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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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TNF-α enhances C. tropicalis killing by neutrophils but not monocytes. WT or CARD9−/− neutrophils (A) or monocytes (B) were isolated from naive bone marrow and treated or not with TNF-α, followed by incubation with C. tropicalis for 2 h. Killing ability was assessed by measuring CFU from neutrophil: C. tropicalis cultures or monocyte: C. tropicalis cultures. (C) Neutrophils were isolated from the blood of WT or CARD9−/− mice infected with C. tropicalis for 2 or 5 d. Neutrophil killing ability was assessed by measuring CFU from neutrophil:C. tropicalis cultures. Data are pooled from two to four experiments (each data point represents an individual mouse). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, Mann–Whitney U test. ns, not significant.
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fig07: TNF-α enhances C. tropicalis killing by neutrophils but not monocytes. WT or CARD9−/− neutrophils (A) or monocytes (B) were isolated from naive bone marrow and treated or not with TNF-α, followed by incubation with C. tropicalis for 2 h. Killing ability was assessed by measuring CFU from neutrophil: C. tropicalis cultures or monocyte: C. tropicalis cultures. (C) Neutrophils were isolated from the blood of WT or CARD9−/− mice infected with C. tropicalis for 2 or 5 d. Neutrophil killing ability was assessed by measuring CFU from neutrophil:C. tropicalis cultures. Data are pooled from two to four experiments (each data point represents an individual mouse). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, Mann–Whitney U test. ns, not significant.

Mentions: TNF-α enhances neutrophil killing of C. albicans and C. glabrata (56, 58), but its effects on C. tropicalis have not been investigated. To test the hypothesis that CARD9-induced TNF-α augments neutrophil killing of C. tropicalis, bone marrow–derived neutrophils from WT or CARD9−/− mice were incubated with this fungus in the presence or absence of TNF-α, and the neutrophil-killing capacity of C. tropicalis was determined by measuring CFU. Incubation with TNF-α significantly enhanced the killing of C. tropicalis by both WT and CARD9−/− neutrophils (Fig. 7A), demonstrating that TNF-α augments neutrophil killing of C. tropicalis. Furthermore, WT and CARD9−/− neutrophils killed C. tropicalis equivalently (Fig. 7A). Thus, CARD9−/− neutrophils are not intrinsically defective in C. tropicalis killing and can respond to exogenous TNF-α to augment their killing activity.


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)

TNF-α enhances C. tropicalis killing by neutrophils but not monocytes. WT or CARD9−/− neutrophils (A) or monocytes (B) were isolated from naive bone marrow and treated or not with TNF-α, followed by incubation with C. tropicalis for 2 h. Killing ability was assessed by measuring CFU from neutrophil: C. tropicalis cultures or monocyte: C. tropicalis cultures. (C) Neutrophils were isolated from the blood of WT or CARD9−/− mice infected with C. tropicalis for 2 or 5 d. Neutrophil killing ability was assessed by measuring CFU from neutrophil:C. tropicalis cultures. Data are pooled from two to four experiments (each data point represents an individual mouse). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, Mann–Whitney U test. ns, not significant.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4592105&req=5

fig07: TNF-α enhances C. tropicalis killing by neutrophils but not monocytes. WT or CARD9−/− neutrophils (A) or monocytes (B) were isolated from naive bone marrow and treated or not with TNF-α, followed by incubation with C. tropicalis for 2 h. Killing ability was assessed by measuring CFU from neutrophil: C. tropicalis cultures or monocyte: C. tropicalis cultures. (C) Neutrophils were isolated from the blood of WT or CARD9−/− mice infected with C. tropicalis for 2 or 5 d. Neutrophil killing ability was assessed by measuring CFU from neutrophil:C. tropicalis cultures. Data are pooled from two to four experiments (each data point represents an individual mouse). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, Mann–Whitney U test. ns, not significant.
Mentions: TNF-α enhances neutrophil killing of C. albicans and C. glabrata (56, 58), but its effects on C. tropicalis have not been investigated. To test the hypothesis that CARD9-induced TNF-α augments neutrophil killing of C. tropicalis, bone marrow–derived neutrophils from WT or CARD9−/− mice were incubated with this fungus in the presence or absence of TNF-α, and the neutrophil-killing capacity of C. tropicalis was determined by measuring CFU. Incubation with TNF-α significantly enhanced the killing of C. tropicalis by both WT and CARD9−/− neutrophils (Fig. 7A), demonstrating that TNF-α augments neutrophil killing of C. tropicalis. Furthermore, WT and CARD9−/− neutrophils killed C. tropicalis equivalently (Fig. 7A). Thus, CARD9−/− neutrophils are not intrinsically defective in C. tropicalis killing and can respond to exogenous TNF-α to augment their killing activity.

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