Integrative Biology of Emerging Infectious Diseases (IBEID) / Principal investigators
Mouse functional Genetics Unit, URA CNRS 2578
Institut Pasteur 25-28 rue du docteur Roux, 75015 Paris
Research area of the Unit
Infectious diseases are more medically relevant than ever. The clinical outcome of infectious diseases is determined by complex interactions between the pathogen and the genome of affected individuals, under the influence of environmental and stochastic factors. A central question for infectiologists is how host genetic factors are involved in susceptibility to infection, and in the severity and clinical outcomes of infectious diseases. We address this question in the context of two emerging and re-emerging diseases, the Plague caused by the bacterium Yersinia pestis and the Rift Valley fever due to an arbovirus, using mouse models of infection. Standardized infection of mice from controlled mating between inbred strains, bred in specific-pathogen-free conditions, with a given dose of pure inoculums offers a powerful approach. This approach eliminates several sources of environmental variance hence making easier the identification of genes influencing host susceptibility.
Contribution to the programme
Clinical and epidemiological genetics studies in humans, together with experimental findings in mice, have convincingly demonstrated the influence of host genetic factors in determining differences in susceptibility to infection and to the pattern of clinical disease. Understanding the way in which host factors are involved in susceptibility to infection as well as in the severity and clinical outcomes of emerging infectious diseases requires the integration of data from human studies and the mouse model. The capacity to manipulate the mouse genome is unparalleled in any other animal species and enables explicit functional analysis of genes associated with infection outcome, a task impossible in humans. Deletion, modification and insertion of genes (including human genes) is possible through transgenic and gene replacement techniques of embryonic stem cell culture. Knock-in or transgenic mice will be developed to assess how genetic variants can modify gene function. Finally, experimental mouse populations composed of interspecific hybrids, currently developed at Institut Pasteur and elsewhere, will identify additional genes and signaling pathways whose relevance will be tested in human populations, thus feeding back into human genetic research
References over the past 5 years
1. Tissue tropism and target cells of NSs-deleted rift valley fever virus in live immunodeficient mice. Gommet C, Billecocq A, Jouvion G, Hasan M, Zaverucha do Valle T, Guillemot L, Blanchet C, van Rooijen N, Montagutelli X, Bouloy M, Panthier JJ. PLoS Negl Trop Dis. 2011 Dec;5(12):e1421.
2. Transgenic expression of full-length 2',5'-oligoadenylate synthetase 1b confers to BALB/c mice resistance against West Nile virus-induced encephalitis. Simon-Chazottes D, Frenkiel MP, Montagutelli X, Guénet JL, Desprès P, Panthier JJ. Virology. 2011 Aug 15;417(1):147-53.
3. A new mouse model reveals a critical role for host innate immunity in resistance to Rift Valley fever. do Valle TZ, Billecocq A, Guillemot L, Alberts R, Gommet C, Geffers R, Calabrese K, Schughart K, Bouloy M, Montagutelli X, Panthier JJ. J Immunol. 2010 Nov 15;185(10):6146-56.
4. Mus spretus SEG/Pas mice resist virulent Yersinia pestis, under multigenic control. Blanchet C, Jaubert J, Carniel E, Fayolle C, Milon G, Szatanik M, Panthier JJ, Montagutelli X. Genes Immun. 2011 Jan;12(1):23-30.
5. Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection. Alberts R, Srivastava B, Wu H, Viegas N, Geffers R, Klawonn F, Novoselova N, do Valle TZ, Panthier JJ, Schughart K. Microbes Infect. 2010 Apr;12(4):309-18.
6. Interspecific recombinant congenic strains between C57BL/6 and mice of the Mus spretus species: a powerful tool to dissect genetic control of complex traits. Burgio G, Szatanik M, Guénet JL, Arnau MR, Panthier JJ, Montagutelli X. Genetics. 2007 Dec;177(4):2321-33.
7. Lymphocytic choriomeningitis infection undetected by dirty-bedding sentinel monitoring and revealed after embryo transfer of an inbred strain derived from wild mice. Ike F, Bourgade F, Ohsawa K, Sato H, Morikawa S, Saijo M, Kurane I, Takimoto K, Yamada YK, Jaubert J, Berard M, Nakata H, Hiraiwa N, Mekada K, Takakura A, Itoh T, Obata Y, Yoshiki A, Montagutelli X. Comp Med. 2007 Jun;57(3):272-81.