Abstract
Candida albicans is a common cause of life-threatening fungal bloodstream infections. In the murine model of systemic candidiasis, the kidney is the primary target organ while the fungal load declines over time in liver and spleen. To better understand these organ-specific differences in host-pathogen interaction, we performed gene expression profiling of murine kidney, liver and spleen and determined the fungal transcriptome in liver and kidney. We observed a delayed transcriptional immune response accompanied by late induction of fungal stress response genes in the kidneys. In contrast, early upregulation of the proinflammatory response in the liver was associated with a fungal transcriptome resembling response to phagocytosis, suggesting that phagocytes contribute significantly to fungal control in the liver. Notably, C. albicans hypha-associated genes were upregulated in the absence of visible filamentation in the liver, indicating an uncoupling of gene expression and morphology and a morphology-independent effect by hypha-associated genes in this organ. Consistently, integration of host and pathogen transcriptional data in an inter-species gene regulatory network indicated connections of C. albicans cell wall remodelling and metabolism to the organ-specific immune responses.
Highlights
Candida albicans is a common cause of life-threatening fungal bloodstream infections
C. albicans initially infects almost all organs; while the fungal load increases over time in kidneys, it declines in liver and spleen[2,3]
Principal component analysis (PCA) of the murine transcriptional data sets showed that 54% of the variance (PC1 and PC2) among all transcripts in the data sets could be attributed to organ-specific expression differences (Fig. 1A)
Summary
Liver, and kidney show different kinetics of transcriptional responses to systemic candidiasis. The second C. albicans cluster showed organ-specific regulation, with increased expression in the kidney and decreased expression in the liver This cluster was significantly enriched for terms associated with the cell surface and included genes like CDC12, CHS3, and MYO2, that influence filamentation and cell wall composition and thereby could affect interaction with the immune system[36]. All of the stress-responsive genes with increased expression in the kidney 24 h p.i. are known to be induced upon oxidative stress[48], possibly indicating interaction with immigrating phagocytes at later stages of infection in the kidney These organ-specific differential expression kinetics of stress-associated fungal genes might reflect the higher abundance of immune cells in the liver. This in turn may lead to structural alterations that can affect interaction with immune cells and possibly contribute to the specific course of infections in different organs
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