Transcriptomic Approaches Elucidate Novel Aspects Of The Host Immune Response To Candidemia

Abstract Objective Examination of the human transcriptome in circulating leukocytes during invasive candidiasis can provide an innovative approach to defining immunologic mechanisms driving the host response to this deadly infection. Methods RNA sequencing was performed on peripheral blood samples from 50 hospitalized patients with blood culture positive invasive candidiasis, along with 30 control subjects. Generalized linear hypothesis testing and weighted gene co-expression network analysis (WGCNA) were used to define biological networks contributing to the host response to Candida infection. Results 1,748 genes were differentially upregulated and 2,149 genes downregulated in the presence of candidemia compared to matched controls. These genes reflected many canonical antifungal immune response pathways including phagocytosis, neutrophil activation, type I interferon responses, and T cell signaling. However, the data also demonstrated activation of some less well described antifungal immune mechanisms, including B cell activation, upregulation of humoral immune response pathways, and a profound alteration in the host regulation of heme synthesis and iron metabolism. While iron is known to be critical for fungal pathogens such as Candida in vitro, this analysis offers evidence that the human host manipulates this system as a part of the overall response to fungal infection. Conclusion Analysis of the transcriptome in circulating white blood cells of infected human subjects offers unique and novel insight into the complex immunologic response to invasive candidiasis.