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Integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents.

Saric J, Li JV, Swann JR, Utzinger J, Calvert G, Nicholson JK, Dirnhofer S, Dallman MJ, Bictash M, Holmes E - J. Proteome Res. (2010)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

O-PLS correlation analysis of plasma obtained from P. berghei-infected mice (n = 5) before infection and on days 2 and 4 postinfection correlated with the individual matched relative levels of IFN-γ. Upward-oriented peaks represent positive correlation of metabolites with IFN-γ concentration and vice versa. a.u. denotes arbitrary unit.
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fig5: O-PLS correlation analysis of plasma obtained from P. berghei-infected mice (n = 5) before infection and on days 2 and 4 postinfection correlated with the individual matched relative levels of IFN-γ. Upward-oriented peaks represent positive correlation of metabolites with IFN-γ concentration and vice versa. a.u. denotes arbitrary unit.

Mentions: The matrices for both the NMR-characterized metabolite profiles and the cytokine data were statistically related using O-PLS analysis in order to obtain information on potentially causal events at the interface of the metabolic and immune systems. The model was constructed using one PLS component and one orthogonal component (O-PLS-DA: R2Y = 0.99, Q2Y = 0.77). There were several statistically significant correlations between the relative cytokine levels and the corresponding plasma spectra of 5 mice preinfection and at days 2 and 4 postinfection in mice infected with P. berghei (Figure 5). A positive correlation was found between IFN-γ and plasma concentrations of N-acetyl glycoprotein fragments, lactate, creatine, and glycine, whereas IFN-γ was anticorrelated with glucose. The same correlation script was applied to urine and plasma spectra from each of the parasite−host models. Although trends in covariation between metabolites and cytokines were established, the correlations between the relative cytokine levels and metabolites were not significant, which may be due to the relatively small group sizes.


Integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents.

Saric J, Li JV, Swann JR, Utzinger J, Calvert G, Nicholson JK, Dirnhofer S, Dallman MJ, Bictash M, Holmes E - J. Proteome Res. (2010)

O-PLS correlation analysis of plasma obtained from P. berghei-infected mice (n = 5) before infection and on days 2 and 4 postinfection correlated with the individual matched relative levels of IFN-γ. Upward-oriented peaks represent positive correlation of metabolites with IFN-γ concentration and vice versa. a.u. denotes arbitrary unit.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865884&req=5

fig5: O-PLS correlation analysis of plasma obtained from P. berghei-infected mice (n = 5) before infection and on days 2 and 4 postinfection correlated with the individual matched relative levels of IFN-γ. Upward-oriented peaks represent positive correlation of metabolites with IFN-γ concentration and vice versa. a.u. denotes arbitrary unit.
Mentions: The matrices for both the NMR-characterized metabolite profiles and the cytokine data were statistically related using O-PLS analysis in order to obtain information on potentially causal events at the interface of the metabolic and immune systems. The model was constructed using one PLS component and one orthogonal component (O-PLS-DA: R2Y = 0.99, Q2Y = 0.77). There were several statistically significant correlations between the relative cytokine levels and the corresponding plasma spectra of 5 mice preinfection and at days 2 and 4 postinfection in mice infected with P. berghei (Figure 5). A positive correlation was found between IFN-γ and plasma concentrations of N-acetyl glycoprotein fragments, lactate, creatine, and glycine, whereas IFN-γ was anticorrelated with glucose. The same correlation script was applied to urine and plasma spectra from each of the parasite−host models. Although trends in covariation between metabolites and cytokines were established, the correlations between the relative cytokine levels and metabolites were not significant, which may be due to the relatively small group sizes.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus