Abstract (Expand)

Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild-type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time-resolved microarray-based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF-kappaB and MAPK signaling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-kappaB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-kappaB was experimentally validated. Furthermore, inhibition of NF-kappaB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF-kappaB activation as an important protective signaling pathway in the response of epithelial cells to C. albicans. This article is protected by copyright. All rights reserved.

Authors: M. Bohringer, S. Pohlers, Sylvie Schulze, Daniela Albrecht-Eckardt, J. Piegsa, M. Weber, R. Martin, Kerstin Hünniger, Jörg Linde, Reinhard Guthke, Oliver Kurzai

Date Published: 12th Jan 2016

Journal: Cell Microbiol

Abstract (Expand)

More than 80 years after its discovery, penicillin is still a widely used and commercially highly important antibiotic. Here, we analyse the metabolic network of penicillin synthesis in Penicillium chrysogenum based on the concept of elementary flux modes. In particular, we consider the synthesis of the invariant molecular core of the various subtypes of penicillin and the two major ways of incorporating sulfur: transsulfuration and direct sulfhydrylation. 66 elementary modes producing this invariant core are obtained. These show four different yields with respect to glucose, notably (1/2), 2/5, 1/3, and 2/7, with the highest yield of (1/2) occurring only when direct sulfhydrylation is used and alpha-aminoadipate is completely recycled. In the case of no recycling of this intermediate, we find the maximum yield to be 2/7. We compare these values with earlier literature values. Our analysis provides a systematic overview of the redundancy in penicillin synthesis and a detailed insight into the corresponding routes. Moreover, we derive suggestions for potential knockouts that could increase the average yield.

Authors: M. T. Prausse, S. Schauble, Reinhard Guthke, Stefan Schuster

Date Published: 19th Aug 2015

Journal: Biotechnol Bioeng



Authors: Sebastian Müller, Clara Baldin, Marco Groth, Reinhard Guthke, Olaf Kniemeyer, Axel A Brakhage, Vito Valiante

Date Published: 2nd Oct 2012

Journal: BMC Genomics

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