|dc.description.abstract||The Rift Valley Fever virus (RVFV) presents an epidemic and epizootic threat in sub-Saharan Africa, Egypt, and the Arabian Peninsula, and has recently gained attention as a potential weapon of bioterrorism due to its ability to infect both livestock and humans. Inbred rat strains show similar characteristic responses to the disease as humans and livestock, making them a suitable model species. Previous studies had shown differences among various inbred rat strains in susceptibility to RVFV hepatic disease, including a higher susceptibility of Wistar-Furth (WF) rats compared to a more resistant Lewis (LEW) strain. Further study revealed that this resistance trait follows the pattern of a dominant gene inherited in Mendelian fashion. A congenic WF.LEW strain resistant to infection with RVFV was derived from the susceptible WF and resistant LEW strains, and a subsequent genome scan revealed two prospective regions for the location of the gene, one on chromosome 3 and the other on chromosome 9. Subsequently, this study employed the methods of backcrossing, genotyping, viral challenges, gene expression studies, and sequencing to define a practicable region of interest and to further identify a viable candidate gene and prospective mechanism by which resistance is conferred.
A program of backcrossing WF.LEW rats to WF rats, genotyping offspring using SNPs and microsatellites, and subsequently challenging N1 litters with RVFV was used to determine that the ~2Mb region on the distal end of chromosome 3 contains the gene conferring resistance. The use of genetic markers to detect recombination in further backcross generations resulted in the identification of two recombinants in this newly established region of interest. Through RVFV challenges, the recombinants narrowed the prospective region of chromosome 3 to ~500Kb containing 20 genes. Comparative qPCR analysis of all 20 genes combined with comparative sequencing studies of the entire region between susceptible WF/NHsd rats and resistant WF.LEW rats facilitated the identification of candidate gene Rtel1 and a proposed mechanism by which resistance is conferred, which will potentially become the basis for developing new preventive measures against the virus.||en