The Syk-Coupled C-Type Lectin Receptors Dectin-2 and Dectin-3 Are Involved in Paracoccidioides brasiliensis Recognition by Human Plasmacytoid Dendritic Cells

Abstract

Plasmacytoid dendritic cells (pDCs), which have been extensively studied in the context of the immune response to viruses, have recently been implicated in host defense mechanisms against fungal infections. Nevertheless, the involvement of human pDCs during paracoccidioidomycosis (PCM), a fungal infection endemic to Latin America, has been scarcely studied. However, pDCs were found in the cutaneous lesions of PCM patients, and in pulmonary model of murine PCM these cells were shown to control disease severity. These findings led us to investigate the role of human pDCs in the innate phase of PCM. Moreover, considering our previous data on the engagement of diverse Toll-like receptors and C-type lectin receptors receptors in Paracoccidioides brasiliensis recognition, we decided to characterize the innate immune receptors involved in the interaction between human pDCs and yeast cells. Purified pDCs were obtained from peripheral blood mononuclear cells from healthy donors and they were stimulated with P. brasiliensis with or without blocking antibodies to innate immune receptors. Here we demonstrated that P. brasiliensis stimulation activates human pDCs that inhibit fungal growth and secrete pro-inflammatory cytokines and type I IFNs. Surprisingly, P. brasiliensis-stimulated pDCs produce mature IL-1β and activate caspase 1, possibly via inflammasome activation, which is a phenomenon not yet described during pDC engagement by microorganisms. Importantly, we also demonstrate that dectin-2 and dectin-3 are expressed on pDCs and appear to be involved (via Syk signaling) in the pDC-P. brasiliensis interaction. Moreover, P. brasiliensis-stimulated pDCs exhibited an efficient antigen presentation and were able to effectively activate CD4+ and CD8+ T cells. In conclusion, our study demonstrated for the first time that human pDCs are involved in P. brasiliensis recognition and may play an important role in the innate and adaptive immunity against this fungal pathogen.

Saccharomyces cerevisiae mannan induces sheep beta-defensin-1 expression via Dectin-2-Syk-p38 pathways in ovine ruminal epithelial cells

“…In immune cells, Dectin-2 is coupled to the Syk kinase, which becomes phosphorylated upon Dectin-2 activation, and further activates the innate immune and host defense responses [41, 42]. In our study, Syk expression in the rumen mucosa and OREC was detected by immunohistochemistry and immunofluorescence, and the localization of Syk in OREC was consistent with that in human bronchial epithelial cells [43].…”

Innate Immune Receptors and Defense Against Primary Pathogenic Fungi

“…In contrast to studies in mice, in vitro studies of human plasmacytoid dendritic cells using antibodies to MCL showed that Dectin-2 and Dectin-3 were important [ 110 ]. Dendritic cells ingested P. brasiliensis and inhibited the organism’s growth and this growth inhibition was blocked by anti-Dectin-2 and anti-Dectin-3.…”

C-type lectin receptor-mediated immune recognition and response of the microbiota in the gut

“…Dectin-3 may use a signaling pathway similar to those of the other three CLRs to mediate intestinal antifungal immunity. More studies are required to gain more detailed and precise information about its structure and activation [42, 45, 46].…”

“…As Dectin-2 recognizes mannans, the mycobiota that Dectin-2 recognizes are C. albicans , Candida glabrata and Cryptococcus neoformans [53]. Dectin-2 can cooperate with Dectin-3 by forming heterodimers to recognize C. albicans [45]. Dectin-2 is also involved in A. fumigatus recognition and its expression is restricted to macrophages [54].…”