Candida albicans-induced EphA2 signaling promotes kidney injury and sepsis during invasive candidiasis

Abstract

Abstract Pattern recognition receptors (PRRs) play key roles in fungal recognition and initiation of host immune responses. Recently, we identified that the ephrin type-A receptor 2 (EphA2) is a key β-glucan receptor on oral epithelial cells and neutrophils which orchestrates innate immune responses thereby preventing oral Candida infection. However, the contribution of this PRR in the pathogenesis of invasive candidiasis (IC) remains unknown. Although no differences in renal fungal burden could be observed, EphA2-deficient mice were more resistant to C. albicans infection suggesting that EphA2 deficiency enhances renal host tolerance to lethal fungal challenge. By testing renal cytokines, serum NGAL, a marker of renal injury, and the sepsis marker TREM-1, we found that EphA2 deficiency altered the pro- and anti-inflammatory response, reduced renal injury, and sepsis during IC. Epha2−/− mice decreased neutrophil and monocyte recruitment during IC. However, dendritic cells lacking EphA2 migrated more efficient to infected tissue. Since EphA2 is highly expressed on both, hematopoietic and stromal cells, we generated bone marrow chimeric mice. Both Epha2+/+ mice reconstituted with Epha2−/− BM and Epha2−/− mice reconstituted with Epha2+/+ BM were more resistant to IC compared to Epha2+/+ mice reconstituted with Epha2+/+BM. However, these chimeric mice were more susceptible than Epha2−/− mice reconstituted with Epha2−/− BM suggesting that EphA2 deficiency within cells of both compartments, the hematopoietic and the stromal, is required for full protection against IC. Collectively, our data highlight a detrimental role of EphA2 in promoting kidney injury and sepsis during lethal fungal infection.