Limits...
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

Pathway and process analyses of genes differentially regulated in the spleen of Ity, Ity3, Ity3.RecG, and Ity3.RecN mice during infection. Gene ontology classifications generated by clustering the genes that are differentially regulated in each strain upon infection. (A) Gene ontology (GO) molecular pathways and (B) Gene ontology (GO) processes (C) pathways (D) Process networks that are enriched in the four mouse strains. The sub-congenic strain Ity3.RecG shows a lower −log(p-value) for chemokine and cytokine receptor activity within the GO molecular pathways as well as lower −log(p-values) for response to bacteria in the GO processes. This is consistent with previous data suggesting that the Ity3.RecG mice have a diminished inflammatory response following infection compared to parental strains (16).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4129629&req=5

Figure 2: Pathway and process analyses of genes differentially regulated in the spleen of Ity, Ity3, Ity3.RecG, and Ity3.RecN mice during infection. Gene ontology classifications generated by clustering the genes that are differentially regulated in each strain upon infection. (A) Gene ontology (GO) molecular pathways and (B) Gene ontology (GO) processes (C) pathways (D) Process networks that are enriched in the four mouse strains. The sub-congenic strain Ity3.RecG shows a lower −log(p-value) for chemokine and cytokine receptor activity within the GO molecular pathways as well as lower −log(p-values) for response to bacteria in the GO processes. This is consistent with previous data suggesting that the Ity3.RecG mice have a diminished inflammatory response following infection compared to parental strains (16).

Mentions: We then used GeneGO (Thomson Reuters, NY, USA) to classify the genes differentially regulated in each strain (Tables S1A–D in Supplementary Material) into gene ontology (GO) molecular pathways, GO processes, pathways, and process networks, in order to identify the pathways differentially regulated in each strain during infection (Figure 2). The strain Ity3.RecG appeared to have fewer genes involved in various pathways and processes related to chemokine and cytokine activity and immune response as demonstrated by the lower –log2 (p-values). These results are consistent with previous observations of reduced inflammatory responses following in vivo Salmonella infection in Ity3.RecG mice (16).


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)

Pathway and process analyses of genes differentially regulated in the spleen of Ity, Ity3, Ity3.RecG, and Ity3.RecN mice during infection. Gene ontology classifications generated by clustering the genes that are differentially regulated in each strain upon infection. (A) Gene ontology (GO) molecular pathways and (B) Gene ontology (GO) processes (C) pathways (D) Process networks that are enriched in the four mouse strains. The sub-congenic strain Ity3.RecG shows a lower −log(p-value) for chemokine and cytokine receptor activity within the GO molecular pathways as well as lower −log(p-values) for response to bacteria in the GO processes. This is consistent with previous data suggesting that the Ity3.RecG mice have a diminished inflammatory response following infection compared to parental strains (16).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129629&req=5

Figure 2: Pathway and process analyses of genes differentially regulated in the spleen of Ity, Ity3, Ity3.RecG, and Ity3.RecN mice during infection. Gene ontology classifications generated by clustering the genes that are differentially regulated in each strain upon infection. (A) Gene ontology (GO) molecular pathways and (B) Gene ontology (GO) processes (C) pathways (D) Process networks that are enriched in the four mouse strains. The sub-congenic strain Ity3.RecG shows a lower −log(p-value) for chemokine and cytokine receptor activity within the GO molecular pathways as well as lower −log(p-values) for response to bacteria in the GO processes. This is consistent with previous data suggesting that the Ity3.RecG mice have a diminished inflammatory response following infection compared to parental strains (16).
Mentions: We then used GeneGO (Thomson Reuters, NY, USA) to classify the genes differentially regulated in each strain (Tables S1A–D in Supplementary Material) into gene ontology (GO) molecular pathways, GO processes, pathways, and process networks, in order to identify the pathways differentially regulated in each strain during infection (Figure 2). The strain Ity3.RecG appeared to have fewer genes involved in various pathways and processes related to chemokine and cytokine activity and immune response as demonstrated by the lower –log2 (p-values). These results are consistent with previous observations of reduced inflammatory responses following in vivo Salmonella infection in Ity3.RecG mice (16).

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