Project-ID: LS17-018
Project start: 08. Juli 2019
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 251.405,00

Brief summary:

The composition of the intestinal microbiome is increasingly recognized as an important factor in preventing diseases. Accordingly, its beneficial manipulation is an envisioned strategy of preventing or treating intestinal diseases. The human intestine is the place where many pathogenic viruses multiply. Among them are diarrhea-causing human adenoviruses. While rather harmless in immunocompetent individuals, the infections can become systemic and, as a consequence, life-threatening in immunocompromised individuals. Solid organ but particularly hematopoietic stem cell transplant recipients are at the highest risk. Among hematopoietic stem cell transplant recipients with disseminated infections mortality rates as high as 80% have been reported. These infections usually start in the intestine before becoming systemic. The efficacy of drugs used to treat adenovirus infections is limited and associated with nephrotoxicity. Hence, given the fact that numbers of transplant recipients are constantly rising, novel treatment strategies are highly needed.

We intend to investigate the in-principle feasibility of neutralizing adenoviruses with living or non-living lactic acid bacteria carrying the virus receptor CAR on their cell surface or with soluble CAR secreted by these bacteria. Soluble CAR has been shown to be capable of neutralizing the viruses in vitro. In an envisioned therapeutic application, CAR-displaying bacteria or secreted CAR may serve as receptor traps which, upon introduction into the intestinal tract, may bind and neutralize the viruses. The strategy is supposed to prevent viral titers to rise to levels at which the viruses usually enter the bloodstream and the infection becomes systemic, hard to be treated, and very often life-threatening.

In a collaborative effort we intend to generate such cellular receptor traps based on the lactic acid bacterium Lactobacillus plantarum which is a regular inhabitant of the intestinal tract, is a food-grade bacterium, and has GRAS status (“generally recognized as safe”). Different cell surface anchors will be assessed for the presentation of the virus receptor on the cell surface, and the bacteria or CAR secreted by the bacteria will be evaluated for their virus-binding capabilities in vitro. Furthermore, we intend to display the virus receptor on the surfac of L. plantarum cells in a way that does not require genetic modification of the bacterium.

Keywords:
Virology, bacteriology, medicine