American journal of respiratory cell and molecular biology 2017 09 08() doi 10.1165/rcmb.2016-0335OC
Pneumocystis remains an important fungal pathogen causing life-threatening pneumonia in patients with AIDS and malignancy. Lung fungal pathogens are recognized by C-type Lectin Receptors (CLRs), which bind specific ligands and stimulate innate immune responses. Previously, a role for the CLR Dectin-1 has been shown to mediate immune responses to Pneumocystis spp. For this reason, we investigated a potential role for Dectin-2. Rats with Pneumocystis pneumonia (PCP) exhibited elevated Dectin-2 mRNA levels. Soluble Dectin-2 CRD fusions protein showed binding to intact Pneumocystis carinii (Pc) and to native Pneumocystis major surface glycoprotein/glycoprotein A (Msg/gpA). RAW macrophage cells expressing V5-tagged Dectin-2 displayed enhanced binding to Pc and increased protein tyrosine phosphorylation. Furthermore, the binding of Pc to Dectin-2 resulted in Fc receptor-γ mediated intracellular signaling. Alveolar macrophages from Dectin-2 deficient mice (Dectin-2-/-) showed significant decreases in phospho-Syk activation after challenge with Pc cell wall components. Stimulation of Dectin-2-/- alveolar macrophages with Pc components showed significant decreases in proinflammatory cytokines IL-6 and TNF-α. Finally, during infection with Pneumocystis murina (Pm), Dectin-2-/- mice displayed down regulated mRNA expression profiles of other C-type Lectin Receptors (CLRs) implicated in fungal immunity. Although Dectin-2-/- alveolar macrophages had reduced proinflammatory cytokine release in vitro, Dectin-2-/- deficiency did not reduce overall resistance of these mice in the PCP model, and organism burdens were statistically similar, both in the long term immunocompromised and in short-term immunocompetent PCP models. These results suggest that Dectin-2 participates in initial innate immune signaling to Pneumocystis, but its deficiency does not impair resistance to the organism.