Project C5

Project Description

The transition of C. albicans from a commensal within the gut to an invasive pathogen is of great clinical importance. However, it is largely unknown which host factors trigger the transition and which fungal factors are essential for translocation through the gut. There is experimental evidence that intestinal ischemia/hypoxia, e.g., during major surgery and shock/sepsis, weakens the intestinal barrier and may promote translocation of C. albicans. We furthermore hypothesise that the environmental alterations during intestinal hypoxia trigger a specific fungal response that is associated with increased translocation. The aim of this project is to dissect the translocation process with regard to the involved anatomical sites and host cells, immune response and fungal factors. Furthermore, the effect of intestinal ischemia/hypoxia on C. albicans translocation will be evaluated. In vitro cell culture experiments will be used to determine intestinal cell barrier functions under different levels of hypoxia and the consequences for interaction with C. albicans. Transcriptional analysis will be used to identify pathways involved in epithelial response to hypoxia and fungal factors contributing to the interaction. The obtained results will be confirmed in murine ex vivo and in vivo models. To determine at which anatomical sites translocation occurs and which host cells are involved, a murine in vivo model of dissemination from the gut will be established and analysed by using fungal reporter strains and imaging (IVIS), determination of fungal burden, histology and immunhistochemistry, FACS and cytokine ELISAs. To test the hypothesis that intestinal ischemia/hypoxia enhances translocation of C. albicans through the gut, the consequences of intestinal hypoperfusion on the colonisation and translocation of C. albicans will be tested in an ex vivo model using externally perfused gut and in vivo. Transcriptional analyses as well as loss-of-function models of both host and fungus will be used to identify factors involved in the translocation process under normoxia and hypoxia in vivo. Furthermore, the transcriptional analyses allow determine whether intestinal ischemia/hypoxia leads to a specific fungal response involved in translocation. Finally, based on the transcriptome analysis and on barcoded mutant libraries, C. albicans mutants will be tested for their translocation potential to identify fungal factors essential for translocation.

Principal Investigators

Prof. Dr. Michael Bauer
Prof. Dr. Michael Bauer

Clinic of Anaesthesiology and Intensive Care Medicine

University Hospital Jena

michael.bauer@med.uni-jena.de

PD Dr. Ilse D. Jacobsen
Prof. Dr. Ilse D. Jacobsen

Research Group Microbial Immunology

Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute  

ilse.jacobsen@leibniz-hki.de

Publications

Author Year Title Journal Links

Jacobsen ID, Lüttich A, Kurzai O, Hube B, Brock M

2014

In vivo imaging of disseminated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifungal therapy.

J Antimicrob Chemother 69: 2785-96

PubMed
Duggan S, Essig F, Hünniger K, Mokhtari Z, Bauer L, Lehnert T, Brandes S, Häder A, Jacobsen ID, Martin R, Figge MT, Kurzai O 2015 Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Cell Microbiol 17: 1259-76 PuMed
Polke M, Hube B, Jacobsen ID 2015 Candida survival strategies.

Adv Appl Microbiol 91: 139-235

PubMed
Hebecker B, Naglik JR, Hube B, Jacobsen ID 2014 Pathogenicity mechanisms and host response during oral Candida albicans infections. Expert Rev Anti Infect Ther 12: 867-79 PubMed
Wartenberg A, Linde J, Martin R, Schreiner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d'Enfert C, Brunke S, Hube B 2014

Microevolution of Candida albicans in macrophages restores filamentation in a nonfilamentous mutant.

PLoS Genet 10: e1004824

PubMed
Schwartze VU, Santiago AL, Jacobsen ID, Voigt K 2014 The pathogenic potential of the Lichtheimia genus revisited: Lichtheimia brasiliensis is a novel, non-pathogenic species. Mycoses 57 Suppl 3: 128-31 PubMed
Kroll K, Shekhova E, Mattern DJ, Thywissen A, Jacobsen ID, Strassburger M, Heinekamp T, Shelest E, Brakhage AA, Kniemeyer O 2016 The hypoxia-induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus.

Mol Microbiol 101: 92-108

PubMed
Hebecker B, Vlaic S, Conrad T, Bauer M, Brunke S, Kapitan M, Linde J, Hube B, Jacobsen ID 2016 Dual-species transcriptional profiling during systemic candidiasis reveals organ-specific host-pathogen interactions. Sci Rep 6: 36055 PubMed
Polke M, Sprenger M, Scherlach K, Albán-Proaño MC, Martin R, Hertweck C, Hube B, Jacobsen ID 2017 A functional link between hyphal maintenance and quorum sensing in Candida albicans.

Mol Microbiol 103: 595-617

PubMed
Luo T, Krüger T, Knüpfer U, Kasper L, Wielsch N, Hube B, Giamarellos-Bourboulis EJ, Kortgen A, Bauer M, Brakhage AA, Kniemeyer O 2016 Immune proteomic analysis of antibody responses to extracellular proteins of Candida albicans revealing the importance of protein glycosylation for antigen recognition. J Proteome Res 15: 2394-406 PubMed
Förster TM, Mogavero S, Dräger A, Graf K, Polke M, Jacobsen ID, Hube B 2016

Enemies and brothers in arms: Candida albicans and gram-positive bacteria.

Cell Microbiol 18: 1709-15

PubMed
Halder LD, Abdelfatah MA, Jo E, Jacobsen ID, Westermann M, Beyersdorf N, Lorkowski S, Zipfel PF, Skerka C 2017 Factor H binds to extracellular DNA traps released from human blood monocytes in response to Candida albicans. Front Immunol 7: 671

PubMed

Schulze B, Rambach G, Schwartze VU, Voigt K, Schubert K, Speth C, Jacobsen ID 2017 Ketoacidosis alone does not predispose to mucormycosis by Lichtheimia in a murine pulmonary infection model.

Virulence doi: 10.1080/21505594.2017.1360460. [Epub ahead of print]

PubMed