Genetics of Human Response to Infection  


  HEADAnavaj SAKUNTABHAI / anavaj@pasteur.fr
  MEMBERSDr Richard Paul D. Phil / Mme Isabelle Casadémont / M. Hervé Blanc / Mlle Chalisa Louicharoen / M. Sarayot Rareongjaï / Mlle Sara Touhami / M. Nimesh Gupta / Mlle 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 vivo will 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 Plasmodium falciparum (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.

Genetic susceptibility to arboviruses

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. We investigated further the role of innate immunity genes in determining the outcome of Dengue and other arboviral infection. Chikungunya virus (CHIKV) infection is an important arthropod-borne disease in expansion throughout Africa and South Asia. CHIKV is a RNA virus (Alphavirus genus) which is sensitive to the interferon (IFN) antiviral response. One of the major IFN antiviral pathways involves the 2’,5’-Oligoadenylate Synthetases (OAS)/RNase L system. We found that OAS3 mediates resistance to CHIKV by preventing viral RNA accumulation through a RNase L-independent pathway. Our data provide the first evidence that the large form of human OAS is able to confer resistance to CHIKV infection and the genetic polymorphism in OAS3 might account in the susceptibility to alphaviral disease.

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. From May 2007 until October 2008, Institut Pasteur has carried out the medical research program whose objective is to complement the health surveys performed by the NTPC’s Health Program Management Unit on the resettled population by a more in-depth study of pathogens and hereditary blood disorders that cannot be easily detected and/or analysed within Lao PDR.

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



  Publications

Sakuntabhai A, Ndiaye R, Casadémont I, Peerapittayamonkol C, Rogier C, Tortevoye P, Tall A, Paul R, Turbpaiboon C, Phimpraphi W, Trape JF, Spiegel A, Heath S, Mercereau-Puijalon O, Dieye A, Julier C. (2008) Genetic determination and linkage mapping of Plasmodium falciparum malaria related traits in Senegal. PLoS ONE 3: e2000. PMID: 18431485

Phimpraphi W, Paul RE, Yimsamran S, Puangsa-art S, Thanyavanich N, Maneeboonyang W, Prommongkol S, Sornklom S, Chaimungkun W, Chavez IF, Blanc H, Looareesuwan S, Sakuntabhai A, Singhasivanon P. (2008) Longitudinal study of Plasmodium falciparum and Plasmodium vivax in a Karen population in Thailand. Malaria J 7: 99. PMID: 18518964

Phimpraphi W, Paul R, Witoonpanich B, Turbpaiboon C, Peerapittayamongkol C, Louicharoen C, Casademont I, Tungpradabkul S, Krudsood S, Kaewkunwal J, Sura T, Looareesuwan S, Singhasivanon P, Sakuntabhai A. (2008) Heritability of P. falciparum and P. vivax malaria in a Karen population in Thailand. PLoS ONE 3(12): e3887. Epub 2008 Dec 8. PMID: 19060954

Malaria Genomic Epidemiology Network. (2008) A global network for investigating the genomic epidemiology of malaria Nature Dec 11;456(7223):732-7. PMID: 19079050

Coffey LL, Mertens E, Brehin AC, Fernandez-Garcia MD, Amara A, Després P, Sakuntabhai A. (2008) Human genetic determinants of dengue virus susceptibility Microbes Infect 2008 Dec 24. Epub ahead of print] PMID: 19121645





Activity Reports 2009 - Institut Pasteur
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