Transmissible prion disease. Further studies, along with a better 15900046 understanding of the origin of CNS vacuoles, will be needed to determine whether PrPSc and loss of MGRN1 act through the same downstream pathways to cause this intriguing phenotype.AcknowledgmentsWe are grateful to Sarah Anderson, Richard Bennett and Julie Amato for technical assistance and Janet Peters and Anita Pecukonis for animal care.Author ContributionsConceived and designed the experiments: TMG GAC GSB. Performed the experiments: DS RP MA DM AO. Analyzed the data: TMG GAC MA SJD. Wrote the paper: TMG.
The incidence of cryptococcosis has increased dramatically over the past decades, due in a large part to the global HIV pandemic. More than 600,000 deaths are estimated to occur each year as a result of cryptococcal meningoencephalitis [1]. The species C. neoformans is an opportunistic pathogen mainly affecting immunocompromised hosts. In contrast, C. gattii mainly causes With an altered PKM2 expression were established using RNA interference (PKM 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]. Cells of the innate immune system are important for initial defense against pathogens. Upon contact with pathogens, they produce pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a, Interleukin (IL)-1b and IL-6, thereby initiating a specific adaptive cellular immune response. Anti-inflammatory cytokines such as IL-1RA are also produced and act as downregulators of this immune response. Of particular interest for fungal infections, the cytokines IL-1b and IL-6 in the presence of IL-23 induce the development of T-helper (Th)17 cells. IL-17 and IL-22, the majorcytokines excreted by Th17 cells, have several pro-inflammatory functions, one of which is eliciting defensin production by epithelial cells [7]. Previous studies have shown a crucial role of Th17 cells in human Title Loaded From File antifungal defense against mucosal Candida albicans infections [8?0]; but the role of this particular Thlymphocyte subset in anti-cryptococcal defense is not clear. Which cytokines are released depends on recognition of microbial components by pattern recognition receptors (PRRs) on the cells of the innate immune system. Toll-like receptors (TLRs), a well-defined set of PRRs, are expressed on a variety of cells and are important mediators of pro-inflammatory cytokine release. However, their role in mediating cytokine response to Cryptococcus spp. is being debated [11?5]. 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. Therefore, in the current study we assessed the cytokine profile of human peripheral blood mononuclear cells (PBMCs) of healthy individuals, after in vitro stimulation with well-defined heatkilled isolates of C. gattii, C. neoformans and several hybrids. InCryptococcus gattii Induced Cytokine Patternaddition, we investigated the involvement of TLR2, TLR4 and TLR9 in the pro-inflammatory cytokine response to C. gattii.Results Quantitative comparison of cytokine induction between different Cryptococcus spp.We.Transmissible prion disease. Further studies, along with a better 15900046 understanding of the origin of CNS vacuoles, will be needed to determine whether PrPSc and loss of MGRN1 act through the same downstream pathways to cause this intriguing phenotype.AcknowledgmentsWe are grateful to Sarah Anderson, Richard Bennett and Julie Amato for technical assistance and Janet Peters and Anita Pecukonis for animal care.Author ContributionsConceived and designed the experiments: TMG GAC GSB. Performed the experiments: DS RP MA DM AO. Analyzed the data: TMG GAC MA SJD. Wrote the paper: TMG.
The incidence of cryptococcosis has increased dramatically over the past decades, due in a large part to the global HIV pandemic. More than 600,000 deaths are estimated to occur each year as a result of cryptococcal meningoencephalitis [1]. The species C. neoformans is an opportunistic pathogen mainly affecting immunocompromised hosts. In contrast, 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]. Cells of the innate immune system are important for initial defense against pathogens. Upon contact with pathogens, they produce pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a, Interleukin (IL)-1b and IL-6, thereby initiating a specific adaptive cellular immune response. Anti-inflammatory cytokines such as IL-1RA are also produced and act as downregulators of this immune response. Of particular interest for fungal infections, the cytokines IL-1b and IL-6 in the presence of IL-23 induce the development of T-helper (Th)17 cells. IL-17 and IL-22, the majorcytokines excreted by Th17 cells, have several pro-inflammatory functions, one of which is eliciting defensin production by epithelial cells [7]. Previous studies have shown a crucial role of Th17 cells in human antifungal defense against mucosal Candida albicans infections [8?0]; but the role of this particular Thlymphocyte subset in anti-cryptococcal defense is not clear. Which cytokines are released depends on recognition of microbial components by pattern recognition receptors (PRRs) on the cells of the innate immune system. Toll-like receptors (TLRs), a well-defined set of PRRs, are expressed on a variety of cells and are important mediators of pro-inflammatory cytokine release. However, their role in mediating cytokine response to Cryptococcus spp. is being debated [11?5]. 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. Therefore, in the current study we assessed the cytokine profile of human peripheral blood mononuclear cells (PBMCs) of healthy individuals, after in vitro stimulation with well-defined heatkilled isolates of C. gattii, C. neoformans and several hybrids. InCryptococcus gattii Induced Cytokine Patternaddition, we investigated the involvement of TLR2, TLR4 and TLR9 in the pro-inflammatory cytokine response to C. gattii.Results Quantitative comparison of cytokine induction between different Cryptococcus spp.We.

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