Genetics of Human Response to Infection  


  HEADAnavaj SAKUNTABHAÏ / anavaj@pasteur.fr
  MEMBERSAnavaj Sakuntabhaï, MD. D.Phil, Richard Paul D. Phil / Isabelle Casadémont / Hervé Blanc / Chalisa Louicharoen, Sarayot Rareongjaï / Cécile Roux


  Annual Report

The study of the role of host genetics in infectious diseases aims at identifying genes influencing host resistance and susceptibility, and increasing our understanding of their function and role in the microbial pathogenesis. Although there is a plethora of infectious agents, both endemic and emergent, targeting man, the immunological bases of the symptomology of infection are shared amongst groups of pathogens. Consistent with a syndromic approach to infection outcome, we aim to identify key suites of genes underlying immuno-pathogenesis following infection. Thus, the process of immunity to infection in vivowill be genetically dissected and the function of individual molecules in achieving protective immunity to infection defined.

Human Genetic Response to Plasmodium species Infection

Most of the genes related to malaria have been identified through case/control association studies, comparing severe malaria to uncomplicated malaria cases. There is no clear picture of the mechanisms of naturally acquired immunity to malaria, and the relationship of mild to severe malaria is still unclear. We designed a family-based genetic study of phenotypes related to infection with Plasmodiumfalciparum (PF) and P. vivax(PV) in 2 malaria endemic regions from Africa (Dielmo & Ndiop in Senegal) and South-East Asia (SuanPhung community in Thailand). We recorded data related to malaria clinical attacks and asymptomatic infections for PF & PV (Thailand only) on a longitudinal, uninterrupted basis for over a decade.

The number of clinical PF attacks showed a highly significant genetic effect in both sites, with an estimated heritability (h2) of 27-29% in Senegal and 10% in Thailand but 19% for PV. House had an important effect for PF and non-malaria fever but not for PV. There was high heritability of parasite density during clinical attack for both PF (21-28%) and PV (41-46%). Asymptomatic PF trophozoite density also showed significant heritability, with h2= 21-33% in Senegal. Interestingly, there was evidence for a significant genetic effect on the prevalence of PF gametocytes, the stages responsible for transmission.

Genome scan linkage study of the phenotypes in Senegal confirmed the previous finding of linkage of chromosome 5q31 to asymptomatic PF trophozoite density. We identified linkage to three additional regions: chromosome 5p15-p13 and 13q13-q22 with the number of PF clinical malaria attacks, and chromosome 12q21-q23 with the maximum parasite density during asymptomatic carriage. While these regions are extensive and contain many putative candidate genes, it is remarkable that 5q31 and these three regions overlap with regions that have been previously identified to be involved in asthma/atopy, hence suggesting that common mechanisms may be involved in both pathogenic mechanisms. These results will provide highly valuable information in the context of integrated studies combining linkage and high density association studies for various malaria phenotypes and conditions. Ultimately, these results will help understand the molecular mechanisms underlying pathogenesis, control of parasite density, and possibly immunotolerance to malaria antigens and the potential relationship with the asthma/atopic disease spectrum.

Role of innate immunity genes in severity of Dengue viral infection

In 2005, we reported an association of a polymorphism on promoter region of DC-SIGN (CD209) associated with dominant protection against dengue fever but not dengue hemorrhagic fever. In 2006, we have recruited more patients from the same hospitals and 2 new hospitals in Thailand. We collected family cohorts in which one of the members developed symptomatic dengue viral infection in 4 countries: Vietnam, Cambodia, French Guiana and Brazil in collaboration with the DENFRAME consortium. We investigated further the role of innate immunity genes in determining the outcome of Dengue viral infection.

Nam Theun 2 public health assessment project

In collaboration with the Nam Theun Power Company, Institut Pasteur has put into place a long-term public health impact study of the Nam Theun 2 hydroelectric project in Laos. Presently, human development is impacting upon the environment at an unprecedented rate all over the globe and an increased burden of disease has been linked to anthropogenic climate change. Radical changes in the local environment, such as those following construction of tropical reservoirs, impose an instantaneous change on the ecosystem, notably animal vector populations of known importance (mosquitoes, molluscs) and hence on pathogen transmission potential, whether of existing or emerging pathogens. As well as assessing the direct impact of the hydroelectric project by documentation of pathogen/vector populations, thereby providing recommendations for health strategies, we aim to establish the relative overall implication of human genetic vs. environmental factors in the burden of disease.

Keywords: Malaria, Dengue, Human Genetics, Innate immunity, Heritability



  Publications

  1. Sakuntabhai A, Turbpaiboon C, Casademont I, Chuansumrit A, Lowhnoo T, Kajaste-Rudnitski A, Kalayanarooj SM, Tangnararatchakit K, Tangthawornchaikul N, Vasanawathana S, Chaiyaratana W, Yenchitsomanus PT, Suriyaphol P, Avirutnan P, Chokephaibulkit K, Matsuda F, Yoksan S, Jacob Y, Lathrop GM, Malasit P, Despres P, Julier C. 2005 A variant in the CD209 promoter is associated with severity of dengue disease. Nat Genet. 37(5):507-13. PMID: 15838506

  2. Ndiaye R, Sakuntabhai A, Casademont I, Rogier C, Tall A, Trape JF, Spiegel A, Dieye A, Julier C. 2005 Genetic study of ICAM1 in clinical malaria in Senegal. Tissue Antigens. 65(5):474-80. PMID: 15853902

  3. Patin E, Barreiro LB, Sabeti PC, Austerlitz F, Luca F, Sajantila A, Behar DM, Semino O, Sakuntabhai A, Guiso N, Gicquel B, McElreavey K, Harding RM, Heyer E, Quintana-Murci L. Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. 2006 Am J Hum Genet. 78(3):423-36. PMID: 16416399

  4. Paul RE, Bonnet S, Boudin C, Tchuinkam T, Robert V. 2007 Age-structured gametocyte allocation links immunity to epidemiology in malaria parasites. Malar J. 6:123. PMID: 17850648

  5. Tocharoentanaphol C, Promso S, Zelenika D, Lowhnoo T, Tongsima S, Sura T, Chantratita W, Matsuda F, Mooney S, Sakuntabhai A. 2008 Evaluation of resequencing on number of tag SNPs of 13 atherosclerosis-related genes in Thai population. J Hum Genet.;53(1):74-86. PMID: 18043865





Activity Reports 2007 - Institut Pasteur
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