Abstract
Understanding more about the host's immune response to different Cryptococcus spp. will provide additional insight into the pathogenesis of cryptocococcis. We hypothesized that the ability of C. gattii to cause disease in immunocompetent humans depends on a distinct innate cytokine response of the host to this emerging pathogen. In the current study we assessed the cytokine profile of human peripheral blood mononuclear cells (PBMCs) of healthy individuals, after in vitro stimulation with 40 different well-defined heat-killed isolates of C. gattii, C. neoformans and several hybrid strains. In addition, we investigated the involvement of TLR2, TLR4 and TLR9 in the pro-inflammatory cytokine response to C. gattii. Isolates of C. gattii induced higher concentrations of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6 and the Th17/22 cytokine IL-17 and IL-22 compared to C. neoformans var neoformans and C. neoformans var grubii. In addition, clinical C. gattii isolates induced higher amounts of cytokines than environmental isolates. This difference was not observed in C. neoformans var. grubii isolates. Furthermore, we demonstrated a likely contribution of TLR4 and TLR9, but no role for TLR2, in the host's cytokine response to C. gattii. In conclusion, clinical heat-killed C. gattii isolates induced a more pronounced inflammatory response compared to other Cryptococcus species and non-clinical C. gattii. This is dependent on TLR4 and TLR9 as cellular receptors.
Highlights
The incidence of cryptococcosis has increased dramatically over the past decades, due in a large part to the global HIV pandemic
In the present study we investigated the in-vitro cytokine production of human peripheral blood mononuclear cells (PBMCs) incubated with 40 different heatkilled isolates of the Cryptococcus neoformans species complex
We demonstrate that C. gattii isolates induces higher concentrations of pro-inflammatory and Th17/22 cytokines compared to C. neoformans var. neoformans and C. neoformans var. grubii
Summary
The incidence of cryptococcosis has increased dramatically over the past decades, due in a large part to the global HIV pandemic. The species C. neoformans is an opportunistic pathogen mainly affecting immunocompromised hosts. C. gattii mainly causes disease in apparently immunocompetent hosts at lower incidence [2,3]. C. gattii is emerging over the past decade as a pathogen in the Pacific North-West of North America and has caused a large outbreak on Vancouver Island [4,5]. This outbreak was mainly caused by a single, hypervirulent genotype of C. gattii, namely AFLP6A/VGIIa [6]
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