Respiratory infections

Dr. Wronski, it is known that bacteria and viruses are constantly changing and can thus adapt to new conditions. Will this continue to be a race in which therapy development is always “one step behind”?

We think that we need to change our strategy to win this race, or to at least be able to find appropriate responses. For example, it is not conducive to count by all means on directly antiviral or antibacterial therapeutics, because these increase the selection pressure and thus promote the development of resistances. Instead, researchers are now trying to develop drugs that will keep pathogens from spreading in the host or will make them less dangerous for humans, for example by means of virulence blockers. Another approach is not to focus on the pathogens themselves, but to support the human immune system in its defense.

What is the approach Fraunhofer ITEM scientists are pursuing?

First, we need to better understand how viruses and bacteria adapt to the human body and how they interact with our immune system. Traditional development of anti-infective drugs often fails to take this into account. This is exactly our starting point. With our precision-cut lung slices model, PCLS for short, we are developing infection models with bacteria and viruses that allow us to study the infection directly in human lung tissue. Our aim is to mimic the situation in patients as closely as possible in our test systems, to eventually obtain results and also insights that will enable prediction with the best possible accuracy of what actually happens in the human body.

With PCLS, you thus have a method available that enables much more predictive studies. Where are you using this method?

We are already using this model in studies on behalf of pharmaceutical companies, for example to test whether potential drug targets actually play a role in human tissue during infection and whether their modulation can positively change the course of the infection or the immune response. Furthermore, in the international project iCAIR^®, our cooperation partners from the Institute for Glycomics in Australia are very successfully developing drugs against influenza and parainfluenza, which we in turn test directly in human PCLS.

Above all, we are very interested in establishing PCLS models of respiratory infections as a genuine alternative to animal studies.

Inhaled administration of drugs is a standard treatment for patients with asthma. What role does this route of administration play in infectious diseases of the lung?

The benefit of inhalation therapies is that they deliver the active ingredient directly to the site of action. This leads to higher concentrations of the active agent in the lungs, as this route circumvents the barriers resulting from drug absorption via the gastrointestinal tract, losses due to insufficient transport into the lungs, metabolization or degradation of the active substance. In addition, systemic exposure is avoided and the risk of side effects is reduced. The development of inhalation therapies requires not only an intact tissue architecture, but furthermore, the route of exposure, i.e. inhalation, and aerosol distribution in the human lung must be taken into account. This is particularly important for lung areas with damaged tissue or that are difficult to access due to infection and inflammation. Unfortunately, these aspects so far can be covered only in animal experiments. Animal infection models, however, are associated with a high burden on the animals and, moreover, have no relation to the human organism. This is why we want to develop alternative models for the testing of inhalable antibiotics.

In the project InhalAB, funded by the German Federal Ministry of Education and Research, we are developing human-based in-vitro models, PCLS, and the ex-vivo model of the isolated perfused rat lung as a complete, intact organ. We then combine these components to enable best possible predictivity regarding drug efficacy, but also substance distribution in healthy vs. damaged lungs. Using standard-of-care antibiotics, we are trying to determine whether and to what extent the combined use of these models will enable a predictive statement about the effect in humans. If we manage to achieve this goal, this will allow us to use these alternative models for future testing of inhalable anti-infectives and will thus reduce animal testing in line with the 3Rs principle.

What vision of modern infection research do you and your colleagues have?

Our vision is to use state-of-the-art methods in infection research to advance the development of new anti-infectives in order to effectively combat infectious diseases. To reach this goal, we have to think beyond the classical methods in infection biology and take into account the host or, more precisely, the host’s immune response as an essential factor. With our approach of investigating infections in human PCLS, we are already getting much closer to this goal. Problems in this context are limited availability of the material and a substantially higher effort compared to other methods. If we succeed in optimizing new technologies such as tissue-on-a-chip, organ-on-a-chip, or artificial lymph nodes to the point that we can reproduce human tissue in its full complexity and function, this would be a quantum leap that would considerably advance the development of effective drugs. And, in principle, this holds true not only for infection research. But that is still a long way off, maybe another 10 to 20 years, before we will have reached this point. We hope to get there by collaborating with our strong partners, to decisively advance the development of new drugs that are effective again.

What do you reckon are the biggest hurdles to the development of new anti-infective drugs?

Despite the increasing threat from infectious diseases, anti-infective research has been at a low point for several years in recent decades, due to the withdrawal of large pharmaceutical companies. Consequently, research on and development of new active agents have been advanced above all by universities, start-ups, and SMEs. These, however, lack the financial means to bring the new active substances to market approval, as this requires expensive preclinical toxicological and, above all, clinical studies.

Fortunately, politicians have recognized the threat infectious diseases pose to public health as one of the most pressing problems of our time: the EU and Germany’s federal government meanwhile are providing more money for infection research and have initiated numerous funded projects. Likewise, the large pharmaceutical companies have recognized that precompetitive collaboration is a key to success. Experts must team up and share resources instead of everyone doing their own thing. At present, this is being practiced only to a limited extent, but I believe that this is the only way to overcome the hurdles, especially considering the massive investments that are needed to bring even a single pharmaceutical to the market.

It seems logical that an application-oriented research institute such as Fraunhofer ITEM can help facilitate the transfer of research results into practical applications, given its commitment to translational medicine. Is that right?

It certainly is. We as Fraunhofer scientists live our commitment to precompetitive collaboration, not only by actively participating in a broad range of consortia funded by the EU and the German Federal Ministry of Education and Research, but above all by our proactive attitude. In the iCAIR^® consortium, we have joined forces with the Australian Institute for Glycomics as a leading institute in the development mainly of antiviral drugs and, together with the Hannover Medical School, have pooled our resources there to develop new anti-infectives.

For anti-infectives in particular, finding an economically viable way is a necessity in view of their very low return on investment. The financial imbalance can be improved, among other things, by earlier go or no-go decisions. By using custom-made infection models closely mimicking the real-life situation, we want to enable the quickest possible and highly predictive selection of drug candidates for further development and thus facilitate the transfer from bench to bedside.