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Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India.

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.

SUBMITTER: Mehrotra S

PROVIDER: S-EPMC3260103 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India.

Mehrotra Sanjana S Fakiola Michaela M Oommen Joyce J Jamieson Sarra E SE Mishra Anshuman A Sudarshan Medhavi M Tiwary Puja P Rani Deepa Selvi DS Thangaraj Kumarasamy K Rai Madhukar M Sundar Shyam S Blackwell Jenefer M JM

BMC medical genetics 20111215

<h4>Background</h4>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.<h4>Methods</h4>Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3 ...[more]

PMID: 22171941

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Project description:Chromosome 6q26-27 is linked to susceptibility to visceral leishmaniasis (VL) in Brazil and Sudan. DLL1 encoding the Delta-like 1 ligand for Notch 3 was implicated as the etiological gene. DLL1 belongs to the family of Notch ligands known to selectively drive antigen-specific CD4 T helper 1 cell responses, which are important in protective immune response in leishmaniasis. Here we provide further genetic and functional evidence that supports a role for DLL1 in a well-powered population-based study centred in the largest global focus of VL in India. Twenty-one single nucleotide polymorphisms (SNPs) at PHF10/C6orf70/DLL1/FAM120B/PSMB1/TBP were genotyped in 941 cases and 992 controls. Logistic regression analysis under an additive model showed association between VL and variants at DLL1 and FAM120B, with top associations (rs9460106, OR=1.17, 95%CI 1.01-1.35, P=0.033; rs2103816, OR=1.16, 95%CI 1.01-1.34, P=0.039) robust to analysis using caste as a covariate to take account of population substructure. Haplotype analysis taking population substructure into account identified a common 2-SNP risk haplotype (frequency 0.43; P=0.028) at FAM120B, while the most significant protective haplotype (frequency 0.18; P=0.007) was a 5-SNP haplotype across the interval 5' of both DLL1 (negative strand) and FAM120B (positive strand) and extending to intron 4 of DLL1. Quantitative RT/PCR was used to compare expression of 6q27 genes in paired pre- and post-treatment splenic aspirates from VL patients (N=19). DLL1 was the only gene to show differential expression that was higher (P<0.0001) in pre- compared to post-treatment samples, suggesting that regulation of gene expression was important in disease pathogenesis. This well-powered genetic and functional study in an Indian population provides evidence supporting DLL1 as the etiological gene contributing to susceptibility to VL at Chromosome 6q27, confirming the potential for polymorphism at DLL1 to act as a genetic risk factor across the epidemiological divides of geography and parasite species.

Project description:BACKGROUND:In Ethiopia, visceral leishmaniasis (VL) is caused by Leishmania donovani. The estimated country-wide incidence of VL in Ethiopia is 3700-7400 cases/year. The balance between anthroponotic and zoonotic transmission is still unknown even though most authors believe that visceral leishmaniasis in East Africa is anthroponotic. Asymptomatic leishmania infections occur more frequently than clinically apparent visceral leishmaniasis cases. The aim of this study was to determine the prevalence of asymptomatic VL infection and assess the degree of exposure among residents in Raya Azebo Woreda villages where cases of VL were recently reported. METHODS:A community based cross-sectional survey was conducted in 2013 between 1st of May and 25th of July. A total of 1099 individuals living in 314 households were included in the study. Socio-demographic and clinical data were collected from each of the participants and venous blood was also collected for the detection of antibodies to visceral leishmaniasis using Direct Agglutination Test. Leishmanin skin test was performed to detect the exposure to the parasite. Data was entered into excel and exported to SPSS version 17 for statistical analysis. Chi-square and the corresponding p-values were used to determine the statistical significance of the proportions/ratios obtained from the cross tabulated data. A p-value < 0.05 was considered statistically significant. RESULT:A total of 1099 study subjects comprising 401 males and 698 females were included in the study. The overall positive leishmanian skin test and sero-prevalence rates respectively were 9.08% and 0.87%. The difference in LST positivity by age group and sero-prevalence by sex were statistically significant (P <0.01 and P<0.05 respectively). Out of the 9 sero-positive individuals, 7 had no history of travel to visceral leishmaniasis endemic areas out of Raya Azebo. CONCLUSION:In general our results suggest occurrence of VL in the study area is, very low. Our survey also indicates that due to the low incidence of the disease, and lack of awareness, some patients remain under diagnosed.

Project description:As India moves toward the elimination of visceral leishmaniasis (VL) as a public health problem, comprehensive timely case detection has become increasingly important, in order to reduce the period of infectivity and control outbreaks. During the 2000s, localized research studies suggested that a large percentage of VL cases were never reported in government data. However, assessments conducted from 2013 to 2015 indicated that 85% or more of confirmed cases were eventually captured and reported in surveillance data, albeit with significant delays before diagnosis. Based on methods developed during these assessments, the CARE India team evolved new strategies for active case detection (ACD), applicable at large scale while being sufficiently effective in reducing time to diagnosis. Active case searches are triggered by the report of a confirmed VL case, and comprise two major search mechanisms: 1) case identification based on the index case's knowledge of other known VL cases and searches in nearby houses (snowballing); and 2) sustained contact over time with a range of private providers, both formal and informal. Simultaneously, house-to-house searches were conducted in 142 villages of 47 blocks during this period. We analyzed data from 5030 VL patients reported in Bihar from January 2018 through July 2019. Of these 3033 were detected passively and 1997 via ACD (15 (0.8%) via house-to-house and 1982 (99.2%) by light touch ACD methods). We constructed multinomial logistic regression models comparing time intervals to diagnosis (30-59, 60-89 and ≥90 days with <30 days as the referent). ACD and younger age were associated with shorter time to diagnosis, while male sex and HIV infection were associated with longer illness durations. The advantage of ACD over PCD was more marked for longer illness durations: the adjusted odds ratios for having illness durations of 30-59, 60-89 and >=90 days compared to the referent of <30 days for ACD vs PCD were 0.88, 0.56 and 0.42 respectively. These ACD strategies not only reduce time to diagnosis, and thus risk of transmission, but also ensure that there is a double check on the proportion of cases actually getting captured. Such a process can supplement passive case detection efforts that must go on, possibly perpetually, even after elimination as a public health problem is achieved.

Project description:In this study we set out to determine whole blood transcriptional profiles that might distinguish asymptomatic infection with Leishmania donovani from active disease, as well as to monitor the changes in transcriptional profiles that accompanied drug treatment. Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon- as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls, and to a lesser extent with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days.

Dataset Information

Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India.

Publications

Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India.

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