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1 te Pas et al – Additional file 5 – Table with summary and detailed results of pathways analysis 2 Table networks results Summary of the pathway analysis. chicken line idfferences-related expression differences and line-specific or general response to Salmonella infection of pathways and networks of pathways. Network names are highlighted in yellow. Line A is faster growing, higher susceptible to Salmonella than line B. Network / Pathway Line Salmonella infection effects Conclusions Remarks / hypotheses differences Line A vs Line A4,5,6 Line B3,4 Line A vs Line 1, 2,3 Line B B1, 2 Actin cytoskeleton Line infection X equal Line A is induced by Genetic makeup of line B differences effect infection to equal sufficient for efficient line B reaction to Salmonella * Adherens junction B>A ↑ ↑ A=B ↑A>B actin polymerization, specifically line A * Tight junction B>A ↑ X A=B line A effect input for Regulation of actin cytoskeleton * Focal adhesion B>A ↑ X A=B line A effect input for Regulation of actin cytoskeleton, actin polymerization, and others * Axon guidance B>A ↑ ↑ A=B ↑A>B three subpathways leading to input for Regulation of actin cytoskeleton * Leukocyte transendothelial B>A ↑ X A=B line A effect input for Regulation of actin migration cytoskeleton * Cell adhesion molecules B>A ↑ (↓) A=B mostly line A effect Interaction with Adherens junction, Tight junction, and Leukocyte transendothelial migration * WNT signaling B>A ↑ X B>A line A effect not input from Adherens junction sufficient to equal line and Focal adhesion pathways B * B-cell receptor signaling A>B ↑ ↓ A=B line B less genes react, input for Regulation of actin but more induced cytoskeleton * T-cell receptor signaling A=B ↑ (↑) A=B mostly line A effect input for Regulation of actin cytoskeleton 3 * Regulation of actin cytoskeleton Apoptosis mechanism B>A no line differences ↑ up regulation (↑) up regulation A=B differences * Apoptosis * JAK-STAT signaling A?B A?B ↑ ↑ ↑ (↑) A>B A>B * Natural Killer cell mediated cytotoxicity * Transforming Growth Factor (TGF) beta A?B ↑ (↑) A>B B>A ↑ X B>A A?B ↑ (↑) B>A line differences for fatty acid metabolism A=B down regulation down regulation B>A, energy availability ↓ X B>A * Fatty acid metabolism * Glycerolipid metabolism B>A A=B ↓ X ↓ X B>A A=B * Pentose phosphate metabolism A=B ↑↓ X A=B * Purine metabolism B>A ↑ ↑ B>A * Insulin signaling Other metabolism pathways * Amino acid metabolism B>A ↑↓ ↑↓ A=B no line ? ? effect * Mitogen-Activated Protein Kinase (MAPK) signaling Energy metabolism * Glycolysis / Gluconeogenesis line B little effect apoptosis and anti apoptosis / proliferation and differentiation effects differ Stress fibre formation induced mostly line A effect cell growth, differentiation; anti apoptosis line B: induced release of cytokines proliferation, differentiation line A effect not sufficient to equal line B mostly line A effect proliferation, differentiation input from and to other energy metabolism pathways line differences may be some effect on input for Glycolysis in line A may be some effect on input for Glycolysis in line A input for Pentose phosphate metabolism input for Glycolysis 4 ** Val, Leu, Ile degradation differences B>A ↑-↓ ↑-↓ questionable A>B / B>A ** Gly, Ser, Thr metabolism ** Beta-Alanine metabolism * Proteasome * Caprolactam degradation B>A A=B A=B B>A X X ↑-↓ ↓ ↓ X X X A=B A=B A=B B>A * Metabolism of Xenobiotics by P450 A=B ↓ ↓ A=B line differences A=B line differences? X line differences? X no overall effect A=B B>A A=B ↑ X X X A=B A=B A=B X X A=B line differences B>A functionality? functionality? functionality? X ↓ B>A B>A B>A ↓ X ↓ ↓ B>A B>A Immune response pathways * Cytokine-cytokine receptor interaction * Adipocytokine signaling * Gap junction * Complement and coagulation cascades Other body functional pathways * Androgen and Estrogen metabolism * Circadian rhythm * Bile acid biosynthesis overall effect uncertain Pathway shows internal confusing regulation porphyrine biosynthesis many links with other pathways difference between the lines increases due to infection Salmonella causes sharp down regulation no regulation observed only input is regulated line differences related? input from cytokine-cytokine receptor pathway no regulation observed line B effect not sufficient to equal line A Estrogen metabolism line B effect not sufficient to equal line A intestine functionality 1: A>B: Expression level of the genes in the pathway differ; the pathway is higher expressed in line A than in line B 2: A=B: Expression levels of some genes in the pathway may be different, but this is not sufficient to call a line-specific difference in the expression of the pathway 5 3: A?B: Regulation observed, but direction (up or down) uncertain and variable 4: ↑: up regulation after Salmonella infection; ↓: down regulation after infection 5: (↑): some up regulation observed after Salmonella infection, but less than in the other line; (↓): some down regulation observed after Salmonella infection, but less than in the other line 6: X: no regulation observed 6 Detailed description of Individual pathways to support the data in the Table Network: Mechanisms of Cytoskeletal changes Adherens junction: Chicken line differences resulted in a higher expression in line B compared to line A of the actin polymerization subpathway. Following Salmonella infection both lines show up regulation of several genes in this pathway, where especially in line A up “Regulation of the actin polymerization” subpathway was found. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. It can be concluded that this equal expression level is the result of a higher up regulation in line A than in line B. Tight junction: Chicken line differences resulted in a higher expression in line B compared to line A of the subpathway leading to input for the Regulation of actin cytoskeleton pathway. Following Salmonella infection line A shows up regulation of the genes in the subpathway leading to input for the “Regulation of actin cytoskeleton” pathway. No such effect was observed in line B. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. It can be concluded that this equal expression level is the result of the up regulation in line A. There is an input subpathway from the “Adherens junction” pathway. Some up regulation of gene expression in line A after infection is seen suggesting that the up regulation of the “Adherens junction” pathway in line A after infection also affects gene expression in the “Tight junction pathway”. Focal adhesion: Chicken line differences resulted in a higher expression in line B compared to line A for the subpathways actin polymerization, cell proliferation, cell motility, phosphatidylinositol signalling, and input for the pathway “Regulation of actin cytoskeleton”. Following Salmonella infection the actin cytoskeleton related traits are up regulated in line A. No such effect was observed in line B. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. It can be concluded that this equal expression levels is the result of the up regulation in line A although some genes are regulated after infection in line B. 7 Axon guidance: The pathway shows three subpathways leading to input for the “Regulation of actin cytoskeleton” pathway. Chicken line differences resulted in a higher expression of all three subpathways in line B compared to line A. Following Salmonella infection both lines show up regulation of the three mentioned subpathways, but this induction is more in line A (more genes induced) than in line B. These subpathways show equal expression between the lines after 24 h infection with Salmonella. It can be concluded that this equal expression levels is the result of a higher up regulation in line A than in line B. Leukocyte transendothelial migration: Activation of leukocytes leading to transendothelial migration may be associated with changed cytoskeletal appearance. The pathway consists of gene networks in both the leukocytes and the endothelial cells and these gene networks are interacting. Chicken line differences resulted in a higher expression in line B compared to line A for subpathways towards transendothelial migration and input for the Regulation of actin cytoskeleton pathway. Following Salmonella infection line A shows up regulation of several genes in both subpathways mentioned above. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. It can be concluded that this equal expression levels is the result of the up regulation in line A. “Cell adhesion molecules” are involved in several steps of the migration. Although many genes show differential expression after Salmonella infection there is no overall effect suggested. Cell adhesion molecules: The KEGG database collects a number of different adhesion mechanisms between cells in this pathway. Interactions with “Adherens junction”, “Tight junction”, and “Leukocyte transendothelial migration” pathways are suggested at several places. Here we focus on the cytoskeleton regulatory mechanisms. Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection line A shows up regulation and line B shows some down regulation of the pathway. The pathway shows equal expression between the lines after 24 h infection with Salmonella. These results are consistent with the results described above. WNT signalling: Contrary to the results described above this pathway shows many both up and down regulated genes. Chicken line differences resulted in a higher expression in line B compared to line A 8 for subpathways leading to stimulation of the cell cycle, which may be affected by the “Adherens junction” pathway, and to Cytoskeletal changes, which may be affected by the “Focal adhesion” pathway. Following Salmonella infection line A shows up regulation of both processes. No such effect was observed in line B. After24 h infection with Salmonella the subpathways are still higher expressed in line B compared to line A. Thus, the up regulation associated with Salmonella infection not sufficient to level the line differences. B-cell receptor signalling: The B-cell receptor pathway may be involved in the reaction of the chicken to Salmonella infection, and one subpathway of this pathway leads to input for the “Regulation of cytoskeleton” pathway. Chicken line differences resulted in a higher expression in line A compared to line B of this latter subpathway. Following Salmonella infection line A shows down regulation and line B shows up regulation of this subpathway. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. It can be concluded that this equal expression levels is the result of the differential regulation of the lines. T cell receptor signalling: Chicken line differences seem not to affect expression of this pathway. Following Salmonella infection both lines show up regulation of several genes in this pathway, where especially in line A more up regulated genes were found than in line B. Only in line A up regulation of the input signal for the “Regulation of actin cytoskeleton” pathway is visible. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. The Regulation of actin cytoskeleton pathway is in the centre of all these regulatory mechanisms. The pathway describes the regulation of several different steps in changes in the actin cytoskeleton and interactions with other pathways. Chicken line differences resulted in a higher expression in line B compared to line A of the subpathways leading to the formation of stress fibres and two different subpathways leading to input in the “Focal adhesion” pathway. Following Salmonella infection line A shows up regulation of one subpathway leading to input in the Focal adhesion pathway (but not the other) and uncertain regulation of stress fibre formation. Line B shows limited regulation. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. 9 Network: Apoptosis mechanism The Apoptosis pathway: Chicken line differences resulted in differential gene expression between the chicken lines, but the direction seems uncertain. Following Salmonella infection both lines react to Salmonella infection with induced expression of several genes of this pathway suggesting that apoptosis is induced as a reaction to infection. This pathway shows differential expression between the lines after 24 h infection with Salmonella including more genes showing lower expression in line B than in line A, but no direction towards a specific effect could be observed. The JAK-STAT signalling pathway is composed of several subpathways directing towards, cell cycle, anti apoptosis, apoptosis, and proteolysis mechanisms. Chicken line differences resulted in some genes in this pathway showing differential expression between the chicken lines but this seems not to be directed towards a specific subpathway. Following Salmonella infection both lines show up regulation of subpathways affecting cell growth and differentiation, and anti apoptosis. This pathway shows higher expression in line A than in line B after 24 h infection with Salmonella. It can be concluded that this differential expression levels is the result of a higher up regulation in line A than in line B. The Natural Killer cell mediated cytotoxicity pathway affects both the apoptosis and the JAK-STAT signalling pathway. Chicken line differences resulted in differential expression of genes in the pathway but no clear effect on the “JAK-STAT pathway” could be found. Following Salmonella infection both lines show up regulation of the subpathway involved in regulating input to the “JAK-STAT” pathway. After 24 h infection with Salmonella infection the subpathway influencing the “JAK-STAT” pathway is higher in line A than in line B. These results suggest that the up regulation is higher in line A than in line B. The effect on the apoptosis pathway may be also affected by the up regulated release of cytokines in line B. This may suggest that the chicken lines differ in the regulation of this pathway following Salmonella infection. The Transforming Growth Factor (TGF) beta pathway is involved in regulating proliferation, differentiation, and apoptosis of tissues mainly of mesodermal origin. Chicken line differences resulted 10 in a higher expression in line B compared to line A. Following Salmonella infection line A shows up regulation of several genes in this pathway. None of the genes of the pathway in line B showed regulation. This subpathway shows higher expression in line B compared to line A after 24 h infection with Salmonella. This suggests that the up regulation of line A is not sufficient to equal the expressions between the lines. The results suggest that the input for the MAPK pathway may be up regulated, especially in line A. The Mitogen-Activated Protein Kinase (MAPK) signalling pathway is involved in many regulatory processes. Here we focus on apoptosis-related effects. Chicken line differences resulted in contradictory expression differences between the chicken lines for the subpathway regulating proliferation and differentiation of cells. Subpathways leading to apoptosis seem not to differ between the lines. Following Salmonella infection both lines show up regulation of the input for the apoptosis pathway although line B to a lesser extends than line A. Line A up regulate the subpathway for stimulation of proliferation and differentiation of cells. However, after 24 h infection with Salmonella infection the proliferation and differentiation affecting subpathway seems to be higher expressed in line B than in line A. Subpathways leading to apoptosis seem not to differ between the lines. Network: Regulation of energy metabolism The Glycolysis / Gluconeogenesis pathway: Chicken line differences not affected expression of the pathway. Following Salmonella infection the expression in line A is reduced in several steps. No such effect could be observed in line B. After 24 h Salmonella infection line B shows higher expression than line A. Thus, the difference in expression after infection is related to regulation in line A. The pathway has several links to other pathways (both input to and from) including “Pentose phosphate” pathway, ”Glycerolipid” pathway, amino acid pathways, and nucleotide pathways, some of which seem to be involved in regulation of energy metabolism too and will be reported and discussed below. The Fatty acid metabolism pathway could be an alternative for the organism to supply energy to the cells. Chicken line differences resulted in a higher expression in line B compared to line A. Following 11 Salmonella infection both lines show down regulation of this pathway. After 24 h infection with Salmonella this subpathway shows a higher expression in line B compared to line A. From these results it cannot be concluded whether both lines react similarly or the reaction differs between the lines. Although connections with other pathways exist these pathways seem not to affect the expression of the “Fatty acid metabolism” pathway. The Glycerolipid metabolism pathway has an output link towards the “Fatty acid metabolism” pathway. Chicken line differences have not affected expression of this pathway. Following Salmonella infection both lines show little regulation perhaps with a small exception for D-glyceraldehyde expression regulation, which seem to be decreased in both lines similarly. This subpathway shows equal expression between the lines after 24 h infection with Salmonella with the same exception. This may be related to the effects found for the Glycolysis / Gluconeogenesis pathway, at least for line A. The Pentose phosphate metabolism pathway: Chicken line differences have not affected expression of this pathway. Following Salmonella infection line A shows some regulation of several genes of the Glycolysis affecting subpathway. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. The Purine metabolism pathway synthesized nucleotides and their precursors. The pathway delivers input for the “Pentose phosphate metabolism” pathway. Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection both lines show up regulation of several genes in this pathway. This subpathway shows higher expression in line B compared to line A after 24 h infection with Salmonella. From the data it is not possible to conclude on differences between the lines. The Insulin signalling pathway may be suggested a regulatory pathway for energy metabolism. The pathway has connections with other pathways including “Glycolysis / Gluconeogenesis”, “Fatty acid metabolism”, and “Apoptosis”, and affect proliferation and differentiation. Chicken line differences resulted in a higher expression in line B compared to line A of the subpathways leading to input for “Glycolysis / Gluconeogenesis”. Following Salmonella infection both lines show some regulation but 12 the data is too limited to direct this to a specific path or process. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. Other Metabolic pathways Three pathways involved in amino acid metabolism were found: Val, Leu, Ile degradation: Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection this is reversed for the first part of the degradation pathways until coupling with CoA. Both lines react similarly to infection: The first part of the degradation pathways until coupling with CoA is up regulated, the latter part, which comprises the actual degradation steps, is down regulated. The observed changes in the expression after 24 h infection with Salmonella of the first part of the degradation pathways until coupling with CoA suggest that the up regulation is much higher in line A than in line B. However, both lines reduce the final steps of amino acid degradation. The Gly, Ser, Thr metabolism pathway: Chicken line differences have limited effect on this pathway: one small subpathway leading to Porphirine biosynthesis may be affected because line B shows higher expression than line A. Following Salmonella infection this subpathway is down regulated in line B. The subpathway shows equal expression between the lines after 24 h infection with Salmonella. Limited information is available for the Beta-Alanine metabolism pathway. Chicken line differences in the reaction to infection seem not to affect expression of the pathway. Therefore, input for other pathways such as “Fatty acid biosynthesis”, “Arginine and proline metabolism”, “Pantothenate and CoA biosynthesis”, and “Pyrimidine” synthesis are also unchanged. Amino acid metabolism also involved breakdown of proteins. The proteasome is important for protein breakdown. The proteasome is a complex molecule consisting of the products of at least 32 different genes. Chicken line differences may have affected expression of a few genes. Following Salmonella infection line A may show some up and down regulation. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. 13 The KEGG database search highlighted more general degradation pathways: Caprolactam (C6H11ON, used for the synthesis of nylon 6) degradation: Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection line A show down regulation. After 24 h infection with Salmonella a higher expression in line B compared to line A was observed. These results suggest that the line difference is enhanced by infection. The Metabolism of Xenobiotics by cytochrome P450 pathway: Chicken line differences showed no marked differences. Following Salmonella infection both lines show sharp down regulation. But after 24 h infection with Salmonella this subpathway shows equal expression between the lines. Immune response pathways Immune response pathways may act via multiple mechanisms. For the T-cell receptor signalling and the B-cell receptor signalling pathways we refer to the section on regulation of actin cytoskeletal changes above. The Cytokine – cytokine-receptor interaction pathway returned by the KEGG database consists of many molecule type-specific interactions. Neither chicken line differences nor reaction to infection seems to affect expression of the pathway. Contrary to this the Adipocytokine signalling pathway: Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection line A shows up regulation of this pathway. No such effect was found for line B. This subpathway shows equal expression between the lines after 24 h infection with Salmonella. The Gap-junction pathway: Neither chicken line differences nor reaction to infection seems to affect expression of the pathway. Chicken line differences influenced the Cytokine-cytokine receptor interactions with which the pathway starts. 14 Many genes of the Complement and coagulation cascades pathway were present on the microarray. However, neither chicken line differences nor reaction to infection seems to affect expression of the pathway. Other body functional pathways The Androgen and estrogen metabolism pathway suggests that gender related mechanisms may be involved. Chicken line differences resulted in a higher expression in line B compared to line A of the Estradiol and Estradiol-17β metabolisms subpathway. Following Salmonella infection several genes in line B show down regulation. No such effect was found in line A. This subpathway shows higher expression in line B compared to line A after 24 h infection with Salmonella. Therefore, it can be concluded that this down regulation is statistically significant, but not big enough to equal the expression between the lines. The Circadian rhythm pathway suggests involvement of day-night rhythm. Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection both lines show down regulation of the pathway. After 24 h infection with Salmonella the expression is higher in line B compared to line A. Bile acids may be directly involved in the resorption of fatty acids by the intestine. The Bile acid biosynthesis pathway: Chicken line differences resulted in a higher expression in line B compared to line A. Following Salmonella infection line B show down regulation of several genes of this pathway. No such effect was found in line A. After 24 h infection with Salmonella the expression is higher in line B compared to line A. Thus we can conclude that the down regulation in line B is not sufficient to equal the expression of the pathway between the lines.