Genetic Predisposition to Self‐Curing Infection with the Protozoan Leishmania chagasi: A Genomewide Scan

Department of Biochemistry, Universidade Federal do Rio Grande do Norte, Natal, Rio de Grande do Norte, Brazil.
The Journal of Infectious Diseases (Impact Factor: 6). 11/2007; 196(8):1261-9. DOI: 10.1086/521682
Source: PubMed


The protozoan Leishmania chagasi can cause disseminated, fatal visceral leishmaniasis (VL) or asymptomatic infection in humans. We hypothesized that host genetic factors contribute to this variable response to infection. A family study was performed in neighborhoods of endemicity for L. chagasi near Natal in northeastern Brazil. Study subjects were assessed for the presence of VL or asymptomatic infection, which was defined by a positive delayed-type hypersensitivity (DTH) skin test response to Leishmania antigen without disease symptoms. A genomewide panel of 385 autosomal microsatellite markers in 1254 subjects from 191 families was analyzed to identify regions of linkage. Regions with potential linkage to the DTH response on chromosomes 15 and 19, as well as a novel region on chromosome 9 with potential linkage to VL, were identified. Understanding the genetic factors that determine whether an individual will develop symptomatic or asymptomatic infection with L. chagasi may identify proteins essential for immune protection against this parasitic disease and reveal strategies for immunotherapy or prevention.

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Available from: Nicholas Ettinger, Apr 19, 2014
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    • "Some studies have investigated genetic differences between healthy infected and symptomatic individuals, but most of these were either not aimed to identify candidate loci [15], [16] or targeted at few candidate genes [17], [10], [18]. Only Jeronimo et al. [19] have studied progression of leishmaniasis following infection using a genome-wide linkage approach in humans based on a few hundred microsatellite markers. In dogs, genetic susceptibility to progression of disease from Leishmania infection is supported by the fact that the percentage of infected dogs in endemic areas is as high as 60% [20] whereas rates of clinical CanL are much lower in these areas [21], [22]. "
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    PLoS ONE 04/2012; 7(4):e35349. DOI:10.1371/journal.pone.0035349 · 3.23 Impact Factor
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    • "Familial clustering, and the range of clinical outcomes from asymptomatic to fatal disease within and between ethnic groups sharing similar risk factors, support a contribution of host genotype to susceptibility [4-8]. Resistance to VL, as determined by a positive antigen-specific DTH response without clinical symptoms, is ~80% heritable in family-based studies [9]. Genetic variability in ability to mount an innate immune response, such as in the influx of polymorphonuclear neutrophils (PMN) during initial hours of infection, could be important in innate killing of the parasite [10], and in providing the cytokine environment in which parasite-specific T cells are primed [11]. "
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    BMC Medical Genetics 12/2011; 12(1):162. DOI:10.1186/1471-2350-12-162 · 2.08 Impact Factor
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    • "The number of VL cases is increasing per year and is predominately pediatric (Jeronimo et al. 2007). "
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    ABSTRACT: The present work reports the isolation, biochemical characterization, and subcellular location of serine proteases from aqueous, detergent soluble, and culture supernatant of Leishmania chagasi promastigote extracts, respectively, LCSII, LCSI, and LCSIII. The active enzyme molecular masses of LCSII were about 105, 66, and 60 kDa; of LCSI, 60 and 58 kDa; and of LCSIII, approximately 76 and 68 kDa. Optimal pH for the enzymes was 7.0 for LCSI and LCSIII and 8.5 for LCSII, and the optimal temperature for all enzymes was 37°C, using α-N-ρ-tosyl-L: -arginine methyl ester as substrate. Assay of thermal stability indicated that LCSIII is the more stable enzyme. Hemoglobin, bovine serum albumin, and ovalbumin were hydrolyzed by LCSII and LCSI but not by LCSIII. Inhibition studies suggested that enzymes belong to the serine protease class modulated by divalent cations. Rabbit antiserum against 56-kDa serine protease of Leishmania amazonensis identified proteins in all extracts of L. chagasi. Furthermore, immunocytochemistry demonstrated that serine proteases are located in flagellar pocket region and cytoplasmic vesicles of L. chagasi promastigotes. These findings indicate that L. chagasi serine proteases differ from L. amazonensis proteases and all known flagellate proteases, but display some similarities with serine proteases from other Leishmania species, suggesting a conservation of this enzymatic activity in the genus.
    Parasitology Research 10/2010; 107(5):1151-62. DOI:10.1007/s00436-010-1983-y · 2.10 Impact Factor
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