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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

(A) Reactive follicular hyperplasia detected in a mouse spleen 4 days after infection with P. berghei. Large germinal centers are shown, formed of immune- and centroblasts. Red pulp congestion was further indicated by abundant hemozoin in cordal macrophages; (B) liver tissue sections from a F. hepatica-infected rat showing typical cavity-like necrotic tunnels that were demarked by a foreign body reaction (100×); (C) lymphofollicular hyperplasia was detected in the spleen of S. mansoni-infected mice and indicated by prominent germinal centers including tangible body macrophages; (D) hepatic hemopoiesis after infection with T. b. brucei.
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fig1: (A) Reactive follicular hyperplasia detected in a mouse spleen 4 days after infection with P. berghei. Large germinal centers are shown, formed of immune- and centroblasts. Red pulp congestion was further indicated by abundant hemozoin in cordal macrophages; (B) liver tissue sections from a F. hepatica-infected rat showing typical cavity-like necrotic tunnels that were demarked by a foreign body reaction (100×); (C) lymphofollicular hyperplasia was detected in the spleen of S. mansoni-infected mice and indicated by prominent germinal centers including tangible body macrophages; (D) hepatic hemopoiesis after infection with T. b. brucei.

Mentions: The establishment of infection in the 4 parasite−rodent models employed was verified by hematologic parameters and histological examination. Worm counts upon dissection were also used in the case of helminths. All parasitic infections induced clear pathology in all infected animals as described in Table 1, with the exception of the S. mansoni−mouse model, where the establishment of infection could not be confirmed for 2 out of 7 infected mice. Images of hematoxylin and eosin stained selected sections of host organs are provided for each of the four infection models in Figure 1, showing pathological events in spleen tissue sections from P. berghei (Figure 1A) and S. mansoni-infected mice (Figure 1C) and in liver sections from F. hepatica-infected rats (Figure 1B), and T. b. brucei-infected mice (Figure 1D). Pathological changes were also observed in the kidney of T. b. brucei-infected mice,(30) which showed interstitial nephritis and F. hepatica-infected rats demonstrated splenic follicular hyperplasia with inflammatory infiltrates found in the kidney (unpublished data) (Table 1).


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)

(A) Reactive follicular hyperplasia detected in a mouse spleen 4 days after infection with P. berghei. Large germinal centers are shown, formed of immune- and centroblasts. Red pulp congestion was further indicated by abundant hemozoin in cordal macrophages; (B) liver tissue sections from a F. hepatica-infected rat showing typical cavity-like necrotic tunnels that were demarked by a foreign body reaction (100×); (C) lymphofollicular hyperplasia was detected in the spleen of S. mansoni-infected mice and indicated by prominent germinal centers including tangible body macrophages; (D) hepatic hemopoiesis after infection with T. b. brucei.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: (A) Reactive follicular hyperplasia detected in a mouse spleen 4 days after infection with P. berghei. Large germinal centers are shown, formed of immune- and centroblasts. Red pulp congestion was further indicated by abundant hemozoin in cordal macrophages; (B) liver tissue sections from a F. hepatica-infected rat showing typical cavity-like necrotic tunnels that were demarked by a foreign body reaction (100×); (C) lymphofollicular hyperplasia was detected in the spleen of S. mansoni-infected mice and indicated by prominent germinal centers including tangible body macrophages; (D) hepatic hemopoiesis after infection with T. b. brucei.
Mentions: The establishment of infection in the 4 parasite−rodent models employed was verified by hematologic parameters and histological examination. Worm counts upon dissection were also used in the case of helminths. All parasitic infections induced clear pathology in all infected animals as described in Table 1, with the exception of the S. mansoni−mouse model, where the establishment of infection could not be confirmed for 2 out of 7 infected mice. Images of hematoxylin and eosin stained selected sections of host organs are provided for each of the four infection models in Figure 1, showing pathological events in spleen tissue sections from P. berghei (Figure 1A) and S. mansoni-infected mice (Figure 1C) and in liver sections from F. hepatica-infected rats (Figure 1B), and T. b. brucei-infected mice (Figure 1D). Pathological changes were also observed in the kidney of T. b. brucei-infected mice,(30) which showed interstitial nephritis and F. hepatica-infected rats demonstrated splenic follicular hyperplasia with inflammatory infiltrates found in the kidney (unpublished data) (Table 1).

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