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In silico modeling of spore inhalation reveals fungal persistence following low dose exposure.

ABSTRACT: The human lung is constantly exposed to spores of the environmental mould Aspergillus fumigatus, a major opportunistic pathogen. The spectrum of resultant disease is the outcome of complex host-pathogen interactions, an integrated, quantitative understanding of which lies beyond the ethical and technical reach permitted by animal studies. Here we construct a mathematical model of spore inhalation and clearance by concerted actions of macrophages and neutrophils, and use it to derive a mechanistic understanding of pathogen clearance by the healthy, immunocompetent host. In particular, we investigated the impact of inoculum size upon outcomes of single-dose fungal exposure by simulated titrations of inoculation dose, from 10(6) to 10(2) spores. Simulated low-dose (10(2)) spore exposure, an everyday occurrence for humans, revealed a counter-intuitive prediction of fungal persistence (>3 days). The model predictions were reflected in the short-term dynamics of experimental murine exposure to fungal spores, thereby highlighting the potential of mathematical modelling for studying relevant behaviours in experimental models of fungal disease. Our model suggests that infectious outcomes can be highly dependent upon short-term dynamics of fungal exposure, which may govern occurrence of cyclic or persistent subclinical fungal colonisation of the lung following low dose spore inhalation in non-neutropenic hosts.

SUBMITTER: Tanaka RJ

PROVIDER: S-EPMC4568477 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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In silico modeling of spore inhalation reveals fungal persistence following low dose exposure.

Tanaka Reiko J RJ Boon Neville J NJ Vrcelj Katarina K Nguyen Anita A Vinci Carmelina C Armstrong-James Darius D Bignell Elaine E

Scientific reports 20150914

The human lung is constantly exposed to spores of the environmental mould Aspergillus fumigatus, a major opportunistic pathogen. The spectrum of resultant disease is the outcome of complex host-pathogen interactions, an integrated, quantitative understanding of which lies beyond the ethical and technical reach permitted by animal studies. Here we construct a mathematical model of spore inhalation and clearance by concerted actions of macrophages and neutrophils, and use it to derive a mechanisti ...[more]

PMID: 26364644

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Project description:BACKGROUND: Cadmium is implicated in prostate carcinogenesis, but its oncogenic action remains unclear. OBJECTIVES: In this study we aimed to decipher changes in cell growth and the transcriptome in an immortalized human normal prostate epithelial cell line (NPrEC) following exposure to low-dose Cd. METHODS: Synchronized NPrEC cells were exposed to different doses of Cd and assayed for cell viability and cell-cycle progression. We investigated changes in transcriptome by global profiling and used Ingenuity Pathways Analysis software to develop propositions about functional connections among differentially expressed genes. A neutralizing antibody was used to negate the effect of Cd-induced up-regulation of tumor necrosis factor (TNF) in NPrEC cells. RESULTS: Exposure of NPrEC to 2.5 μM Cd enhanced cell viability and accelerated cell-cycle progression. Global expression profiling identified 48 genes that exhibited ≥ 1.5-fold changes in expression after 4, 8, 16, and 32 hr of Cd treatment. Pathway analyses inferred a functional connection among 35 of these genes in one major network, with TNF as the most prominent node. Fourteen of the 35 genes are related to TNF, and 11 exhibited an average of > 2-fold changes in gene expression. Real-time reverse transcriptase-polymerase chain reaction confirmed the up-regulation of 7 of the 11 genes (ADAM8, EDN1, IL8, IL24, IL13RA2, COX2/PTGS2, and SERPINB2) and uncovered a 28-fold transient increase in TNF expression in Cd-treated NPrEC cells. A TNF-neutralizing antibody effectively blocked Cd-induced elevations in the expression of these genes. CONCLUSIONS: Noncytotoxic, low-dose Cd has growth-promoting effects on NPrEC cells and induces transient overexpression of TNF, leading to up-regulation of genes with oncogenic and immunomodulation functions. KEY WORDS: carcinogenesis, cytokine, global expression profiling, heavy metals, immune response, inflammation, Ingenuity Pathway Analysis, knowledge-based analysis, prostate cancer.

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In silico modeling of spore inhalation reveals fungal persistence following low dose exposure.

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In silico modeling of spore inhalation reveals fungal persistence following low dose exposure.

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