Syk Signaling in Dendritic Cells Orchestrates Innate Resistance to Systemic Fungal Infection

Abstract

Host protection from fungal infection is thought to ensue in part from the activity of Syk-coupled C-type lectin receptors and MyD88-coupled toll-like receptors in myeloid cells, including neutrophils, macrophages and dendritic cells (DCs). Given the multitude of cell types and receptors involved, elimination of a single pathway for fungal recognition in a cell type such as DCs, primarily known for their ability to prime T cell responses, would be expected to have little effect on innate resistance to fungal infection. Here we report that this is surprisingly not the case and that selective loss of Syk but not MyD88 in DCs abrogates innate resistance to acute systemic Candida albicans infection in mice. We show that Syk expression by DCs is necessary for IL-23p19 production in response to C. albicans, which is essential to transiently induce GM-CSF secretion by NK cells that are recruited to the site of fungal replication. NK cell-derived-GM-CSF in turn sustains the anti-microbial activity of neutrophils, the main fungicidal effectors. Thus, the activity of a single kinase in a single myeloid cell type orchestrates a complex series of molecular and cellular events that underlies innate resistance to fungal sepsis.

Immunity against fungi

“…Consistent with SYK/CARD9 being central for CLR signal integration, mice with hematopoietic or DC-specific Syk deletion or with global CARD9 deficiency are highly susceptible to C. albicans (29,60) and A. fumigatus (43) challenge. CARD9/SYK-dependent susceptibility maps to defective cytokine responses that control neutrophil, NK, and T cell trafficking or activation.…”

“…CARD9/SYK-dependent susceptibility maps to defective cytokine responses that control neutrophil, NK, and T cell trafficking or activation. During systemic candidiasis, DCs secrete IL-23 in a SYK-dependent manner, prompting IL-17A-dependent (hereafter referred to as IL-17) NK cell release of GM-CSF, thereby activating candidacidal neutrophils at infection sites (60,61).…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…35 Previously, it is a general thought that DCs have little effect on innate resistance to fungal infection. However, a recent study revealed that selective loss of Syk in DCs abrogates innate resistance to acute systemic C. albicans infection in mice, 155 which indicates that a single kinase in DCs might orchestrate a complex series of molecular and cellular events in innate resistance to C. albicans. Actually, full protection against most pathogens requires an adaptive response, which is initiated and directed by DCs.…”

Innate immune cell response uponCandida albicansinfection

“…Moreover, human NK cells activated by C. albicans can secret GM-CSF, IFN-g, and TNF-a. 140,141 However, previous studies showed that the production of IFN-g by murine NK cells was down-regulated by C. albicans.…”