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Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Cote d'Ivoire.

ABSTRACT: Human African Trypanosomiasis (HAT) or sleeping sickness is a Neglected Tropical Disease. Long regarded as an invariably fatal disease, there is increasing evidence that infection by T. b. gambiense can result in a wide range of clinical outcomes, including latent infections, which are long lasting infections with no parasites detectable by microscopy. The determinants of this clinical diversity are not well understood but could be due in part to parasite or host genetic diversity in multiple genes, or their interactions. A candidate gene association study was conducted in Côte d'Ivoire using a case-control design which included a total of 233 subjects (100 active HAT cases, 100 controls and 33 latent infections). All three possible pairwise comparisons between the three phenotypes were tested using 96 SNPs in16 candidate genes (IL1, IL4, IL4R, IL6, IL8, IL10, IL12, IL12R, TNFA, INFG, MIF, APOL1, HPR, CFH, HLA-A and HLA-G). Data from 77 SNPs passed quality control. There were suggestive associations at three loci in IL6 and TNFA in the comparison between active cases and controls, one SNP in each of APOL1, MIF and IL6 in the comparison between latent infections and active cases and seven SNP in IL4, HLA-G and TNFA between latent infections and controls. No associations remained significant after Bonferroni correction, but the Benjamini Hochberg false discovery rate test indicated that there were strong probabilities that at least some of the associations were genuine. The excess of associations with latent infections despite the small number of samples available suggests that these subjects form a distinct genetic cluster different from active HAT cases and controls, although no clustering by phenotype was observed by principle component analysis. This underlines the complexity of the interactions existing between host genetic polymorphisms and parasite diversity.

SUBMITTER: Ahouty B

PROVIDER: S-EPMC5695625 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Côte d'Ivoire.

Ahouty Bernardin B Koffi Mathurin M Ilboudo Hamidou H Simo Gustave G Matovu Enock E Mulindwa Julius J Hertz-Fowler Christiane C Bucheton Bruno B Sidibé Issa I Jamonneau Vincent V MacLeod Annette A Noyes Harry H N'Guetta Simon-Pierre SP

PLoS neglected tropical diseases 20171023 10

Human African Trypanosomiasis (HAT) or sleeping sickness is a Neglected Tropical Disease. Long regarded as an invariably fatal disease, there is increasing evidence that infection by T. b. gambiense can result in a wide range of clinical outcomes, including latent infections, which are long lasting infections with no parasites detectable by microscopy. The determinants of this clinical diversity are not well understood but could be due in part to parasite or host genetic diversity in multiple ge ...[more]

PMID: 29059176

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Project description:BackgroundLittle is known about the diagnostic performance of rapid diagnostic tests (RDTs) for passive screening of human African trypanosomiasis (HAT) in Côte d'Ivoire. We determined HAT prevalence among clinical suspects, identified clinical symptoms and signs associated with HAT RDT positivity, and assessed the diagnostic tests' specificity, positive predictive value and agreement.MethodsClinical suspects were screened with SD Bioline HAT, HAT Sero-K-Set and rHAT Sero-Strip. Seropositives were parasitologically examined, and their dried blood spots tested in trypanolysis, ELISA/Tbg, m18S-qPCR and LAMP. The HAT prevalence in the study population was calculated based on RDT positivity followed by parasitological confirmation. The association between clinical symptoms and signs and RDT positivity was determined using multivariable logistic regression. The tests' Positive Predictive Value (PPV), specificity and agreement were determined.ResultsOver 29 months, 3433 clinical suspects were tested. The RDT positivity rate was 2.83%, HAT prevalence 0.06%. Individuals with sleep disturbances (p<0.001), motor disorders (p = 0.002), convulsions (p = 0.02), severe weight loss (p = 0.02) or psychiatric problems (p = 0.04) had an increased odds (odds ratios 1.7-4.6) of being HAT RDT seropositive. Specificities ranged between 97.8%-99.6% for individual RDTs, and 93.3-98.9% for subsequent tests on dried blood spots. The PPV of the individual RDTs was below 14.3% (CI 2-43), increased to 33.3% (CI 4-78) for serial RDT combinations, and reached 67% for LAMP and ELISA/Tbg on RDT positives. Agreement between diagnostic tests was poor to moderate (Kappa ≤ 0.60), except for LAMP and ELISA/Tbg (Kappa = 0.66).ConclusionIdentification of five key clinical symptoms and signs may simplify referral for HAT RDT screening. The results confirm the appropriateness of the diagnostic algorithm presently applied, with screening by SD Bioline HAT or HAT Sero-K-Set, supplemented with trypanolysis. ELISA/Tbg could replace trypanolysis and is simpler to perform.Trial registrationClinicalTrials.gov NCT03356665.

Project description:Background: Human African trypanosomiasis (HAT), a lethal disease induced by Trypanosoma brucei gambiense, has a range of clinical outcomes in its human host in West Africa: an acute form progressing rapidly to second stage, spontaneous self-cure and individuals able to regulate parasitaemia at very low levels, have all been reported from endemic foci. In order to test if this clinical diversity is influenced by host genetic determinants, the association between candidate gene polymorphisms and HAT outcome was investigated in populations from HAT active foci in Guinea.Methodology and results: Samples were collected from 425 individuals; comprising of 232 HAT cases, 79 subjects with long lasting positive and specific serology but negative parasitology and 114 endemic controls. Genotypes of 28 SNPs in eight genes passed quality control and were used for an association analysis. IL6 rs1818879 allele A (p = 0.0001, OR = 0.39, CI95 = [0.24-0.63], BONF = 0.0034) was associated with a lower risk of progressing from latent infection to active disease. MIF rs36086171 allele G seemed to be associated with an increased risk (p = 0.0239, OR = 1.65, CI95 = [1.07-2.53], BONF = 0.6697) but did not remain significant after Bonferroni correction. Similarly MIF rs12483859 C allele seems be associated with latent infections (p = 0.0077, OR = 1.86, CI95 = [1.18-2.95], BONF = 0.2157). We confirmed earlier observations that APOL1 G2 allele (DEL) (p = 0.0011, OR = 2.70, CI95 = [1.49-4.91], BONF = 0.0301) is associated with a higher risk and APOL1 G1 polymorphism (p = 0.0005, OR = 0.45, CI95 = [0.29-0.70], BONF = 0.0129) with a lower risk of developing HAT. No associations were found with other candidate genes.Conclusion: Our data show that host genes are involved in modulating Trypanosoma brucei gambiense infection outcome in infected individuals from Guinea with IL6 rs1818879 being associated with a lower risk of progressing to active HAT. These results enhance our understanding of host-parasite interactions and, ultimately, may lead to the development of new control tools.

Project description:BackgroundEnteropathogenic Yersinia circulate in the pig reservoir and are the third bacterial cause of human gastrointestinal infections in Europe. In West Africa, reports of human yersiniosis are rare. This study was conducted to determine whether pathogenic Yersinia are circulating in pig farms and are responsible for human infections in the Abidjan District.Methodology/principal findingsFrom June 2012 to December 2013, pig feces were collected monthly in 41 swine farms of the Abidjan district. Of the 781 samples collected, 19 Yersinia strains were isolated in 3 farms: 7 non-pathogenic Yersinia intermedia and 12 pathogenic Yersinia enterocolitica bioserotype 4/O:3. Farm animals other than pigs and wild animals were not found infected. Furthermore, 2 Y. enterocolitica 4/O:3 strains were isolated from 426 fecal samples of patients with digestive disorders. All 14 Y. enterocolitica strains shared the same PFGE and MLVA profile, indicating their close genetic relationship. However, while 6 of them displayed the usual phage type VIII, the other 8 had the highly infrequent phage type XI. Whole genome sequencing and SNP analysis of individual colonies revealed that phage type XI strains had unusually high rates of mutations. These strains displayed a hypermutator phenotype that was attributable to a large deletion in the mutS gene involved in DNA mismatch repair.Conclusions/significanceThis study demonstrates that pathogenic Y. enterocolitica circulate in the pig reservoir in Côte d'Ivoire and cause human infections with a prevalence comparable to that of many developed countries. The paucity of reports of yersiniosis in West Africa is most likely attributable to a lack of active detection rather than to an absence of the microorganism. The identification of hypermutator strains in pigs and humans is of concern as these strains can rapidly acquire selective advantages that may increase their fitness, pathogenicity or resistance to commonly used treatments.

Dataset Information

Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Cote d'Ivoire.

Publications

Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Côte d'Ivoire.

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