Molecular Mechanisms of Candida Sepsis
Acronym: MomCanSep
Principal Investigator: Prof. Bernhard Hube
Team: Ilse Jacobsen, Betty Hebecker, Tony Pawlik, Nadja Jablonowski
Research Area: D Sepsis related Organ Failure
Project Number: D1.15
Duration: 01.08.2012 - 31.07.2015
Module: In-house Professorship Group
The aim of this project is to identify and characterize sepsis-associated fungal factors and their molecular interaction with host cells and thus to elucidate the molecular basis of Candida albicans sepsis
Project summary
Candida albicans is the most common cause of life-threatening nosocomial fungal infections. The mortality of sepsis caused by Candida is >50%, higher than for bacterial septicaemias. During systemic infections, C. albicans can infect almost all organs, however, the host response and the ability to clear C. albicans cells is organ-specific. In the murine model of haematogenously disseminated candidiasis, which is the gold standard for investigating the pathogenesis of C. albicans bloodstream infections, mice die of progressive sepsis, kidney inflammation and failure, while fungal load declines in all other infected organs without causing pathological alterations. These data suggest that fungal pathogenicity is not only due to damage caused by the fungus, but also due to an inappropriate host response leading to damage caused by immune cells.
In this project, we aim to identify and characterise fungal factors which are responsible for the organ-specific host responses and the immunopathology in the kidneys. We propose that, (1) in addition to general cell wall components, distinct factors or activities are recognised and responsible for the differential host response and immunopathology; (2) fungal genes exist, which are not required for causing host damage, but for an organ-specific host response which is either protective or non-protective. We will use in vivo transcriptional profiling and large scale C. albicans mutant collection screening to identify such genes. Proof-of-principle candidate genes which have such characteristics have already been identified. These genes and their role during systemic C. albicans infection will be investigated in detail.
Therefore, this project aims at understanding the molecular mechanisms of sepsis induction triggered by C. albicans. The knowledge of the mechanisms responsible for sepsis caused by systemic candidiasis may provide potential targets for novel ways of immune therapy.
Work program
The work program comprises four main parts:
Part 1: Identification of stage-, tissue-, organ-, and infection-associated fungal genes potentially responsible for host responses
Part 2: Production of mutants lacking virulence associated genes and collection of large scale mutant libraries
Part 3: Large scale host response screening of mutant collections
Part 4: Detailed analysis of identified candidate genes for triggering sepsis
Vision
In this project, we aim at understanding the molecular mechanisms of sepsis induction triggered by C. albicans by identifying the fungal genes, factors or activities which are responsible for or contribute to the differential host responses in the different organs. Ultimately, the knowledge of the mechanisms responsible for sepsis caused by systemic candidiasis may provide potential targets for novel ways of immune therapy.
Selected publications
Seider K, Gerwien F, Kasper L, Allert S, Brunke S, Jablonowski N, Schwarzmüller T, Barz D, Rupp S, Kuchler K, Hube B (2014) Immune evasion, stress resistance, and efficient nutrient acquisition are crucial for intracellular survival of Candida glabrata within macrophages. Eukaryotic Cell 13:170-183
Brunke S, Hube B (2013) Two unlike cousins: Candida albicans and C. glabrata infection strategies. Cell Microbiol. 15(5):701-708
Lüttich A, Brunke S, Hube B, Jacobsen ID (2013) Serial passaging of Candida albicans in systemic murine infection suggests that the wild type strain SC5314 is well adapted to the murine kidney. PloS one 8: e64482
Martin R, Albrecht-Eckardt D, Brunke S, Hube B, Hünniger K, Kurzai O (2013) A Core Filamentation Response Network in Candida albicans Is Restricted to Eight Genes. PloS one 8: e58613
Mayer FL, Wilson D, Hube B (2013) Candida albicans pathogenicity mechanisms. Virulence 4: 119-128
Mayer FL, Wilson D, Hube B (2013) Hsp21 potentiates antifungal drug tolerance in Candida albicans. PloS one 8: e60417
Miramon P, Kasper L, Hube B (2013) Thriving within the host: Candida spp. interactions with phagocytic cells. Med Microbiol Immunol 202: 183-195
Pietrella D, Pandey N, Gabrielli E, Pericolini E, Perito S, Kasper L, Bistoni F, Cassone A, Hube B, Vecchiarelli A. (2013) Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome. Eur J Immunol. 43: 679-692
Citiulo F, Jacobsen ID, Miramon P, Schild L, Brunke S, Zipfel P, Brock M, Hube B, Wilson D (2012) Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog 8: e1002777 (→ Publication award of the DMyk)
Gow NA, Hube B (2012) Importance of the Candida albicans cell wall during commensalism and infection. Current Opinion in Microbiology 15: 406-412
Jacobsen ID, Wilson D, Wächtler B, Brunke S, Naglik JR, Hube B (2012) Candida albicans dimorphism as a therapeutic target. Expert Rev Anti Infect Ther. 10(1):85-93
Lüttich A, Brunke S, Hube B. (2012) Isolation and amplification of fungal RNA for microarray analysis from host samples. Methods Mol Biol. 845:411-21
Mayer FL, Wilson D, Jacobsen ID, Miramon P, Slesiona S, Bohovych IM, Brown AJ, Hube B (2012) Small but crucial: the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans. PloS one 7: e38584
Miramón P, Dunker C, Windecker H, Bohovych IM, Brown AJ, Kurzai O, Hube B. (2012) Cellular Responses of Candida albicans to Phagocytosis and the Extracellular Activities of Neutrophils Are Critical to Counteract Carbohydrate Starvation, Oxidative and Nitrosative Stress. PLoS One. 7(12):e52850
Contact
Tel. + 49 (0)3641 - 532 1401 oder 00
Abteilung Mikrobielle Pathogenitätsmechanismen
Leibniz Institut für Naturstoff-Forschung und Infektionsbiologie e.V.
Hans-Knöll-Institut (HKI)
Beutenbergstraße 11a
07745 Jena
Website of the Department of Microbial Pathogenicity Mechanisms (MPM) at the HKI