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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    ABSTRACT: The current disease model for leishmaniasis suggests that only a proportion of infected individuals develop clinical disease, while others are asymptomatically infected due to immune control of infection. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, although previous studies suggest a role for host genetics. Our hypothesis was that canine leishmaniasis is a complex disease with multiple loci responsible for the progression of the disease from Leishmania infection.
    Full-text · Article · Apr 2012 · PLoS ONE
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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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    ABSTRACT: IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India. Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients. Family-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021). This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India.
    Full-text · Article · Dec 2011 · BMC Medical Genetics
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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.
    Full-text · Article · Oct 2010 · Parasitology Research
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