Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry, and Vishnu Mohanan, doctoral student in biological sciences, both at the University of Delaware, write about their findings in the Journal of Biological Chemistry.
Our gut is home to over a trillion bacteria, without which we would not be able to digest our food and convert it into protein, vitamins, minerals, and other essential nutrients our cells need.
At the same time, our immune system has the complex job of protecting us against pathogens - foreign organisms that cause harm - a task made even more challenging by the presence of our friendly gut flora.
Immune system relies on receptors to distinguish friendly from unfriendly bacteria
To help distinguish friendly from unfriendly microbes, the immune system relies on a complex array of receptors or specialized proteins that can sense patterns that are unique to bacteria, such as small pieces of their cell wall. The receptors bind to the fragments and send a signal to other parts of the immune system to come and collect and eliminate the corresponding pathogen, or if the fragment belongs to a friendly microbe then to come and help control its growth.
More than 58 variants of NOD2 have been linked to various diseases - 80% of them to Crohn's disease.
But things go wrong when one or more of these specialized bacteria-sensing proteins starts malfunctioning or mutates. For instance, it can send the wrong signal, or fail to send a signal at all, or not bind properly, causing the immune system to attack friendly bacteria. There is speculation that such breakdowns in the immune system are what leads to chronic inflammatory diseases like Crohn's.
One of the bacteria-sensing receptors, the protein NOD2 - short for nucleotide-binding oligomerization domain containing protein 2 - is already known to researchers. More than 58 variants of NOD2 have been linked to various diseases - 80% of them to Crohn's disease.
It was while they were investigating NOD2's signaling mechanism and how it breaks down, that the team came across another protein, HSP70 - heat shock protein 70 - a chaperone protein that helps proteins fold themselves into correct three-dimensional shapes.
Increasing expression of the bodyguard protein keeps bacteria-sensing protein stable
Prof. Grimes says they found if they increased the expression of HSP70, mutant versions of NOD2 found in Crohn's disease were able to sense bacterial cell wall fragments and send the right signals to the immune system. They had essentially found a fix for mutant NOD2, now they just needed to work out how the fix was working.
Further experiments showed that HSP70 acts as a bodyguard to the receptor protein and stabilizes it. The chaperone molecule "enhances NOD2's activity and increases its half-life," they note.
"Basically, HSP70 keeps the protein around - it kind of watches over and protects NOD2, and keeps it from going in the cellular trash can," Prof. Grimes explains.
So far the team has only run tests using human cell lines. They are now planning to study human tissue through a collaboration with Nemours/A.I. duPont Hospital for Children to find out if levels of NOD2 can be controlled by varying expression of HSP70.
They also want to find out if mutated NOD2 leads to increased inflammation, and how the underlying signaling works.
Rates of Crohn's disease are increasing worldwide. In the US there are around 700,000 people with Crohn's, according to the Crohn's and Colitis Foundation of America. The disease affects men and women equally, and while it can occur at any age, it is more prevalent among young people between the ages of 15 and 35.
The researchers say that identifying proteins that interact with and help to stabilize NOD2 is an important first step to finding new treatments for Crohn's.
A grant from the National Institutes of Health helped to finance the study.
Meanwhile, Medical News Today recently learned how another group of researchers found how changes in gut bacteria may predict infection and inflammation before symptoms emerge. They believe their findings will help doctors better understand how foreign bacteria disrupt gut microbes, and from that find better treatments for gastrointestinal conditions.