Breakthrough method sheds light on how immune receptors detect infections

Researchers from the University of Bonn use an innovative method to watch immune receptors do their work.

Immune cells can detect infections much like a sniffer dog, using special sensors known as Toll-like receptors, or TLRs for short. But which signals activate TLRs, and what is the relationship between the magnitude and nature of this activation and the substance being detected? In a recent study, researchers from the University of Bonn and the University Hospital Bonn (UKB) used an innovative method to answer these questions. The approach they took could accelerate the search for drugs against infectious diseases, cancer, diabetes or dementia. Their findings have been published in the journal ‘Nature Communications’.

TLRs are found in large numbers on the surface of many of our cells, especially in the mucous membranes and those of our immune system.

They act like the olfactory receptors in our nose and activate when they encounter a specific chemical signal. The alarm they activate causes a series of reactions in the cells. For example, when scavenger cells “sniff out” a bacterium, they initiate a process known as phagocytosis by engulfing and digesting the bacterium, while other immune cells release special messengers that request reinforcement, causing inflammation.

TLRs activated by danger signals

There are different groups of TLRs, each responding to different ‘odors’. “These are molecules that have crystallized into important danger signals in the course of evolution,” explains Professor Günther Weindl from the Pharmaceutical Institute of the University of Bonn. These include lipopolysaccharides (LPS), which form integral parts of the cell wall of a bacterium.

“What we do not yet know for sure in many cases is which reactions are caused by a detected signal,” says Weindl, who is also a member of the Transdisciplinary Research Areas (TRAs) ‘Life & Health’ and ‘Sustainable Futures’. “For example, it is entirely possible that different molecules stimulate the same TLR but cause different responses.”

Researchers usually try to answer this question by marking molecules in a different color, so that they know, for example, when the receptor activates a certain signaling pathway in which these molecules play an important role. However, this method is very time-consuming and labor-intensive and requires that the observer is already well acquainted with the signaling pathways.

“Instead, we tried a different technique that doesn’t require color coding and has already been used successfully to shed light on how other receptors work,” Weindl reveals. “We have now used this method for the first time to study TLRs.” The process is based on the fact that cells tend to change shape when they come into contact with a signaling molecule, for example to prepare to ‘swallow’ a bacterium or to transform into infected tissue.

Changing the wavelength to visualize TLR activation

This change in shape is very easy to see by placing the cells on a specially coated transparent plate and shining a broadband light source on them from below. Certain areas (wavelengths) of the light spectrum are reflected where the light meets the coating. Which areas in particular will depend on the processes and changes taking place in the cell.

“We were able to show that these changes in the reflected wavelengths occur within a few minutes of adding the signaling molecule,” says Weindl’s colleague Dr. Janine Holze. “We also brought cells into contact with E. coli and Salmonella lipopolysaccharides. Although both cell wall components stimulate the same TLR, the reflected spectrum changed differently after introducing the E. coli LPS than after adding their Salmonella counterparts.” This suggests that the same receptor is activated in different ways by different molecules and then triggers specific responses depending on the signal.

This method therefore enables a much more nuanced explanation than before of how the receptors work and simplifies the search for potential drugs with a very specific action profile.”

Professor Günther Weindl, Pharmaceutical Institute, University of Bonn

Potential applications include boosting the immune response so that the body’s own defenses can fight cancer cells more effectively. In diseases like diabetes, rheumatism or Alzheimer’s, by contrast, the goal is to weaken specific aspects of the immune response that could otherwise damage healthy tissue, and the new method could take researchers a step further toward this goal .