Gene network and pathway analysis of bovine mammary tissue challenged with Streptococcus uberis reveals induction of cell profileration and inhibition of PPARγ signaling as potential mechanism for the negative relationships between immune response and lipid metabolism

BackgroundInformation generated via microarrays might uncover interactions between the mammary gland andStreptococcus uberis(S. uberis) that could help identify control measures for the prevention and spread ofS. uberismastitis, as well as improve overall animal health and welfare, and decrease economic losses to dairy farmers. The main objective of this study was to determine the most affected gene networks and pathways in mammary tissue in response to an intramammary infection (IMI) withS. uberisand relate these with other physiological measurements associated with immune and/or metabolic responses to mastitis challenge withS. uberisO140J.ResultsStreptococcus uberisIMI resulted in 2,102 (1,939 annotated) differentially expressed genes (DEG). Within this set of DEG, we uncovered 20 significantly enriched canonical pathways (with 20 to 61 genes each), the majority of which were signaling pathways. Among the most inhibited wereLXR/RXR SignalingandPPARα/RXRα Signaling. Pathways activated by IMI wereIL-10 SignalingandIL-6 Signalingwhich likely reflected counter mechanisms of mammary tissue to respond to infection. Of the 2,102 DEG, 1,082 were up-regulated during IMI and were primarily involved with the immune response, e.g.,IL6,TNF,IL8, IL10, SELL, LYZ, andSAA3. Genes down-regulated (1,020) included those associated with milk fat synthesis, e.g.,LPIN1, LPL, CD36, andBTN1A1. Network analysis of DEG indicated thatTNFhad positive relationships with genes involved with immune system function (e.g.,CD14, IL8, IL1B, andTLR2) and negative relationships with genes involved with lipid metabolism (e.g.,GPAM,SCD,FABP4,CD36, andLPL) and antioxidant activity (SOD1).ConclusionResults provided novel information into the early signaling and metabolic pathways in mammary tissue that are associated with the innate immune response toS. uberisinfection. Our study indicated that IMI challenge withS. uberis(strain O140J) elicited a strong transcriptomic response, leading to potent activation of pro-inflammatory pathways that were associated with a marked inhibition of lipid synthesis, stress-activated kinase signaling cascades, and PPAR signaling (most likely PPARγ). This latter effect may provide a mechanistic explanation for the inverse relationship between immune response and milk fat synthesis.