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| Bioinformatics Mapping of Genetic Loci Modulating Susceptibility to Severe Streptococcal Sepsis using a Reference Population of Recombinant Inbred Mice | |||||||||
| Nourtan Abdeltawab1,2, Ramy K. Aziz1,2,3, Rita Kansal1,2, Lu Lu1, Robert W. Williams1, Malak Kotb1,2 | |||||||||
| The role of host immunogenetics in modulating the outcome of group A Streptococcal (GAS) infections has become evident. Individuals infected with the same GAS strain develop different disease progression and outcome. We previously reported the role of host genetic variation in streptococcal toxic shock syndrome and its association with HLA class II alleles polymorphism. To determine the contribution of other allelic variants to disease outcome, we developed recombinant inbred (RI) BXD mouse model of GAS infection and combined it with GeneNetwork (GN) and WebQTL. We exposed 358 mice belonging to 27 BXD recombinant inbred strains and parental strains (B6 and D2) to intravenous tail injection of 2 ± 1 x107 CFUs of M1T1 GAS clinical isolate. Survival and other phenotypic traits were monitored at 8 h intervals for 6 d. Bacteremia was evident in all mice 24h post-infection in varying levels; however, mortality rates varied greatly among strains. Focusing on mortality and bacteremia as phenotypes, we mapped host susceptibility to a significant quantitative trait locus (QTL) on Chr 2. To narrow down our locus, we generated a candidate gene list based on chromosomal location, literature correlation with host susceptibility to infection and single nucleotide polymorphism (SNP) analysis. We measured the relative expression levels of three immunologically relevant genes in our gene list, namely interleukin 1 receptor antagonist (Il1rn), TNF receptor associated factors, Traf-1 and Traf-2. We found that expression levels of interleukin 1 receptor antagonist (Il1rn) in resistant strain did not change in infected vs. control mice, while susceptible strain showed a 22.3 fold increase (p<0.0001). On the other hand, Traf-1 had 4 folds decrease in infected vs. control mice of resistant strain (P<0.0001) while there was no significant difference in susceptible strain. Traf2 expression levels did not show significant differences between infected vs. control mice in both resistant and susceptible strains. The biological relevance of differences in these genes expression along with other genes will be further studied to interrogate for their contribution to sepsis severity, thus generating a network of pathways that can be translated to human susceptibility to GAS sepsis. | |||||||||
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1University of Tennessee Health Science Center, Memphis, TN 2Veterans Administration Medical Center, Memphis, TN 3Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt |
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