Unit: Mouse functional Genetics

Director: PANTHIER Jean-Jacques

The clinical outcome of infectious diseases in humans and domestic animals is determined by complex interactions between the pathogen and the host genomes, under the influence of environmental and stochastic factors. The discovery of mechanisms of host defence that are crucial to effective and protective responses to infections is a major medical challenge. We develop research programmes with the aim of understanding the mechanisms of susceptibility or resistance to viral and bacterial infections taking advantage of the mouse as model animal.

The laboratory focuses its scientific activity on three main topics:

Development of interspecific recombinant congenic (IRCS) or consomic (ICS) strains

[Gaëtan Burgio, Xavier Montagutelli, Marek Szatanik (collaboration with Daniel Vaiman (INSERM)]

We developed a set of 55 Interspecific Recombinant Congenic strains (IRCS) derived from Mus musculus domesticus C57BL/6 and Mus spretus SEG parents. Each IRCS contains from 1 to 4% of DNA from the SEG parent on the background of DNA from the C57BL/6 parent and altogether 40% of the Mus spretus genome have been transferred in independent IRCS. These 55 IRCS have proved extremely useful to analyse quantitative traits. Several quantitative traits are currently studied using these tools.

The host genetic determinism of susceptibility to Yersinia pestis infection

[Charlne Blanchet, Jean Jaubert, Xavier Montagutelli, Jean-Jacques Panthier, Marek Szatanik (collaboration with Elisabeth Carniel (IP), Jean-Marc Cavaillon (IP), Michel Huerre (IP), Genevive Milon (IP)]

The plague has left an indelible mark in the human mind, although it is mainly a disease of rodents, which is transmitted by fleabites. We have found that the clinical outcome of infection with Y. pestis, the etiologic agent of the plague, differs widely with the genotype of the inoculated mice, demonstrating the existence of genetic determinants for mouse susceptibility to plague. We are using genetic approaches to identify critical region(s) and candidate genes responsible for the resistance and susceptibility to Yersinia pestis infection.

The host genetic determinism of susceptibility to arbovirus infection

[Xavier Montagutelli, Jean-Jacques Panthier, Dominique Simon (collaboration with MichŽle Bouloy (IP), Yann Herault (OrlŽans), Philippe Desprs (IP),]

West Nile (WN) virus was first isolated in 1937 from the blood of a patient in Uganda with mild febrile illness. Birds are the natural reservoir (amplifying) hosts, and WN virus is maintained in nature in a mosquito-bird-mosquito transmission cycle primarily involving Culex sp mosquitoes. Recent epidemics have been reported and the strain associated with the latter outbreaks is characterized by a high avian death rate and an increased neurovirulence. The variable outcome to WN virus infection in mice and humans suggests that host genetic factors may explain the differing degrees of severity observed following exposure. In support of this hypothesis, we have identified the Oas1b gene encoding 1b isoform of the 2'-5' oligoadenylate synthase as a candidate gene underlying the susceptibility of classical inbred strains of mice to WN virus. To establish that Oas1b gene is able to confer to susceptible mice the resistance to WN virus and to analyze the function of individual Oas genes, we are preparing mice with various alleles at the Oas1b locus. It is well established that resistance to WN infection is mediated by other pathways. Hence we are currently searching additional resistance genes for WN virus infection. Susceptibility of mice to Rift Valley fever virus is also being considered.

Keywords: experimental infection, innate response, arbovirus, Yersinia pestis, resistance/susceptibility

Activity Reports 2005 - Institut Pasteur

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