Parenchymal organ, and not splenic, immunity correlates with host survival during disseminated candidiasis - PubMed (original) (raw)

Parenchymal organ, and not splenic, immunity correlates with host survival during disseminated candidiasis

Brad Spellberg et al. Infect Immun. 2003 Oct.

Abstract

We examined the relationship between host survival and renal and splenic immune responses in a murine model of hematogenously disseminated candidiasis. Male BALB/c mice were infected via tail vein injection with wild-type C. albicans or with an isogenic, Deltaefg1/Deltaefg1 hypha-deficient mutant. Host survival, organ fungal burden, intracellular cytokine content of splenic and kidney lymphocytes, and whole-organ cytokine profiles were determined. Wild-type C. albicans induced type 2 splenocyte responses with both nonfatal and fatal inocula. In the kidney, conversely, wild-type inocula causing no or low mortality induced type 1 responses and 100% fatal inocula induced type 2 or interleukin-10 (IL-10)-dominant responses. Hypha-deficient mutant C. albicans caused no or low mortality while inducing type 1 responses in both the spleen and kidney. To our knowledge, this is the first demonstration that host survival during systemic infection correlates with the type of immune response engendered in a nonlymphoid, parenchymal organ and not with the response in the spleen. Furthermore, the results provide in vivo confirmation that hyphal formation by C. albicans induces type 2 or IL-10-dominant host responses in tissues.

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Figures

FIG. 1.

FIG. 1.

Tissue fungal burden of kidneys and spleens from mice infected via the tail vein with 1 × 102, 1 × 103, 1 × 104, 1 × 105, or 5 × 105 blastospores of wild-type C. albicans (A) or with 1 × 103 or 1 × 105 blastospores of wild-type or hypha-deficient mutant C. albicans (B). The lower boundary of the y axis on each graph represents the limit of detectability of quantitative colony counting for each organ (1 CFU/g of kidney versus 2 CFU/g of spleen). Data are displayed as medians ± interquartile ranges from two to five experiments with 6 to 15 mice per group. *, P ≤ 0.02 by the Mann-Whitney U test compared to mice infected with the same strain at 72 h; **, P = 0.0005 by the Mann-Whitney U test at 1 week for mutant versus wild-type strains.

FIG. 2.

FIG. 2.

Frequencies of Th1 and Th2 cells isolated from the spleens of mice 1 week after inoculation with 102, 103, 104, or 105 wild-type C. albicans organisms or with PBS (0). Data are displayed as medians ± interquartile ranges from three experiments with nine mice per group. *, P < 0.05 by the Steel test versus values for uninfected (0) mice.

FIG. 3.

FIG. 3.

Th1 and Th2 splenocyte responses of mice 1 week after inoculation with 103 or 105 wild-type or hypha-deficient mutant C. albicans organisms or with PBS (Uninfected). (A) Th1/Th2 splenocyte ratios. (B) Frequencies of Th1 and Th2 splenocytes. Data are displayed as medians ± interquartile ranges from two experiments with six mice per group. *, P ≤ 0.05 versus values for uninfected mice; **, P < 0.05 for hypha-deficient mutant versus values for wild-type strains (both P values determined by the Steel test).

FIG. 4.

FIG. 4.

Whole-organ cytokine analysis by ELISA of spleens from mice inoculated with 1 × 102, 1 × 103, 1 × 104, 1 × 105, or 5 × 105 wild-type C. albicans organisms or with PBS (0). Whole-spleen IFN-γ and IL-4 concentrations at 72 h (A) and 1 week (B) after inoculation are indicated. The lowest points on the y axes represent the lower limits of detection of the ELISAs. Data are displayed as medians ± interquartile ranges from two experiments with six mice per group. *, P < 0.05 versus the uninfected mice; **, P < 0.05 versus values for uninfected mice and mice inoculated with 102, 103, or 104 organisms (both P values determined by the Steel test).

FIG. 5.

FIG. 5.

Whole-organ IFN-γ and IL-4 analysis by ELISA of kidneys from mice inoculated with 1 × 102, 1 × 103, 1 × 104, 1 × 105, or 5 × 105 wild-type C. albicans organisms or with PBS (0). Kidneys were harvested at 72 h (A) or 1 week (B) after infection. The lowest points on the y axes represent the lower limits of detection of the ELISAs. Data are displayed as medians ± interquartile ranges from two experiments with six mice per group. *, P < 0.05 versus values for uninfected mice; **, P < 0.05 versus values for mice inoculated with 102, 103, or 104 organisms per mouse (both P values determined by the Steel test).

FIG. 6.

FIG. 6.

Whole-organ IL-10 analysis by ELISA of kidneys from mice inoculated with 1 × 102, 1 × 103, 1 × 104, 1 × 105, or 5 × 105 wild-type C. albicans organisms or with PBS (0). The lowest points on the y axes represent the lower limits of detection of the ELISA. Data are displayed as medians ± interquartile ranges from two experiments with six mice per group. *, P < 0.05 by the Steel test versus values for uninfected mice.

FIG. 7.

FIG. 7.

(A) Whole-organ IFN-γ, IL-4, and IL-10 analysis by ELISA of kidneys from mice inoculated 1 week earlier with 103 or 105 wild-type or hypha-deficient mutant C. albicans organisms or with PBS (0). The lowest points on the y axes represent the lower limits of detection of the ELISAs. (B) Ratio of total IFN-γ to total IL-4 and IL-10. For organs in which IL-4 or IL-10 levels were undetectable, ratios were calculated using the lower limits of the IL-4 and IL-10 ELISA standard curves. Data are displayed as medians ± interquartile ranges from two experiments with six mice per group. *, P < 0.05 versus values for uninfected mice; **, P < 0.05 for values for the hypha-deficient mutant versus values for wild-type stains (both P values determined by the Steel test).

FIG. 8.

FIG. 8.

Normalized kidney IFN-γ/IL-4 (A) and splenic Th1/Th2 (B) ratios compared to survival durations of 42 infected mice (8 per group). Normalized ratios of <1 indicate the presence of a type 2 response, and ratios of >1 indicate the presence of a type 1 response. The Th1/Th2 ratios were measured at 72 h postinfection for inocula of 5 × 105 organisms and at 1 week postinfection for other inoculum levels. (A) P < 0.001 and rho = 0.7 (determined by Spearman rank sum test). (B) _P_ > 0.1 and rho = 0.2 (determined by Spearman rank sum test).

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