MicroRNA regulation of bovine monocyte inflammatory and metabolic networks in an in vivo infection model.
Bovine mastitis is an inflammation-driven disease of the bovine mammary gland that costs the global dairy industry several billion dollars per year. Because disease susceptibility is a multifactorial complex phenotype, an integrative biology approach is required to dissect the molecular networks involved. Here, we report such an approach using next-generation sequencing combined with advanced network and pathway biology methods to simultaneously profile mRNA and miRNA expression at multiple time points (0, 12, 24, 36 and 48 hr) in milk and blood FACS-isolated CD14(+) monocytes from animals infected in vivo with Streptococcus uberis. More than 3700 differentially expressed (DE) genes were identified in milk-isolated monocytes (MIMs), a key immune cell recruited to the site of infection during mastitis. Upregulated genes were significantly enriched for inflammatory pathways, whereas downregulated genes were enriched for nonglycolytic metabolic pathways. Monocyte transcriptional changes in the blood, however, were more subtle but highlighted the impact of this infection systemically. Genes upregulated in blood-isolated monocytes (BIMs) showed a significant association with interferon and chemokine signaling. Furthermore, 26 miRNAs were DE in MIMs and three were DE in BIMs. Pathway analysis revealed that predicted targets of downregulated miRNAs were highly enriched for roles in innate immunity (FDR < 3.4E-8), particularly TLR signaling, whereas upregulated miRNAs preferentially targeted genes involved in metabolism. We conclude that during S. uberis infection miRNAs are key amplifiers of monocyte inflammatory response networks and repressors of several metabolic pathways.
Animal and Bioscience Research Department, Animal and Grassland Research and Innovation Centre, Teagasc, Grange, Dunsany, County Meath, Ireland School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
Nathan
N
Lawless
United States Department of Agriculture, Agricultural Research Services, National Animal Disease Center, Ames, Iowa 50010.
Timothy A
TA
Reinhardt
Animal and Bioscience Research Department, Animal and Grassland Research and Innovation Centre, Teagasc, Grange, Dunsany, County Meath, Ireland.
Kenneth
K
Bryan
Iowa State University, DNA Facility, Molecular Biology Building, Ames, Iowa 50010.
Mike
M
Baker
United States Department of Agriculture, Agricultural Research Services, National Animal Disease Center, Ames, Iowa 50010.
Bruce
B
Pesch
United States Department of Agriculture, Agricultural Research Services, National Animal Disease Center, Ames, Iowa 50010.
Duane
D
Zimmerman
Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation, East Geelong Victoria 3219, Australia.
Kurt
K
Zuelke
United States Department of Agriculture, Agricultural Research Services, Beltsville, Maryland 20705-1350.
Tad
T
Sonstegard
School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
Cliona
C
O'Farrelly
United States Department of Agriculture, Agricultural Research Services, National Animal Disease Center, Ames, Iowa 50010 david.lynn@teagasc.ie john.lippolis@ars.usda.gov.
John D
JD
Lippolis
Animal and Bioscience Research Department, Animal and Grassland Research and Innovation Centre, Teagasc, Grange, Dunsany, County Meath, Ireland david.lynn@teagasc.ie john.lippolis@ars.usda.gov.
David J
DJ
Lynn
D000818:Animals; D002417:Cattle; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008414:Mastitis, Bovine / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D053858:Metabolic Networks and Pathways; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D013291:Streptococcus
D018950:Lipopolysaccharide Receptors; D035683:MicroRNAs; D012333:RNA, Messenger
RNAseq; complex genetics; complex immunity; infection; innate immunity; microRNA; resistance; tolerance; transcriptional networks