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Genetic dissection of the ity3 locus identifies a role for ncf2 co-expression modules and suggests selp as a candidate gene underlying the ity3.2 locus.

Khan RT, Chevenon M, Yuki KE, Malo D - Front Immunol (2014)

Bottom Line: Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries.In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus.Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University , Montreal, QC , Canada ; Complex Traits Group, McGill University , Montreal, QC , Canada.

ABSTRACT
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.

No MeSH data available.


Related in: MedlinePlus

Genes that are differentially expressed in all susceptible and intermediate strains are under the influence of Ity3.1 sub-locus. Box plots of the expression pattern of two genes (A)Tor3a (torsin family 3, member A) and (B)Fam20b (family with sequence similarity 20, member B) are shown as examples to illustrate the expression pattern seen in the gene list provided in Table S2I in Supplementary Material. This list of genes show a similar expression in Ity3, Ity3.RecG, and Ity3.RecN and highlights the complex nature of the Ity3 locus as there are multiple genes in which expression is influenced by the combination of the two sub-loci. The genes that show a similar expression pattern in Ity3, Ity3.RecG, and Ity3.RecN were studied using GeneMania and the results are shown (C,D), with the query genes being highlighted in black. Genes, which are known to be co-expressed, co-localized, have shared domains or predicted interactions with the list of genes in Table S2I in Supplementary Material are shown. The functional categories, which are enriched within this gene list, are inflammatory response, angiogenesis, and integrin mediated signaling pathways shown in yellow, blue, and red, respectively. Genes that were not differentially expressed but important in these pathways are shown in gray. (D) Co-expression of query genes, as well as other genes within these pathways, with Ncf2 is shown.
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Figure 4: Genes that are differentially expressed in all susceptible and intermediate strains are under the influence of Ity3.1 sub-locus. Box plots of the expression pattern of two genes (A)Tor3a (torsin family 3, member A) and (B)Fam20b (family with sequence similarity 20, member B) are shown as examples to illustrate the expression pattern seen in the gene list provided in Table S2I in Supplementary Material. This list of genes show a similar expression in Ity3, Ity3.RecG, and Ity3.RecN and highlights the complex nature of the Ity3 locus as there are multiple genes in which expression is influenced by the combination of the two sub-loci. The genes that show a similar expression pattern in Ity3, Ity3.RecG, and Ity3.RecN were studied using GeneMania and the results are shown (C,D), with the query genes being highlighted in black. Genes, which are known to be co-expressed, co-localized, have shared domains or predicted interactions with the list of genes in Table S2I in Supplementary Material are shown. The functional categories, which are enriched within this gene list, are inflammatory response, angiogenesis, and integrin mediated signaling pathways shown in yellow, blue, and red, respectively. Genes that were not differentially expressed but important in these pathways are shown in gray. (D) Co-expression of query genes, as well as other genes within these pathways, with Ncf2 is shown.

Mentions: In order to define the gene expression profile of the susceptible strains, we identified genes that had a similar pattern of expression in the susceptible strain, Ity3 as well as the two sub-congenic strains Ity3.RecN and Ity3.RecG. Figures 4A,B highlights two genes, Tor3a and Fam20b as examples of the expression pattern of the list of genes provided in Table S2H in Supplementary Material, which have a similar expression pattern in Ity3, Ity3.RecN, and Ity3.RecG. Only 7 of the 47 genes were within the Ity3 interval, and almost all of them were within the genomic region common to Ity3.RecN and Ity3.RecG. This gene list was classified within functional categories (Figure 4C) such as inflammatory response and regulation of angiogenesis. A large proportion of the genes were either co-expressed, co-localized, or have shared domains or predicted interactions with Ncf2 (Figure 4D). We have previously shown that the MOLF/Ei allele at the Ity3.1 locus contributed the strongest effect on susceptibility to Salmonella infection and was responsible for high bacterial burden and low ROS and cytokine production (16). The fact that a number of genes differentially regulated in Ity3, Ity3.RecN, and Ity3.RecG strains, were co-expressed with Ncf2, supports the important contribution of the Ity3.1 locus on the pathogenesis of infection in MOLF/Ei and its interaction with the other sub-locus Ity3.2 to enhance the impact of Ncf2 on ROS production.


Genetic dissection of the ity3 locus identifies a role for ncf2 co-expression modules and suggests selp as a candidate gene underlying the ity3.2 locus.

Khan RT, Chevenon M, Yuki KE, Malo D - Front Immunol (2014)

Genes that are differentially expressed in all susceptible and intermediate strains are under the influence of Ity3.1 sub-locus. Box plots of the expression pattern of two genes (A)Tor3a (torsin family 3, member A) and (B)Fam20b (family with sequence similarity 20, member B) are shown as examples to illustrate the expression pattern seen in the gene list provided in Table S2I in Supplementary Material. This list of genes show a similar expression in Ity3, Ity3.RecG, and Ity3.RecN and highlights the complex nature of the Ity3 locus as there are multiple genes in which expression is influenced by the combination of the two sub-loci. The genes that show a similar expression pattern in Ity3, Ity3.RecG, and Ity3.RecN were studied using GeneMania and the results are shown (C,D), with the query genes being highlighted in black. Genes, which are known to be co-expressed, co-localized, have shared domains or predicted interactions with the list of genes in Table S2I in Supplementary Material are shown. The functional categories, which are enriched within this gene list, are inflammatory response, angiogenesis, and integrin mediated signaling pathways shown in yellow, blue, and red, respectively. Genes that were not differentially expressed but important in these pathways are shown in gray. (D) Co-expression of query genes, as well as other genes within these pathways, with Ncf2 is shown.
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Related In: Results  -  Collection

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Figure 4: Genes that are differentially expressed in all susceptible and intermediate strains are under the influence of Ity3.1 sub-locus. Box plots of the expression pattern of two genes (A)Tor3a (torsin family 3, member A) and (B)Fam20b (family with sequence similarity 20, member B) are shown as examples to illustrate the expression pattern seen in the gene list provided in Table S2I in Supplementary Material. This list of genes show a similar expression in Ity3, Ity3.RecG, and Ity3.RecN and highlights the complex nature of the Ity3 locus as there are multiple genes in which expression is influenced by the combination of the two sub-loci. The genes that show a similar expression pattern in Ity3, Ity3.RecG, and Ity3.RecN were studied using GeneMania and the results are shown (C,D), with the query genes being highlighted in black. Genes, which are known to be co-expressed, co-localized, have shared domains or predicted interactions with the list of genes in Table S2I in Supplementary Material are shown. The functional categories, which are enriched within this gene list, are inflammatory response, angiogenesis, and integrin mediated signaling pathways shown in yellow, blue, and red, respectively. Genes that were not differentially expressed but important in these pathways are shown in gray. (D) Co-expression of query genes, as well as other genes within these pathways, with Ncf2 is shown.
Mentions: In order to define the gene expression profile of the susceptible strains, we identified genes that had a similar pattern of expression in the susceptible strain, Ity3 as well as the two sub-congenic strains Ity3.RecN and Ity3.RecG. Figures 4A,B highlights two genes, Tor3a and Fam20b as examples of the expression pattern of the list of genes provided in Table S2H in Supplementary Material, which have a similar expression pattern in Ity3, Ity3.RecN, and Ity3.RecG. Only 7 of the 47 genes were within the Ity3 interval, and almost all of them were within the genomic region common to Ity3.RecN and Ity3.RecG. This gene list was classified within functional categories (Figure 4C) such as inflammatory response and regulation of angiogenesis. A large proportion of the genes were either co-expressed, co-localized, or have shared domains or predicted interactions with Ncf2 (Figure 4D). We have previously shown that the MOLF/Ei allele at the Ity3.1 locus contributed the strongest effect on susceptibility to Salmonella infection and was responsible for high bacterial burden and low ROS and cytokine production (16). The fact that a number of genes differentially regulated in Ity3, Ity3.RecN, and Ity3.RecG strains, were co-expressed with Ncf2, supports the important contribution of the Ity3.1 locus on the pathogenesis of infection in MOLF/Ei and its interaction with the other sub-locus Ity3.2 to enhance the impact of Ncf2 on ROS production.

Bottom Line: Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries.In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus.Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University , Montreal, QC , Canada ; Complex Traits Group, McGill University , Montreal, QC , Canada.

ABSTRACT
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.

No MeSH data available.


Related in: MedlinePlus