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New advanced blood infection model (finished project)

Thomas Emil Andersen

Blood infections are a major problem compromising around 12.000 Danish cases each year, of who around 2.000 die. Blood infections occur, when microorganisms spread from e.g. wounds or the urinary tract to the bloodstream, where the microorganism can cause a serious infection such as septic shock or endocarditis.
Today, research in blood infections and drug development uses simple cell culture-based laboratory models and animal experiments.

The problem with standard, cell culture-based models, however, is that they often are too simplified and only to a limited extend mimic the conditions in the human body. This means that results from these experiments often deviate from the following animal experiments and clinical trials.

In this project, we utilize our experience with biofilm and cell culture-based models under flow to develop a new advanced endothelial infection model that closely mimics the conditions of the human blood vessel. This enables detailed studies of blood infection including infections caused by the bacterium Staphylococcus aureus. This research is highly relevant, since this bacterium in particular is known for its virulence when spreading through the bloodstream.

In the project, we will focus on the optimization of the model to allow studies of biofilm formation under flow of human blood plasma both on blood catheter surfaces (the main entry of the bacterium in hospitalized patients) and on endothelial surfaces. For this, methods such as time-lapse microscopy are employed using fluorescent bacteria, blood components, and biofilm markers. The results will subsequently be compared with results previously obtained from animal models. It is expected that the model will improve the quality of research results in relation to standard cell culture-based models, and also limit the use of animals in research and development at universities and in the industry.

Short status at the end of project

Laboratory models of blood infections are currently limited by being too simplified thus preventing them from replacing animal models. In this 3R-funded project, we have established a model that permits detailed studies of bloodstream infections, including infections of the heart valves. For this we have used blood vessel cells isolated from human umbilical cords, which we culture into a blood vessel epithelium layer in flow chambers. The blood vessel epithelium is then infected with bacteria, and by using microscopy and molecular biology methods, we can study how the bacterium establishes itself and penetrates the epithelium. This first step of metastatic spreading through the bloodstream and invasion of organs is a critical step during blood infections, and can with this method for the first time be studied directly and at close range during long-term experiments, without the use of animals. The results are currently being compared with samples from a separate animal infection project, from which we will be able to see to what degree that our enhanced artificial blood vessel model can replace the use of animals. In this way, we will expect that our model can create new knowledge about bloodstream infections, which for example can be used to improve treatment, and furthermore to replace the use of animals for blood infection experiments. The results are currently being compiled in two articles about the gene expression of invading staphylococci and the pathogenesis of heart valve infection, respectively.

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