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.
Highlights
Toll-Like receptors (TLRs) belong to the family of pattern-recognition receptors with a crucial function of recognising pathogen-associated molecular patterns (PAMPs)
Unstimulated cells ingested cryptococci at a lower rate compared to cells stimulated with TLR agonists
Pre-stimulation of microglial cells with different TLR agonists caused an increase in the uptake of cryptococci
Summary
Toll-Like receptors (TLRs) belong to the family of pattern-recognition receptors with a crucial function of recognising pathogen-associated molecular patterns (PAMPs). Cryptococcus neoformans (C. neoformans) is an encapsulated yeast which causes life-threatening infections in immunocompromised individuals, especially in patients with AIDS who are often unable to eliminate cryptococci completely from the cerebrospinal fluid (CSF) in an advanced stage of disease [1,2,3]. Cryptococcosis primarily affects these patients, but recently it has been observed in immunocompetent individuals [4,5,6,7,8]. Upon TLR stimulation, the ability of microglia to phagocytose Gram-positive and Gram-negative bacteria is increased [20,21] We hypothesized that this mechanism could be a therapeutic option in fungal CNS infections. We studied the phagocytosis of C. neoformans by microglial cells after TLR stimulation
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