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Early-expressed chemokines predict kidney immunopathology in experimental disseminated Candida albicans infections.

MacCallum DM, Castillo L, Brown AJ, Gow NA, Odds FC - PLoS ONE (2009)

Bottom Line: Levels of the chemokine KC as early as 12 h after challenge correlated significantly with all later measurements of lesion severity.Early renal IL-6 and MIP-1beta concentrations also correlated with subsequent damage levels, but less significantly than for KC.Spleen levels of KC at all times showed significant associations with kidney lesion measurements.

View Article: PubMed Central - PubMed

Affiliation: Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, United Kingdom.

ABSTRACT

Background: The mouse intravenous challenge model of Candida albicans infection is widely used to determine aspects of host-fungus interaction. We investigated the production of cytokines in the kidneys and spleen of animals up to 48 h after challenge with virulent and attenuated isolates and related these responses to semi-quantitative estimations of histopathological changes in the kidney.

Methodology/principal findings: Progression of Candida albicans infection of the kidney in response to highly virulent fungal strains was characterized by higher levels of host cellular infiltrate, higher lesion densities and greater quantities of fungal elements at 24 and 48 h, and by higher kidney concentrations of IL-1beta, MCP-1, KC, IL-6, G-CSF, TNF, MIP-2 and MIP-1beta, among the immune effectors measured. Levels of the chemokine KC as early as 12 h after challenge correlated significantly with all later measurements of lesion severity. Early renal IL-6 and MIP-1beta concentrations also correlated with subsequent damage levels, but less significantly than for KC. All chemokines tested appeared in kidney homogenates, while most of the cytokines were undetectable in kidney and spleen homogenates. GM-CSF and IL-10 showed inverse correlations with measures of lesion severity, suggesting these alone may have exerted a defensive role. Spleen levels of KC at all times showed significant associations with kidney lesion measurements.

Conclusions/significance: Elevated chemokine levels, including KC, represent the earliest responses to C. albicans infection in the mouse kidney. Fungal strains of low mouse virulence stimulate a lower innate response and less host infiltrate than more virulent strains. These findings are consistent with immunopathological damage to kidneys in the mouse C. albicans infection model and with growing evidence implicating some TLR pathways as the main point of interaction between fungal surface polysaccharides and leukocytes.

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Time course of concentrations (ng/g) of the chemokine MIP-1β in kidney and spleen samples, and of four cytokines measured in kidney samples.Among the latter only IL-10 was measurable in spleen samples (see text). Details as in Fig. 4.
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pone-0006420-g006: Time course of concentrations (ng/g) of the chemokine MIP-1β in kidney and spleen samples, and of four cytokines measured in kidney samples.Among the latter only IL-10 was measurable in spleen samples (see text). Details as in Fig. 4.

Mentions: By 24 h after C. albicans challenge, kidney levels of IL-1β (Fig. 4), G-CSF, IL-6, TNF, and MIP-1β (all Fig. 6) had risen substantially. For these effectors, as well as chemokines KC (Fig. 5), MCP-1 (Fig. 4), and MIP-2 (where measured; see supplementary table S1), levels in infected kidneys by 48 h were generally highest for mice infected with the most virulent strains (Table 1). Among the kidney samples, data for IL-10 alone (Fig. 6) showed no consistent trend. Mean levels of IL-10 for kidneys from mice infected with pmr1Δ and AM2003/0074 were higher than for mice infected with the other 9 strains throughout the time course. At 24 h kidney levels of RANTES (Fig. 5) were also higher in mice infected with the more virulent strains, but this pattern was lost by 48 h. Among the 20 cytokines and chemokines measured in kidney samples 12, 24 and 48 h after challenge, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-9, IL-12p70, IL-13 and IL-17 levels were undetectable in more than 90% of kidney samples at any time. To confirm this unexpected negative finding we retested IFN-γ and IL-12p70 by immunoassay as many samples as residual homogenate volumes allowed, together with two homogenates spiked with IFN-γ and IL-12p70. The results estimated the spiked cytokine levels to within 20% of the spiked concentrations, but confirmed there were no detectable levels of the cytokines listed above in the native samples. In spleen samples, the same cytokines plus G-CSF, IL-6 and TNF were undetectable in more than 90% of samples. Hence data for these immune effectors were not analyzed further.


Early-expressed chemokines predict kidney immunopathology in experimental disseminated Candida albicans infections.

MacCallum DM, Castillo L, Brown AJ, Gow NA, Odds FC - PLoS ONE (2009)

Time course of concentrations (ng/g) of the chemokine MIP-1β in kidney and spleen samples, and of four cytokines measured in kidney samples.Among the latter only IL-10 was measurable in spleen samples (see text). Details as in Fig. 4.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2712765&req=5

pone-0006420-g006: Time course of concentrations (ng/g) of the chemokine MIP-1β in kidney and spleen samples, and of four cytokines measured in kidney samples.Among the latter only IL-10 was measurable in spleen samples (see text). Details as in Fig. 4.
Mentions: By 24 h after C. albicans challenge, kidney levels of IL-1β (Fig. 4), G-CSF, IL-6, TNF, and MIP-1β (all Fig. 6) had risen substantially. For these effectors, as well as chemokines KC (Fig. 5), MCP-1 (Fig. 4), and MIP-2 (where measured; see supplementary table S1), levels in infected kidneys by 48 h were generally highest for mice infected with the most virulent strains (Table 1). Among the kidney samples, data for IL-10 alone (Fig. 6) showed no consistent trend. Mean levels of IL-10 for kidneys from mice infected with pmr1Δ and AM2003/0074 were higher than for mice infected with the other 9 strains throughout the time course. At 24 h kidney levels of RANTES (Fig. 5) were also higher in mice infected with the more virulent strains, but this pattern was lost by 48 h. Among the 20 cytokines and chemokines measured in kidney samples 12, 24 and 48 h after challenge, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-9, IL-12p70, IL-13 and IL-17 levels were undetectable in more than 90% of kidney samples at any time. To confirm this unexpected negative finding we retested IFN-γ and IL-12p70 by immunoassay as many samples as residual homogenate volumes allowed, together with two homogenates spiked with IFN-γ and IL-12p70. The results estimated the spiked cytokine levels to within 20% of the spiked concentrations, but confirmed there were no detectable levels of the cytokines listed above in the native samples. In spleen samples, the same cytokines plus G-CSF, IL-6 and TNF were undetectable in more than 90% of samples. Hence data for these immune effectors were not analyzed further.

Bottom Line: Levels of the chemokine KC as early as 12 h after challenge correlated significantly with all later measurements of lesion severity.Early renal IL-6 and MIP-1beta concentrations also correlated with subsequent damage levels, but less significantly than for KC.Spleen levels of KC at all times showed significant associations with kidney lesion measurements.

View Article: PubMed Central - PubMed

Affiliation: Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, United Kingdom.

ABSTRACT

Background: The mouse intravenous challenge model of Candida albicans infection is widely used to determine aspects of host-fungus interaction. We investigated the production of cytokines in the kidneys and spleen of animals up to 48 h after challenge with virulent and attenuated isolates and related these responses to semi-quantitative estimations of histopathological changes in the kidney.

Methodology/principal findings: Progression of Candida albicans infection of the kidney in response to highly virulent fungal strains was characterized by higher levels of host cellular infiltrate, higher lesion densities and greater quantities of fungal elements at 24 and 48 h, and by higher kidney concentrations of IL-1beta, MCP-1, KC, IL-6, G-CSF, TNF, MIP-2 and MIP-1beta, among the immune effectors measured. Levels of the chemokine KC as early as 12 h after challenge correlated significantly with all later measurements of lesion severity. Early renal IL-6 and MIP-1beta concentrations also correlated with subsequent damage levels, but less significantly than for KC. All chemokines tested appeared in kidney homogenates, while most of the cytokines were undetectable in kidney and spleen homogenates. GM-CSF and IL-10 showed inverse correlations with measures of lesion severity, suggesting these alone may have exerted a defensive role. Spleen levels of KC at all times showed significant associations with kidney lesion measurements.

Conclusions/significance: Elevated chemokine levels, including KC, represent the earliest responses to C. albicans infection in the mouse kidney. Fungal strains of low mouse virulence stimulate a lower innate response and less host infiltrate than more virulent strains. These findings are consistent with immunopathological damage to kidneys in the mouse C. albicans infection model and with growing evidence implicating some TLR pathways as the main point of interaction between fungal surface polysaccharides and leukocytes.

Show MeSH
Related in: MedlinePlus