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Genes at Human Chromosome 5Q31.1 Regulate Delayed-Type Hypersensitivity Responses Associated with Leishmania Chagasi Infection

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Genes at Human Chromosome 5Q31.1 Regulate Delayed-Type Hypersensitivity Responses Associated with Leishmania Chagasi Infection Genes and Immunity (2007) 8, 539–551 & 2007 Nature Publishing Group All rights reserved 1466-4879/07 $30.00 www.nature.com/gene ORIGINAL ARTICLE Genes at human chromosome 5q31.1 regulate delayed-type hypersensitivity responses associated with Leishmania chagasi infection SMB Jeronimo1, AKB Holst2, SE Jamieson3, R Francis3, DRA Martins1, FL Bezerra1, NA Ettinger2, ET Nascimento1, GR Monteiro1, HG Lacerda1, EN Miller3, HJ Cordell4, P Duggal5, TH Beaty6, JM Blackwell3,7 and ME Wilson2,7 1Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, RN, Brazil; 2Departments of Internal Medicine, Microbiology, Epidemiology and the Molecular Biology Program, University of Iowa and the VA Medical Center, Iowa City, IA, USA; 3Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK; 4Institute of Human Genetics, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne, UK; 5Inherited Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA and 6Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA Visceral leishmaniasis (VL) caused by Leishmania chagasi is endemic to northeast Brazil. A positive delayed-type hypersensitivity skin test response (DTH þ ) is a marker for acquired resistance to disease, clusters in families and may be genetically controlled. Twenty-three single nucleotide polymorphisms (SNPs) were genotyped in the cytokine 5q23.3–q31.1 region IRF1-IL5-IL13-IL4-IL9-LECT2-TGFBI in 102 families (323 DTH þ ; 190 DTHÀ; 123 VL individuals) from a VL endemic region in northeast Brazil. Data from 20 SNPs were analyzed for association with DTH þ /À status and VL using family-based, stepwise conditional logistic regression analysis. Independent associations were observed between the DTH þ phenotype and markers in separate linkage disequilibrium blocks in LECT2 (OR 2.25; P ¼ 0.005; 95% CI ¼ 1.28–3.97) and TGFBI (OR 1.94; P ¼ 0.003; 95% CI ¼ 1.24–3.03). VL child/parent trios gave no evidence of association, but the DTHÀ phenotype was associated with SNP rs2070874 at IL4 (OR 3.14; P ¼ 0.006; 95% CI ¼ 1.38–7.14), and SNP rs30740 between LECT2 and TGFBI (OR 3.00; P ¼ 0.042; 95% CI ¼ 1.04–8.65). These results indicate several genes in the immune response gene cluster at 5q23.3–q31.1 influence outcomes of L. chagasi infection in this region of Brazil. Genes and Immunity (2007) 8, 539–551; doi:10.1038/sj.gene.6364422; published online 23 August 2007 Keywords: delayed type hypersensitivity; visceral leishmaniasis; genetic control; chromosome 5q31.1 Introduction parasites is quite variable. In most individuals, infection with L. donovani complex parasites is asymptomatic, Leishmaniasis refers to a spectrum of diseases caused by usually accompanied by a positive delayed-type hyper- protozoa belonging to the genus Leishmania. Distinct sensitivity (DTH þ ) skin test response to leishmania clinical forms of leishmaniasis are typically caused by antigen, called a Montenegro response. Progressive different species of the parasite. The leishmaniases are infection is associated with high titers of anti-leishmania caused by the Leishmania spp. protozoa, and parasites are antibodies and a negative DTH (DTHÀ).3–5 Antibody acquired through the bite of infected sand flies. titers are detected by enzyme-linked immunosorbent Leishmaniasis is endemic in 88 countries (Electronic assay (ELISA) using soluble crude leishmania antigen Database Information 1). The clinical form of leishma- lysates or the recombinant antigen k39, which is an niasis that causes the most fatalities is visceral leishma- indicator of acute VL in some populations including niasis (VL), a disease usually caused by members of the Brazil.6–8 Symptomatic VL is accompanied by hepatos- Leishmania donovani species complex, L. infantum or L. plenomegaly, fever, cachexia and progressive suppres- donovani in the Old World and L. infantum/chagasi in Latin sion of cellular immunity, eventually leading to death if America.1,2 However, the outcome of infection with these treatment does not intervene. The death rate from VL varies from 5 to 10% in endemic regions, even where Correspondence: Professor ME Wilson, Department of Internal treatment is available.2,4 Medicine, The University of Iowa, 200 Hawkins Drive, Iowa City, IA Variability in human Leishmania chagasi infection is 52242, USA. explained in part by host factors that increase suscept- E-mail: [email protected] 2,9 7These authors contributed equally to this work. ibility, for example, young age and nutritional status. Received 22 March 2007; revised 18 July 2007; accepted 18 July 2007; Heterogeneity in parasite isolates contribute,10–12 but published online 23 August 2007 there is gathering evidence that host genetic factors also DTH responses in L. chagasi infection SMB Jeronimo et al 540 play a role in determining the outcome of human and routine cell counts, and DNA was extracted from infection with parasites causing VL.13–15 A role for host 10 ml of blood leukocytes as described previously.33 Skin genetics was first suggested by studies in mice showing test results were read 48–72 h after test placement, at that polymorphism at Slc11a1 (formerly Nramp1/Lsh/Ity/ which time subjects were informed of test results and Bcg) determines innate macrophage-mediated resistance referred to the appropriate medical facility for any to infection with L. donovani16 and L. infantum/chagasi,17 medical conditions found. The diagnosis of VL was whereas the murine major histocompatibility complex confirmed by compatible clinical symptoms, response to controls acquired T-cell-mediated recovery.17,18 Candi- glucantime therapy and visualization of the parasite on a date gene studies in humans have confirmed a role for Giemsa stain of a bone marrow aspirate. The antigen SLC11A1 in human VL,19,20 with variable evidence for a for ELISA was prepared from a lysate of whole L. chagasi role of human HLA genes in regulating clinical dis- promastigotes, and/or from recombinant k39 kindly ease.21–25 In addition, human studies show increased provided by Steven Reed, PhD, IDRI, Seattle, WA, circulating levels of the T-helper 2 cytokine interleukin-4 USA.6,34 (IL-4) in VL patients,26,27 and candidate gene analysis has also demonstrated association between clinical VL and Phenotype definitions polymorphisms at IL4.28 In a previous report32 of 1106 exposed individuals, we Thus far, the emphasis of human genetic studies of VL described four main phenotypes associated with L. has been on finding associations between genetic chagasi infection in our study area; VL are individuals variants and clinical disease. Epidemiological studies with current or prior symptomatic VL (12%); DTH þ , have shown that a positive DTH response (DTH þ )isa individuals with positive delayed-type hypersensitivity marker for developing acquired resistance to disease.29 In response with no history of VL (35%); Ab þ , individuals Brazil, DTH þ shows marked clustering in families,30 with DTHÀ response and seropositive (2%); and DTHÀ and appears to be under genetic control.31 To investigate are individuals with DTHÀ who are seronegative (51%). genetic factors that might be associated with the DTH þ Upon reviewing the data of 1698 individuals enrolled for phenotype, we have been working in a site in northeast genetic studies between 1996 and 2004, and for whom Brazil where the prevalence of VL in peri-urban areas complete data (clinical, Montenegro and anti-leishmania has been high for the past two decades.32 Using this antibodies) are available, we found a total of 524 subjects population we have been able to discern not only (30.85%) who were DTH þ with no history of VL. Of symptomatic individuals, but also asymptomatic DTH þ these, 51 (9.7%) remained weakly positive for anti- infected persons and individuals who remain DTH leishmania antibodies at last survey. None have devel- negative (DTHÀ) despite prolonged residence in a oped VL. Of the DTH þ subjects followed over 5–10 dwelling where there is demonstrated risk of L. chagasi years after first DTH response, 92% remain DTH þ . infection. Here, we report on a study of candidate genes Hence, a DTH response in the absence of any history of on chromosome 5q23.3–q31.1, near the cluster of genes clinical VL provides a measure of acquired resistance to encoding type II cytokines, and their association with infection. Treated VL subjects also convert to a DTH þ DTH þ and DTHÀ phenotypes in subjects exposed to response at 6 months to 1 year after treatment, L. chagasi. concomitant with a substantial decrease in anti-leishma- nia antibody levels as previously reported.6 Of 155 VL patients studied longitudinally, only one patient with an Methods underlying immunosuppressive condition at the time of second DTH placement has become DTHÀ. Hence, it is Study subjects and study procedures important to have accurate information on history of Brazilian subjects with active VL were identified because symptomatic VL and treatment in the study area to they were admitted to one of three public hospitals in define phenotypes for genetic analysis. Natal, northeast Brazil. Transmission of L. chagasi is both For the present study, VL index cases identified focal and cyclic, and this allowed us to identify through the hospitals were used to ascertain a total of neighborhoods in Natal, Rio Grande do Norte, Brazil 102 leishmaniasis (mixed for VL and DTH þ ), or with ongoing or recent transmission of L. chagasi neighborhood (DTH þ only) pedigrees (156 nuclear infection. Clinical and epidemiological characteristics of families; Table 1). Phenotypes within families (Table 1) an overlapping population from the region have been were defined as previously;32 that is, VL, including published previously.32 Hospitalized patients with VL historic cases or cases current at the time of study; were interviewed for their level of interest in the study, DTH þ , including individuals with a positive skin test and the location of their houses was determined.
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