Critical Analysis of Articles



Critical Analysis of Articles

Introduction

The three articles we have selected have the same working hypothesis. The articles have approximately the same working criteria. All these researches were conducted in order to analyze numerous genes have been identified to date that contribute to the host response to systemic Salmonella Typhimurium infection in mice. We have previously identified two loci, Ity2 and Ity3, which control survival to Salmonella infection in the wild-derived inbred MOLF/Ei mouse using a (C57BL/6J 3 MOLF/ Ei) F2cross. We validated the existence of these two loci by creating congenic mice carrying each quantitative trait locus (QTL) in isolation. Subcongenic mice generated for each locus allowed us to define the critical intervals underlying Ity2 and Ity3. Furthermore, expression profiling was carried out with the aim of identifying differentially expressed genes within the critical intervals as potential candidate genes.

Genomewide expression arrays were used to interrogate expression differences in the Ity2 congenics, leading to the identification of a new candidate gene (Havcr2, hepatitis A virus cellular receptor 2). Interval-specific oligonucleotide arrays were created for Ity3, identifying one potential candidate gene (Chi3l1, chitinase 3-like 1) to be pursued further. The combination of the use of congenics in QTL confirmation and fine mapping and in the identification of candidate genes by expression profiling has been successful and represents a step toward quantitative gene(s) identification.

Previous genetic analyses using a mouse model of infection with a highly virulent Salmonella Typhimurium serotype have demonstrated the complexity of the host immune response to infection and its polygenic nature in wild-derived MOLF/Ei mice (Sebastiani et al. 1998, 2002). Wild-derived mice are an important source of new disease-resistance alleles and provide a broader range of genetic variation to be studied compared with classical inbred laboratory strains because of their evolutionary divergence (Guenet 2003). MOLF/Ei mice were shown to be extremely susceptible to Salmonella Typhimurium infection despite the fact that they carry resistant alleles at two well-defined innate immune genes, Slc11a1 and Tlr4, known to play a major role in innate resistance to infection with Salmonella Typhimurium (O'Brien et al. 1980; Vidal et al. 1995; Qureshi et al. 1996; Sebastiani et al. 1998).

Three genomic regions named Ity (Immunity to Typhimurium locus), Ity2, and Ity3 were shown to influence survival time during Salmonella Typhimurium infection in MOLF/Ei mice, as a result of a linkage analysis carried out in a MOLF/Ei · C57BL/6J cross. A Salmonella-resistant phenotype was linked to Ity on Chromosome 1 with a peak LOD score of 18.8 at D1Mcg4, accounting for 37% of the phenotypic variance. D1Mcg4 is located within 6 kb of Slc11a1; therefore, this quantitative trait locus (QTL) was explained by the nonfunctional Slc11a1Asp169 allele inherited from C57BL/6J. The two other QTLs were observed only after controlling for Slc11a1. Another Salmonella-resistant QTL was detected on Chromosome 11 and named Ity2. It has a maximum LOD score of 7.0 at D11Mit5 and explains 10% of the phenotypic variance. The third QTL identified, Ity3, was mapped to distal Chromosome ...