the disease (Bucheton et al. 2002, 2003c). Cases clustered in families and ethnic groups. Analysis showed that Aringa families originally from western Sudan were worst affected (Bucheton et al. 2003a). These families were studied to try and resolve any genetic basis for susceptibility. A number of genetic markers were used to carry out a genome-wide linkage study (Bucheton et al. 2003a). A total of 63 Sudanese families were studied using 380 markers. This showed evidence of significant linkage for markers on chromosome 22q12. By contrast among the Masalit ethnic group, a genome-wide linkage analysis defined susceptibility loci at 1p22 and 6q27 that were of Y chromosome lineage and were village-specific (Miller et al. 2007). Chromosome 6q27 was among a number of loci identified on a genome-wide linkage scan for visceral leishmaniasis carried out in Brazil, other loci were 7q11.22 and 17q11.2 (Jamieson et al. 2007). A number of candidate gene studies have also found varying associations with the markers in the MHC, IL4 and IFNGR1 (encoding interferon gamma receptor 1) (Lipoldova and Demant 2006).

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