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Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.

Whibley N, Jaycox JR, Reid D, Garg AV, Taylor JA, Clancy CJ, Nguyen MH, Biswas PS, McGeachy MJ, Brown GD, Gaffen SL - J. Immunol. (2015)

Bottom Line: Consistently, WT mice depleted of TNF-α were more susceptible to C. tropicalis, and CARD9-deficient neutrophils and monocytes failed to produce TNF-α following stimulation with C. tropicalis Ags.However, TNF-α treatment of neutrophils in vitro enhanced their ability to kill C. tropicalis.Moreover, CARD9-dependent production of TNF-α enhances the candidacidal capacity of neutrophils, limiting fungal disease during disseminated C. tropicalis infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;

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CARD9 is crucial for protection against disseminated C. tropicalis infection. WT and CARD9−/− mice were infected i.v. with 1 × 104 CFU/g C. tropicalis yeast cells. (A) Survival was monitored for 28 d postinfection. Data are pooled from six experiments (WT, n = 36; CARD9−/−, n = 16). ****p < 0.0001, log-rank (Mantel–Cox) test. (B) Organ fungal burdens were measured at day 5. Data are pooled from two experiments (each data point represents an individual mouse). ***p < 0.001, Mann-Whitney U test. Kidneys isolated from day 5–infected mice were stained with H&E (C) or PAS (D). Arrows indicate immune cell infiltrate (H&E) and C. tropicalis cells (PAS). Scale bars, 200 μm. (E) WT, Dectin-2−/−, and Dectin-1−/− mice were infected with 1 × 104 CFU/g C. tropicalis yeast cells, and survival was monitored for 28 d. Data are pooled from two experiments (WT, n = 16; Dectin1−/−, n = 15; Dectin-2−/−, n = 8). *p < 0.05, log-rank (Mantel–Cox) test.
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fig01: CARD9 is crucial for protection against disseminated C. tropicalis infection. WT and CARD9−/− mice were infected i.v. with 1 × 104 CFU/g C. tropicalis yeast cells. (A) Survival was monitored for 28 d postinfection. Data are pooled from six experiments (WT, n = 36; CARD9−/−, n = 16). ****p < 0.0001, log-rank (Mantel–Cox) test. (B) Organ fungal burdens were measured at day 5. Data are pooled from two experiments (each data point represents an individual mouse). ***p < 0.001, Mann-Whitney U test. Kidneys isolated from day 5–infected mice were stained with H&E (C) or PAS (D). Arrows indicate immune cell infiltrate (H&E) and C. tropicalis cells (PAS). Scale bars, 200 μm. (E) WT, Dectin-2−/−, and Dectin-1−/− mice were infected with 1 × 104 CFU/g C. tropicalis yeast cells, and survival was monitored for 28 d. Data are pooled from two experiments (WT, n = 16; Dectin1−/−, n = 15; Dectin-2−/−, n = 8). *p < 0.05, log-rank (Mantel–Cox) test.

Mentions: To determine whether CARD9 is required for protection against disseminated C. tropicalis infection, WT and CARD9−/− mice were infected i.v. with 1 × 104 CFU/g C. tropicalis yeast cells, and survival and fungal burden were assessed. With this infective dose, ∼40% mortality was observed in WT mice at day 28 postinfection (Fig. 1A). In contrast, CARD9−/− mice infected with C. tropicalis showed 100% mortality by day 10 postinfection, a time point at which all WT mice remained alive (Fig. 1A). Consistent with their early mortality, CARD9−/− mice exhibited higher fungal burdens in visceral organs (kidneys, brain, and liver) than did WT mice, which was measured at day 5 when all mice were still viable (Fig. 1B). There was no difference in CFU in spleens of WT and CARD9−/− mice (Fig. 1B), suggesting tissue-specific differences in C. tropicalis infection.


Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.

Whibley N, Jaycox JR, Reid D, Garg AV, Taylor JA, Clancy CJ, Nguyen MH, Biswas PS, McGeachy MJ, Brown GD, Gaffen SL - J. Immunol. (2015)

CARD9 is crucial for protection against disseminated C. tropicalis infection. WT and CARD9−/− mice were infected i.v. with 1 × 104 CFU/g C. tropicalis yeast cells. (A) Survival was monitored for 28 d postinfection. Data are pooled from six experiments (WT, n = 36; CARD9−/−, n = 16). ****p < 0.0001, log-rank (Mantel–Cox) test. (B) Organ fungal burdens were measured at day 5. Data are pooled from two experiments (each data point represents an individual mouse). ***p < 0.001, Mann-Whitney U test. Kidneys isolated from day 5–infected mice were stained with H&E (C) or PAS (D). Arrows indicate immune cell infiltrate (H&E) and C. tropicalis cells (PAS). Scale bars, 200 μm. (E) WT, Dectin-2−/−, and Dectin-1−/− mice were infected with 1 × 104 CFU/g C. tropicalis yeast cells, and survival was monitored for 28 d. Data are pooled from two experiments (WT, n = 16; Dectin1−/−, n = 15; Dectin-2−/−, n = 8). *p < 0.05, log-rank (Mantel–Cox) test.
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fig01: CARD9 is crucial for protection against disseminated C. tropicalis infection. WT and CARD9−/− mice were infected i.v. with 1 × 104 CFU/g C. tropicalis yeast cells. (A) Survival was monitored for 28 d postinfection. Data are pooled from six experiments (WT, n = 36; CARD9−/−, n = 16). ****p < 0.0001, log-rank (Mantel–Cox) test. (B) Organ fungal burdens were measured at day 5. Data are pooled from two experiments (each data point represents an individual mouse). ***p < 0.001, Mann-Whitney U test. Kidneys isolated from day 5–infected mice were stained with H&E (C) or PAS (D). Arrows indicate immune cell infiltrate (H&E) and C. tropicalis cells (PAS). Scale bars, 200 μm. (E) WT, Dectin-2−/−, and Dectin-1−/− mice were infected with 1 × 104 CFU/g C. tropicalis yeast cells, and survival was monitored for 28 d. Data are pooled from two experiments (WT, n = 16; Dectin1−/−, n = 15; Dectin-2−/−, n = 8). *p < 0.05, log-rank (Mantel–Cox) test.
Mentions: To determine whether CARD9 is required for protection against disseminated C. tropicalis infection, WT and CARD9−/− mice were infected i.v. with 1 × 104 CFU/g C. tropicalis yeast cells, and survival and fungal burden were assessed. With this infective dose, ∼40% mortality was observed in WT mice at day 28 postinfection (Fig. 1A). In contrast, CARD9−/− mice infected with C. tropicalis showed 100% mortality by day 10 postinfection, a time point at which all WT mice remained alive (Fig. 1A). Consistent with their early mortality, CARD9−/− mice exhibited higher fungal burdens in visceral organs (kidneys, brain, and liver) than did WT mice, which was measured at day 5 when all mice were still viable (Fig. 1B). There was no difference in CFU in spleens of WT and CARD9−/− mice (Fig. 1B), suggesting tissue-specific differences in C. tropicalis infection.

Bottom Line: Consistently, WT mice depleted of TNF-α were more susceptible to C. tropicalis, and CARD9-deficient neutrophils and monocytes failed to produce TNF-α following stimulation with C. tropicalis Ags.However, TNF-α treatment of neutrophils in vitro enhanced their ability to kill C. tropicalis.Moreover, CARD9-dependent production of TNF-α enhances the candidacidal capacity of neutrophils, limiting fungal disease during disseminated C. tropicalis infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;

Show MeSH
Related in: MedlinePlus