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

Abstract

BackgroundToll-Like receptors (TLRs) belong to the family of pattern-recognition receptors with a crucial function of recognising pathogen-associated molecular patterns (PAMPs). Cryptococcal meningitis is a potentially fatal disease with a high mortality and risk of neurological sequelae.MethodsWe studied the ability of microglial cells to increase the phagocytosis of cryptococci after stimulation with agonists of TLR1/2, TLR3, TLR4 and TLR9.ResultsStimulation of murine microglial cells with these TLR agonists for 24 h increased the phagocytosis of encapsulated Cryptococcus neoformans. Stimulation increased the release of TNF-α, CXCL1 (KC), IL-6, IL-10 and MIP-2, which indicated the activation of microglial cells. Unstimulated and TLR agonist-stimulated MyD88-deficient cells showed a reduced ability to phagocytose cryptococci compared to their wild-type counterpart. Intracellular killing of cryptococci was also increased in TLR-stimulated cells compared to unstimulated microglial cells.ConclusionOur observation suggests that stimulation of microglial cells by TLR agonists can increase the resistance of the brain against CNS infections caused by Cryptococcus neoformans. This may be of interest when an immunocompromised patient is unable to eliminate Cryptococcus neoformans despite antifungal therapy.

CD4 + T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

“…This is likely due to the poor response of CNS resident cells in recognizing and responding to C. neoformans. The fact that we did not observe full activation of microglia until 21 days postinfection is supported by previous studies showing that C. neoformans can be phagocytosed and induce cytokine and chemokine production by microglia, including CCL3, CCL4, and CCL5, but these effects are severely hindered in the absence of opsonizing antibody or additional stimulatory factors (45,47,50,51,53). Thus, it appears that substantial time is required to overcome the poor activation and impaired phagocytosis of C. neoformans by microglia and to provide significant antigenic stimulation to prompt local reactivation and proliferation of peripherally licensed T cells surveilling the CNS.…”

“…As brain resident macrophages, microglia are among the first cells to encounter C. neoformans during CNS infection and are capable of antimicrobial effector responses (22,45,(50)(51)(52)(53). Thus, we initially anticipated that these cells would become activated in response to C. neoformans within the infected CNS early during infection prior to the accumulation of BIL.…”

Host Immunity to Cryptococcus Neoformans

“…TLR2, TLR4 and TLR9 have been shown to bind and interact with zymosan (yeast β-glucan), GXM and fungal DNA, respectively [69–71]. Redlich et al demonstrated that stimulation of microglial cells by these TLR agonists enhanced C. neoformans phagocytosis [72]. …”

High temperature affects the phagocytic activity of human peripheral blood mononuclear cells

“…Zhao et al [17] and Yan et al [18] have shown that LPS-stimulated human macrophages and dendritic cells preheated to 39.5 o C show an increase in toll like receptor-4 expression. Bearing in mind that TLRs are phagocytosis-promoting factors [15,19], their enhanced expression by elevated temperature may serve as an additional mechanism for heat-stimulated phagocytosis. It is notable that phagocytosis of various pathogens, depends on a relatively large number of factors that either enhance [20][21][22], or reduce this cell activity [23].…”