Fungal infections triggering sepsis have increased dramatically in recent years. All septic fungal infections have two things in common: they are difficult to diagnose and they have an above-average mortality rate. For this reason Fungal Septomics focuses specifically on infection biology of systemic fungal infections.
The spectrum of pathogenic agents that cause sepsis has changed a great deal in industrialized countries since the 1980s. In particular, pathogenic fungi have become increasingly common as triggers for sepsis infections. In the USA, yeasts of the genus Candida have become the fourth most frequent cause of septic infections and in clinical studies they repeatedly accounted for 5-10% of cases. In addition to primary sepsis caused by Candida, secondary systemic fungal infections can develop in the course of a bacterial sepsis infection due to sepsis associated immune-paralysis. These infections have a considerable influence on the outcome and increase the costs of patient care. Other fungal infections, like invasive aspergillosis infections caused by Aspergillus species, are also increasingly common as secondary complications in sepsis cases.
Figure: Candida albicans (light microscopic image) is a polymorphic fungus: it can appear in different growth forms (left: round yeast form, right: filamentous form).
Fungal Septomics aims at analyzing both the variability of the pathogen and the regulation of the human immune system during sepsis. The most important model organism is the polymorphic yeast Candida albicans, which is a harmless colonizer of the intestinal tract in most healthy individuals. Under certain conditions, however, including impaired activity of the immune system, C. albicans can translocate across the intestinal barrier and cause invasive infection. Fungal Septomics investigates how C. albicans can transform from a harmless ‘resident’ into an invasive pathogen. This transition is actively driven by the pathogen. The ability of C. albicans to switch from its yeast form to filamentous forms, enabling tissue-invasive growth is essential for pathogenesis. Fungal Septomics analyses the mechanisms of this morphotypic switch in parallel with the associated changes in the epithelial barrier.
Figure: Confocal microscope image of an epithelial cell layer. Under certain conditions C. albicans forms filamentous morphotypes (white) that are able to invade and cross the cell layer (cell membrane, green and cytoskeleton, red) of the epithelial cells.
However, sepsis caused by C. albicans is almost always also associated with a dysfunction of the host’s immune response. Here, neutrophilic granulocytes are of particular importance. These cells are capable of specifically recognizing filamentous forms of C. albicans and reacting with a morphotype-specific activation program. The action of neutrophilic granulocytes in the concert of other components of the immune system as well as the functions of other immune cells are yet to be fully understood. The work of Fungal Septomics focuses on these questions, using established infection models for primary human immune cells, as well as a whole-blood infection model, as a simple but meaningful in vitro infection model.
Figure: With fluorescence microscopy we can observe how the immune system controls a fungal infection: a granulocyte (white blood cell, purple) recognizes Candida cells (green with red cell wall) and starts to enclose them (bottom). Another granulocyte already phagocyted a Candida cell (green) to destroy it (top).
Diverse studies show that the risk for developing fungal infections is also determined by a patient’s individual genetic background. Modern tools in molecular biology and innovative sequencing strategies now enable us to carry out genome-wide association analyses, in which more than a million genetic markers can be analyzed at a time. The essential prerequisite for such analyses is the availability of large numbers of patients. The Fungal Septomics research group is coordinating a European multi-centre study on the genetic risk for invasive Aspergillosis (AspIRS – Aspergillosis intrinsic risk stratification study), in which 20 partners from eight countries are involved. The data obtained from this study will also be used for comparative analyses with the clinically more heterogeneous disease pattern of invasive candidosis and sepsis in general. Furthermore, on the basis of these results, data from basic research projects can be used as a source for potential biomarker molecules. Biomarkers can enable a better diagnosis of fungal sepsis and may serve as potential targets for anti-infective therapies. To achieve this, Fungal Septomics is cooperating with the Host and Clinical Septomics research groups, and other partners at the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, as well as Jena University Hospital. Comprehensively characterized clinical samples in the Septomics Biobank provide the best possible resource for this work.