title: Integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents.
abstract: Parasitic infections cause a myriad of responses in their mammalian hosts, on immune as well as on metabolic level. A multiplex panel of cytokines and metabolites derived from four parasite-rodent models, namely, Plasmodium berghei-mouse, Trypanosoma brucei brucei-mouse, Schistosoma mansoni-mouse, and Fasciola hepatica-rat were statistically coanalyzed. (1)H NMR spectroscopy and multivariate statistical analysis were used to characterize the urine and plasma metabolite profiles in infected and noninfected animals. Each parasite generated a unique metabolic signature in the host. Plasma cytokine concentrations were obtained using the 'Meso Scale Discovery' multi cytokine assay platform. Multivariate data integration methods were subsequently used to elucidate the component of the metabolic signature which is associated with inflammation and to determine specific metabolic correlates with parasite-induced changes in plasma cytokine levels. For example, the relative levels of acetyl glycoproteins extracted from the plasma metabolite profile in the P. berghei-infected mice were statistically correlated with IFN-gamma, whereas the same cytokine was anticorrelated with glucose levels. Both the metabolic and the cytokine data showed a similar spatial distribution in principal component analysis scores plots constructed for the combined murine data, with samples from all infected animals clustering according to the parasite species and whereby the protozoan infections (P. berghei and T. b. brucei) grouped separately from the helminth infection (S. mansoni). For S. mansoni, the main infection-responsive cytokines were IL-4 and IL-5, which covaried with lactate, choline, and d-3-hydroxybutyrate. This study demonstrates that the inherently differential immune response to single- and multicellular parasites not only manifests in the cytokine expression, but also consequently imprints on the metabolic signature, and calls for in-depth analysis to further explore direct links between immune features and biochemical pathways.
authors.affiliation: Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Saric
authors.forename: Jia V
authors.initials: JV
authors.lastname: Li
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Swann
authors.forename: Jürg
authors.initials: J
authors.lastname: Utzinger
authors.forename: Gail
authors.initials: G
authors.lastname: Calvert
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Maggie J
authors.initials: MJ
authors.lastname: Dallman
authors.forename: Magda
authors.initials: M
authors.lastname: Bictash
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D016002:Discriminant Analysis; D004195:Disease Models, Animal; D005210:Fasciola hepatica / Q000502:physiology; D005260:Female; D006651:Histocytochemistry; D006790:Host-Parasite Interactions; D055442:Metabolome; D051379:Mice; D015999:Multivariate Analysis; D019906:Nuclear Magnetic Resonance, Biomolecular; D010272:Parasitic Diseases / Q000097:blood / Q000378:metabolism* / Q000469:parasitology* / Q000473:pathology; D010641:Phenotype; D010962:Plasmodium berghei / Q000502:physiology; D025341:Principal Component Analysis; D051381:Rats; D012550:Schistosoma mansoni / Q000502:physiology; D014346:Trypanosoma brucei brucei / Q000502:physiology
chemical_list: D016207:Cytokines