Poster 6
Presenter: Jean-Jacques Panthier
Thursday, 4:00 – 6:00pm

Genetic control of susceptibility to infection with Rift Valley fever virus in mice.

Satoko Tokuda1, Tânia Zaverucha do Valle1, Laurent Guillemot1, Dominique Simon1, Leandro Batista1, Claudia Pommerenke2, Robert Geffers3, Jeremy Johnson4, Klaus Schughart3, Marie Flamand5, Michèle Bouloy6, Xavier Montagutelli1, Jean-Jacques Panthier1
1Mouse Functional Genetics Unit, CNRS URA 2578, Institut Pasteur, Paris, France 2Experimental Mouse Genetics, Helmholtz Centre fur Infection Research, Braunschweig, Germany 3Array Facility/Cell Biology, Helmholtz Centre fur Infection Research, Braunschweig, Germany 4Vertebrate Biology Group, Broad Institute, Cambridge, USA 5Structural Virology, Institut Pasteur, Paris, France 6 Molecular Genetics of Bunyaviruses, Institut Pasteur, Paris, France

Infection of Rift Valley fever (RVF) virus can cause mild to severe diseases in humans and animals. Host genetic determinants seem to play an important role in modeling RVF outcome. At present, it is impossible to dissect host genetic determinants of RVF severity in humans as no one has access to the large numbers of cases that would be needed to perform a genome-wide association study. This also held true for livestock. Studies in livestock are also problematic because domestic animals do not share the very same environment thus the analysis of the susceptibility of livestock to RVF are influenced to some degree by aspects of the environment that cannot be controlled by the investigator. The use of the mouse seems particularly advantageous in this context. We previously demonstrated that MBT/Pas mice (Mus m. musculus) are highly susceptible to RVFV and die within 4 days post-infection (dpi) whereas BALB/cByJ mice survive on average for 7 dpi, indicating the existence of host genetic determinants to infection with the RVF virus (RVFV) (do Valle et al., J Immunol., 2010). A linkage analysis with a MBT/Pas × BALB/cByJ intercross infected with the virulent RVFV ZH548 strain found three QTLs associated with survival time. The loci were named Rvfs (Rift Valley fever susceptible locus)-1, -2 and -3 on chromosome 2, 11 and 5, respectively. To test their contribution to susceptibility, Rvfs loci from MBT/Pas were introgressed into the BALB/cByJ background. C.MBT-Rvfs congenic mice were challenged with RVFV; they exhibited significantly shorter survival times in one or both of the two genders. RVFV was detected at 3 dpi in both C.MBT-Rvfs2 and BALB/cByJ mice. However higher peaks of viral RNA load were observed in whole blood from C.MBT-Rvfs2 than in BALB/cByJ mice. To narrow the candidate gene list, we performed microarray analysis in macrophages from C.MBT-Rvfs2 and BALB/cByJ mice, and searched for non-synonymous SNPs or Indels in MBT/Pas exome. Combining these different approaches will allow us to prioritize candidate genes for Rvfs2.