Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-α-Dependent, IL-17-Independent Mechanism.
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.
Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;Show MeSH
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Mentions: These results pointed to myeloid cells as likely mediators of immunity to C. tropicalis. Consistent with this idea is the fact that CARD9 is primarily expressed in myeloid lineage cells (12). Furthermore, neutropenia is a risk factor for disseminated C. tropicalis infection in humans, and mice deficient in neutrophils or monocytes/macrophages display increased susceptibility to disseminated C. albicans infection (25, 40–43). Accordingly, we first investigated a role for neutrophils in immunity to C. tropicalis by treating WT mice with anti-Ly6G Abs to deplete this population (Fig. 3A). Mice were given Abs on days −1 and +1 postinfection, and survival following C. tropicalis infection was assessed. As predicted, WT mice given anti-Ly6G Abs were significantly more susceptible to disseminated C. tropicalis infection compared with controls (Fig. 3B). All anti-Ly6G Ab–treated mice succumbed to infection by day 17 in contrast to only ∼10% mortality observed in controls at this time point (Fig. 3B). We also treated WT mice with anti-Gr1 Abs to deplete both neutrophils and monocytes (Fig. 3A). Anti-Gr1 Ab–treated mice were even more susceptible to C. tropicalis than were anti-Ly6G Ab–treated mice, with 100% mortality by day 8 (Fig. 3B). These results suggest that neutrophils are crucial for protective responses to C. tropicalis. Moreover, depletion of both neutrophils and monocytes leads to further enhanced susceptibility to disseminated C. tropicalis infection compared with depletion of neutrophils alone.
Affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261;