Recherche de facteurs génétiques contrôlant la résistance de lignées de souris consanguines à une infection expérimentale par Yersinia pestis, l’agent de la peste.

Abstract : Yersinia pestis, the agent of plague, is a deadly gram-negative bacterium classified as a re-emerging pathogen and class A biological weapon. The appearance of a multi-resistant strain highlights the need to better understand how this pathogen kills its host. To identify genetic factors of host susceptibility to plague, our laboratory is investigating the response of resistant versus susceptible mice to Y. pestis. Our strategy to decipher genetic determinants involved in resistance to plague combines Quantitative Trait Loci (QTL) mapping with gene expression analysis. We previously described the Mus spretus-derived SEG/Pas strain as the first to resist fully virulent Y. pestis, while most inbred strains, such as C57BL/6, are highly susceptible. Crosses between these two strains identified three QTLs (located on chromosome 3, 4 and 6) contributing to resistance. Two of the QTLs (on chromosome 4 and 6) were confirmed through creation of congenic mice. Up to 40% of the congenic mice heterozygous at these two QTLs, on a C57BL/6J background, survived the infection while all C57BL/6J mice died. Further dissection of these two QTLs, through the use of subcongenic strains, enabled us to refine the genetic architecture of resistance to plague in SEG/Pas mice. We concluded that a minimum of four genetic factors, within these two QTLs, are required to increased resistance to Y. pestis in mice. Despite production of numerous congenic strains, including triple congenic mice, we were not able to confirm the existence of the third QTL identified on chromosome 3. In parallel to genetic studies, we determined that SEG/Pas and C57BL/6J macrophages exhibit distinct characteristics upon in vitro exposure to Y. pestis. The underlying molecular differences were investigated by using microarrays. Our results show strong activation of cytokines in SEG/Pas macrophages in response to Y. pestis, which is not found in C57BL/6J macrophages. These results suggest that SEG/Pas mice are able to better activate innate immune response to Y. pestis than C57BL/6J mice.We further studied the expression of 44 genes in a kinetic study on macrophages in vitro of SEG/Pas, C57BL/6J and bicongenic mice (carrying QTLs on chromosome 4 and 6). This study confirmed that SEG/Pas mice are able to build a stronger inflammatory response at early time of infection. Nevertheless no significant differences were observed in the bicongenic strain compared to C57BL/6J. Further studies will be required to understand the mechanisms involved in the intermediate resistance of this strain. This combination of genetic dissection and gene expression analysis of resistant and susceptible mouse strains will enhance our ability to better understand the host response to plague.
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Lucie Chevallier. Recherche de facteurs génétiques contrôlant la résistance de lignées de souris consanguines à une infection expérimentale par Yersinia pestis, l’agent de la peste.. Médecine humaine et pathologie. AgroParisTech, 2012. Français. ⟨NNT : 2012AGPT0077⟩. ⟨pastel-00880257⟩

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