Cryptococcus neoformanssuppresses the activation of bone marrow–derived dendritic cells stimulated with its own DNA, but not with DNA from other fungi

Abstract

DNA from Cryptococcus neoformans activates bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. In this study, we examined the effect of the culture supernatants of C. neoformans on the activation of BM-DCs caused by its own DNA. C. neoformans supernatants suppressed IL-12p40, IL-6 production and CD40 expression by BM-DCs stimulated with its own DNA, but not with CpG-ODN and DNA from Candida albicans, Saccharomyces cerevisiae or Escherichia coli. In a confocal microscopic analysis, C. neoformans DNA was colocalized with LAMP-1, a late endosomal marker, and TLR9. The culture supernatants did not show any apparent suppression of these responses. In a luciferase reporter assay, C. neoformans supernatants inhibited NFjB activation caused by its own DNA. These inhibitory activities were attenuated by treatment with heat or trypsin. These results indicate that C. neoformans secrete certain proteinous molecules that suppress the activation of BM-DCs caused by its own DNA.

Interactions of Cryptococcus with Dendritic Cells

“…Later studies identified a specific URA5 gene fragment of cryptococcal DNA that can activate bone marrow-derived DCs (BMDCs) in a TLR9-dependent manner [ 10 ]. Additionally, although DNA of C. neoformans activates BMDCs via TLR9 [ 9 ], the culture supernatants from Cryptococcus neoformans suppress activation of BMDCs stimulated with cryptococcal DNA, but not with DNA from other fungi [ 11 ]. Mice lacking TLR9 have an increased susceptibility to C. neoformans infection, and TLR9 appears to be required for recruitment of DCs to the site of infection [ 9 , 12 , 13 ] ( Table 1 ).…”

Fungal pathogens—a sweet and sour treat for toll-like receptors

“…and several other fungi secrete polysaccharides and protein cargos through dedicated exosomes upon host interaction. Supernatant of C. neoformans cultures inhibit TLR9 activation by C. neoformans DNA (Yamamoto et al, 2011). Similarly, A. fumigatus cell wall components differentially modulate TLR2 and TLR4 signaling (Chai et al, 2011).…”

Toll-like receptor stimulation increases phagocytosis of Cryptococcus neoformans by microglial cells

“…Microglial cells express Toll-like receptors (TLRs) which can identify pathogen-associated molecular patterns (PAMPs) and thereby play an important role as regulators of the innate immune response [14,15]. While bacterial lipoproteins and zymosan, a component of Saccharomyces cerevisiae ( S. cerevsiae ), are recognized by TLR2, lipopolysaccharide (LPS) from Gram-negative bacteria and glucuronoxylomannan, the major capsular polysaccharide of C. neoformans , are ligands of TLR4, and bacterial and also fungal DNA activates TLR9 [16-19]. Upon TLR stimulation, the ability of microglia to phagocytose Gram-positive and Gram-negative bacteria is increased [20,21].…”