Abstract
Circulatory inflammatory proteins play a significant role in anti-Candida host immune defence. However, little is known about the genetic variation that contributes to the variability of inflammatory responses in response to C. albicans. To systematically characterize inflammatory responses in Candida infection, we profiled 91 circulatory inflammatory proteins in peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans yeast isolated from 378 individuals of European origin from the 500 Functional Genomics (500FG) cohort of the Human Functional Genomics Project (HFGP) and Lifelines Deep cohort. To identify the genetic factors that determine variation in inflammatory protein responses, we correlated genome-wide single nucleotide polymorphism (SNP) genotypes with protein abundance (protein quantitative trait loci, pQTLs) produced by the Candida-stimulated PBMCs. Furthermore, we investigated whether differences in survival of candidaemia patients can be explained by modulating levels of inflammatory proteins. We identified five genome-wide significant pQTLs that modulate IL-8, MCP-2, MMP-1, and CCL3 in response to C. albicans. In addition, our genetic analysis suggested that GADD45G from rs10114707 locus that reached genome-wide significance could be a potential core gene that regulates a cytokine network upon Candida infection. Last but not least, we observed that a trans-pQTL marked from SNP rs7651677 at chromosome 3 that influences urokinase plasminogen activator (uPA) is strongly associated with patient survival (P survival = 3.52 x 10-5, OR 3). Overall, our genetic analysis showed that genetic variation determines the abundance of circulatory proteins in response to Candida infection.
Highlights
Candida species are by far the most common fungal pathogens that cause both invasive and mucosal fungal infections
By studying the genetics of only six different cytokines upon Candida-stimulation, we showed that host genetics play a major role in inter-individual variability in cytokine responses, and single nucleotide polymorphisms (SNPs) affecting cytokine responses are associated with susceptibility to candidaemia [9,10,11]
We observed an increased inter-individual variation in inflammatory responses in peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans compared to RPMI 1640 medium-stimulated samples (Supplementary Figure 7), suggesting that-genetic factors influence cytokine production capacity in humans
Summary
Candida species are by far the most common fungal pathogens that cause both invasive and mucosal fungal infections. They have been described as the fourth most common cause of nosocomial bloodstream infection in the United States [1, 2]. Infection occurs only if the epithelial barrier function is impaired and/or there are microbiome imbalances and/or the host immune system is compromised. Under these conditions, Candida can invade tissue and reach blood circulation. The bloodstream carries Candida to almost all vital organs, leading to systemic infections and, eventually, to organ failure followed by death
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