Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanism Discovered to Activate the Immune System against Bacteria and Regulate the Microbiome

13.02.2019

A group of researchers at the University Hospital Tübingen has now reported for the first time that they have discovered a mechanism on how the body’s own endogenous antimicrobial defense shield regulates the microbiome and its bacterial composition; the article has been published in a recent edition of “Proceedings” by the National Academy of Science USA” (PNAS). This mechanism provides a fundamental understanding of the structure of the intestinal barrier and host microbial interaction. “It throws open the door for future approaches to new treatments, but also for developing antibiotics and beneficial microbiome modulation,” says the head of the working group, Professor Dr. Jan Wehkamp.

The microbiome in our intestine plays a vital role in people’s health and the immune system Any lack of balance there has not only been linked to chronic inflammatory intestinal inflammation, but also type 2 diabetes and other diseases.


Summary of Paneth cell defensins mediated antimicrobial defense mechanisms.

Jan Wehkamp, University Hospital Tübingen

Cluster bomb effect of defensin HD-5 strengthens the immune system

The researchers discovered a new “cluster bomb” like effect created by the body’s own antibiotics, the so-called defensins (peptides), which are formed and secreted in the Paneth granule cells, in the small intestine. “The HD-5 defensin, which the body produces naturally and releases in the intestine, splinters into fragments if it is exposed to bacteria in the gastrointestinal wall in certain circumstances.

These fragments do not, however, consist of ineffective waste, as was thought in the past, but they have an antimicrobial effect against commensal, harmless bacteria and bacteria that are pathogenic,” says Prof. Wehkamp, describing the discovery. The researchers have found 250 new antibiotic combinations in all in the different fragments, when examining them in a laboratory. “This mechanism dramatically increases the antimicrobial spectrum against possible intruders,” Wehkamp adds.

The working group in Tübingen, which has been conducting research into the microbiome for many years, was already able to publish an article in “Nature” in 2011 indicating that defensins play an important role in maintaining the balance between bacteria and the body surfaces in all organisms, particularly in the intestine (but not only there).

The scientists use the latest publication in PNAS to demonstrate how the prevailing conditions inside our intestines affect the activity and structure of the peptides: In reduced conditions with only limited oxygen – a situation that often occurs in the intestine – the HD-5 peptide, which was originally secreted in a folded (oxidized) form, is opened and activated.

It becomes more prone to degrading through its new linear structure: As a result, the proteases occurring in the intestinal mucus layer can break up the HD-5 defensin into many fragments – so activating this antimicrobial weapon. Out of one peptide the body creates endless combinations of attacking and controlling microboes which is a very smart and efficient way of defense.

Nothing passes through the HD-6 defensin net

Interestingly, nature has created a completely different defense mechanism in the other Paneth cell defensin peptide – defensin HD-6: In contrast to HD-5 it is protected from any degradation by the proteases because it is able to form an impenetrable net.

The scientists report that the HD-6 defensin remains completely stable in the natural gastrointestinal mucus, while HD-5 is broken down into fragments in the same location.
The researchers were able to artificially produce individual fragments of the HD-5 defensin during a following stage and exposed them to different kinds of bacteria.

The results were impressive: The fragments demonstrated amazing, variable, antimicrobial activity against harmless and pathogenic bacteria, including gram-negative bacteria, which are notorious for forming resistance to antibiotics.

Greater variety of intestinal flora in mice

The working group in Tübingen was also able to prove that HD-5 fragments affect the composition of bacteria in the intestine of mice and increase the variety of flora in the small intestine. A particular HD-5 fragment was fed to mice orally, for instance – in contrast to a control group, which received normal food. The results were surprising: Administering the fragment led to a higher proportion of akkermansia sp. bacteria in the intestine of the mice.

A decrease in the presence of these “good” bacteria had been associated with various diseases like diabetes mellitus and metabolic syndrome in earlier studies. “The fragmentation increases the variability of the antimicrobial defenses, particularly because the initial peptide is one of the most commonly produced and secreted peptides in the whole organism,” says Jan Wehkamp.

Treatment opportunities and new antibiotics

”This pioneer work has opened the door to an entirely new understanding of how host defense functions when confronted by bacteria, but also how the microbiome is regulated. This will be very interesting, as an enormous amount of research work is taking place on the microbiome around the globe,” says Jan Wehkamp, summarizing developments. The discovery made by the group in Tübingen opens up opportunities of finding new antibiotic substances as modulators of the microbiome or new types of antibiotics.

However, the ongoing analysis of fragments of antimicrobial peptides and their role in providing defenses against microorganisms – including possible approaches to treatment for bacteria that are resistant to antibiotics – is only at a very early stage. It is easy to reproduce the fragments discovered by the working group in Tübingen and they could play a role in treating various diseases in the future.

The work of the group, is part of Jan Wehkamp’s Heisenberg Professorship for Innate Immunity at the Medical University Clinic at Tübingen, is also originated as part of the Research Excellence Cluster at the University of Tübingen.

Illustration
Summary of Paneth cell defensins mediated antimicrobial defense mechanisms.
Here we show the different kinds of antimicrobial defense mechanism of Paneth cell defensins. While HD-5ox has a direct antimicrobial activity, HD-5red is digested by proteases leading to different, still antimicrobial active, fragments. In contrast to HD-5, neither HD-6ox nor HD-6red is susceptible to proteolytic digestion. While HD-6ox and HD-6red are able to form nanonets to entrap bacteria, only HD-6red showed an additional direct antimicrobial activity. All of these mechanisms are working together to protect the epithelial surface as schematically shown in the left part.

Wissenschaftliche Ansprechpartner:

University Hospital Tübingen
Medical University Clinic, Internal Medicine I
Professor Dr. Jan Wehkamp
Otfried-Müller-Strasse 10, 72076 Tübingen
Phone 07071 29-86004
E-mail: Jan.Wehkamp@med.uni-tuebingen.de

Originalpublikation:

Proceedings of the National Academy of Sciences of the United States of America

Paneth cell α-Defensins HD-5 and HD-6 display differential degradation into active antimicrobial Fragments

Dirk Ehmann, Judith Wendler, Louis Koeninger, Ida Larsen, Thomas Klag, Jürgen Berger, André Marette, Martin Schaller, Eduard Stange, Nisar Malek, Benjamin Jensen, Jan Wehkamp

Weitere Informationen:

https://www.pnas.org/cgi/doi/10.1073/pnas.1817376116

Bianca Hermle | idw - Informationsdienst Wissenschaft
Further information:
http://www.medizin.uni-tuebingen.de/

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The spin state story: Observation of the quantum spin liquid state in novel material

New insight into the spin behavior in an exotic state of matter puts us closer to next-generation spintronic devices

Aside from the deep understanding of the natural world that quantum physics theory offers, scientists worldwide are working tirelessly to bring forth a...

Im Focus: Excitation of robust materials

Kiel physics team observed extremely fast electronic changes in real time in a special material class

In physics, they are currently the subject of intensive research; in electronics, they could enable completely new functions. So-called topological materials...

Im Focus: Electrons in the fast lane

Solar cells based on perovskite compounds could soon make electricity generation from sunlight even more efficient and cheaper. The laboratory efficiency of these perovskite solar cells already exceeds that of the well-known silicon solar cells. An international team led by Stefan Weber from the Max Planck Institute for Polymer Research (MPI-P) in Mainz has found microscopic structures in perovskite crystals that can guide the charge transport in the solar cell. Clever alignment of these "electron highways" could make perovskite solar cells even more powerful.

Solar cells convert sunlight into electricity. During this process, the electrons of the material inside the cell absorb the energy of the light....

Im Focus: The lightest electromagnetic shielding material in the world

Empa researchers have succeeded in applying aerogels to microelectronics: Aerogels based on cellulose nanofibers can effectively shield electromagnetic radiation over a wide frequency range – and they are unrivalled in terms of weight.

Electric motors and electronic devices generate electromagnetic fields that sometimes have to be shielded in order not to affect neighboring electronic...

Im Focus: Gentle wall contact – the right scenario for a fusion power plant

Quasi-continuous power exhaust developed as a wall-friendly method on ASDEX Upgrade

A promising operating mode for the plasma of a future power plant has been developed at the ASDEX Upgrade fusion device at Max Planck Institute for Plasma...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Contact Tracing Apps against COVID-19: German National Academy Leopoldina hosts international virtual panel discussion

07.07.2020 | Event News

International conference QuApps shows status quo of quantum technology

02.07.2020 | Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

 
Latest News

Looking at linkers helps to join the dots

10.07.2020 | Materials Sciences

Surprisingly many peculiar long introns found in brain genes

10.07.2020 | Life Sciences

Goodbye Absorbers: High-Precision Laser Welding of Plastics

10.07.2020 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>