ABSTRACT: We identified a rare C5 gene variant in individuals with a history of Neisseria meningitis, suggesting a complement deficiency as a predisposing factor.
Project description:Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.
Project description:The C5/TRAF1 locus is a well validated genetic risk factor for RA. Upon further investigation of this region we recently discovered that the intergenic region between these two immune-related genes is activelly transcribed in a variety of tissues and is up-regulated in PBMCs, monocytes, B- and T-cells upon immune stimulation. The present study aimed to characterize the biological function of this newly identified C5/TRAF1 intergenic transcript, by analysing the effect of its knockdow on the gene expression profiles of Huh7 and THP1 cells.
