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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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Development of kidney lesion parameters over 48 h from intravenous challenge of mice with 11 C. albicans strains.Data show means±SEMs for data from 3 mice per time point per strain. X-axis values have been jittered to facilitate visualization of the data. (a) Viable fungal burdens in kidneys. (b) C. albicans per lesion as PAS-positive pixels/lesion. (c) Lesion density (lesions/kidney section). (d) Host infiltrate pixels/mm2. Strains are depicted as follows. J990102, open circles; J951361, filled squares; AM2003-020, open triangles; IHEM16614, open diamonds; SC5314, closed circles; s20175.016, open squares; AM2003/0074, filled diamonds; AM2003/0069, open circles with dotted lines; HUN96, filled squares with dotted lines; Capmr1, open triangles with dotted lines; Capmr1+PMR1, filled triangles with dotted lines.
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pone-0006420-g002: Development of kidney lesion parameters over 48 h from intravenous challenge of mice with 11 C. albicans strains.Data show means±SEMs for data from 3 mice per time point per strain. X-axis values have been jittered to facilitate visualization of the data. (a) Viable fungal burdens in kidneys. (b) C. albicans per lesion as PAS-positive pixels/lesion. (c) Lesion density (lesions/kidney section). (d) Host infiltrate pixels/mm2. Strains are depicted as follows. J990102, open circles; J951361, filled squares; AM2003-020, open triangles; IHEM16614, open diamonds; SC5314, closed circles; s20175.016, open squares; AM2003/0074, filled diamonds; AM2003/0069, open circles with dotted lines; HUN96, filled squares with dotted lines; Capmr1, open triangles with dotted lines; Capmr1+PMR1, filled triangles with dotted lines.

Mentions: Our first objective was to evaluate how well the three new semi-quantitative histopathology measurements, viz. lesion density, C. albicans pixels per lesion and infiltrate pixels per mm2 kidney (Fig. 1), compared with viable kidney burdens, the conventional measurements of infection progression in the mouse model. Fig. 2 shows the data for the four lesion parameters at 24 and 48 h, and, additionally, at 12 h for viable kidney burdens. Error bars were often substantial because only 3 mice were analyzed per time point for each strain. The data showed an increase in each measurement from 24 h to 48 h for the majority of infecting strains. Two of the least virulent strains, HUN96 and pmr1Δ (Table 1) showed a decrease in viable kidney burdens between 24 and 48 h (Fig. 2a), while the highest burdens at 48 h were for AM2003-020, J951361, IHEM16614 and SC5314 (Fig. 2a), which were 4 of the 5 most virulent strains in a previous study (Table 1). The highest densities of PAS-positive pixels, representing fungal material in the kidney lesions (Fig. 2b), lesion densities (lesions/mm2 section; Fig. 2c) and host infiltrate pixel densities were again all recorded for the most virulent strains in the panel (Table 1). Thus overall strain virulence was related not only to viable kidney burdens, but also to the density of kidney lesions, the amount of host leukocyte infiltrate and the amount of PAS-positive material as measured histopathologically. The virulence rank scores for the 9 strains studied previously (Table 1) showed strong statistical correlations with the 48 h means of these four parameters (Fig. 2): mean viable burdens, r = −0.67 (p = 0.025), mean kidney lesions/mm2, r = −0.74 (p = 0.011), mean PAS-positive pixels in PAS-positive lesions, r = −0.64 (p = 0.031), and mean host infiltrate pixels/mm2, r = −0.52 (p = 0.078).


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)

Development of kidney lesion parameters over 48 h from intravenous challenge of mice with 11 C. albicans strains.Data show means±SEMs for data from 3 mice per time point per strain. X-axis values have been jittered to facilitate visualization of the data. (a) Viable fungal burdens in kidneys. (b) C. albicans per lesion as PAS-positive pixels/lesion. (c) Lesion density (lesions/kidney section). (d) Host infiltrate pixels/mm2. Strains are depicted as follows. J990102, open circles; J951361, filled squares; AM2003-020, open triangles; IHEM16614, open diamonds; SC5314, closed circles; s20175.016, open squares; AM2003/0074, filled diamonds; AM2003/0069, open circles with dotted lines; HUN96, filled squares with dotted lines; Capmr1, open triangles with dotted lines; Capmr1+PMR1, filled triangles with dotted lines.
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pone-0006420-g002: Development of kidney lesion parameters over 48 h from intravenous challenge of mice with 11 C. albicans strains.Data show means±SEMs for data from 3 mice per time point per strain. X-axis values have been jittered to facilitate visualization of the data. (a) Viable fungal burdens in kidneys. (b) C. albicans per lesion as PAS-positive pixels/lesion. (c) Lesion density (lesions/kidney section). (d) Host infiltrate pixels/mm2. Strains are depicted as follows. J990102, open circles; J951361, filled squares; AM2003-020, open triangles; IHEM16614, open diamonds; SC5314, closed circles; s20175.016, open squares; AM2003/0074, filled diamonds; AM2003/0069, open circles with dotted lines; HUN96, filled squares with dotted lines; Capmr1, open triangles with dotted lines; Capmr1+PMR1, filled triangles with dotted lines.
Mentions: Our first objective was to evaluate how well the three new semi-quantitative histopathology measurements, viz. lesion density, C. albicans pixels per lesion and infiltrate pixels per mm2 kidney (Fig. 1), compared with viable kidney burdens, the conventional measurements of infection progression in the mouse model. Fig. 2 shows the data for the four lesion parameters at 24 and 48 h, and, additionally, at 12 h for viable kidney burdens. Error bars were often substantial because only 3 mice were analyzed per time point for each strain. The data showed an increase in each measurement from 24 h to 48 h for the majority of infecting strains. Two of the least virulent strains, HUN96 and pmr1Δ (Table 1) showed a decrease in viable kidney burdens between 24 and 48 h (Fig. 2a), while the highest burdens at 48 h were for AM2003-020, J951361, IHEM16614 and SC5314 (Fig. 2a), which were 4 of the 5 most virulent strains in a previous study (Table 1). The highest densities of PAS-positive pixels, representing fungal material in the kidney lesions (Fig. 2b), lesion densities (lesions/mm2 section; Fig. 2c) and host infiltrate pixel densities were again all recorded for the most virulent strains in the panel (Table 1). Thus overall strain virulence was related not only to viable kidney burdens, but also to the density of kidney lesions, the amount of host leukocyte infiltrate and the amount of PAS-positive material as measured histopathologically. The virulence rank scores for the 9 strains studied previously (Table 1) showed strong statistical correlations with the 48 h means of these four parameters (Fig. 2): mean viable burdens, r = −0.67 (p = 0.025), mean kidney lesions/mm2, r = −0.74 (p = 0.011), mean PAS-positive pixels in PAS-positive lesions, r = −0.64 (p = 0.031), and mean host infiltrate pixels/mm2, r = −0.52 (p = 0.078).

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