Dennis Kasper. Image: Rick Groleau
At a glance:
- Kasper discovered the language in which gut bacteria communicate to educate the immune system.
- His work sets the stage for the design of microbe-based treatments for autoimmune diseases and other immune-mediated disorders.
- The Paul Ehrlich and Ludwig Darmstaedter Prize is Germany’s most prestigious biomedical award.
Harvard Medical School researcher Dennis Kasper has been named the recipient of the 2024 Paul Ehrlich and Ludwig Darmstaedter Prize, Germany’s most prestigious medical award.
This award honors scientists who have made critical contributions in the fields of immunology, cancer research, hematology, microbiology and chemotherapy — areas transformed by the work of Nobel Prize laureate Paul Ehrlich, the German physician-scientist considered one of the founding fathers of immunology and a pioneer in chemotherapy.
The award, which will be presented at a March 14 ceremony in Frankfurt, comes with €120,000 (approximately $130,000).
Kasper, the William Ellery Channing Professor of Medicine at HMS, is being recognized for his transformative contributions to elucidating the mechanisms by which gut microbes interact directly and indirectly with the immune system to ensure its healthy development.
Kasper’s work has opened up a new dynamic field of research and laid the groundwork for the treatment of autoimmune diseases and other immune-mediated disorders. Importantly, his work goes beyond mere association and, for the first time, established a causal link between a specific gut microbe and immune system response.
“Dennis Kasper was the first to succeed in uncovering communication channels in the superorganism that humans and their microbiome form,” said Thomas Boehm, chairman of the scientific council of the Paul Ehrlich Foundation. “Through him, we have learned which signals intestinal bacteria use in our immune system to ensure a healthy balance between aggressiveness and dampening of inflammation. This will have far-reaching clinical consequences.”
Learning the language of microbes
Around 10 trillion bacteria live in the human colon, making up the main part of the human microbiome, the collection of microorganisms that inhabit the human body. A growing body of evidence points to the myriad roles that these microorganisms play in human health.
But precisely how bacteria interact with their hosts’ immune systems has remained poorly understood. Kasper’s research has shed light on this interplay primarily using a microorganism called Bacteroides fragilis.
He discovered two specific molecules used by this gut microbe to train the immune system of its host. Kasper’s research showed that chemical signals sent by the microbe act to modulate the immune system and rein it in from launching an attack on its own tissues and organs.
B. fragilis is a bacterial species that colonizes the human intestines soon after birth. Kasper began to study this penicillin-resistant bacterium in the mid-1970s for its role in often-fatal infections that typically occur as a result of injury and subsequent invasion of the normally sterile abdominal cavity.
Within the intact intestine, however, B. fragilis is harmless. Why?
How a microbe issues its commands
To protect themselves from the environment, some bacteria form a capsule. Kasper discovered that in B. fragilis, this capsule is characterized by an extraordinary variability.
While most bacterial capsules are made of a single sugar molecule, B. fragilis can produce eight different ones and combine them into new patterns. In this way, it appears to the host immune system in constantly changing “clothing” and evades recognition.
To do this, B. fragilis primarily uses the most commonly expressed of these capsule-making sugars, which Kasper named PSA, a large molecule made up of as many as 200 units of four different sugars linked together and attached to the capsule’s membrane with a fatty anchor.
Furthermore, Kasper discovered that PSA communicates with a class of immune cells called dendritic cells that act as sentinels surveying the body for pathogens and signaling the immune system when they detect one.
Kasper’s research demonstrated that dendritic cells take up the bacterial sugar, process it, and display it on their surface, thereby stimulating the production of certain T cells, the body’s most powerful immune cells.
Kasper’s work showed that PSA can induce dendritic cells to stimulate regulatory T cells — those charged with reining in the immune system from overacting to ensure self-tolerance — to produce a key anti-inflammatory molecule called interleukin-10. Kasper thus deciphered in detail the signaling pathways through which PSA exerts this immune-modulating effect.
The discovery redefined the scientific understanding of a major surveillance-and-detection pathway in immunology, known as the MHC-II pathway. Before Kasper’s discovery, this mechanism was believed to be activated only by foreign proteins invading from the outside.
Kasper’s work, however, demonstrated that a resident microbe that produces bacterial sugars that he called zwitterionic polysaccharides can also activate this pathway and provide a balance between different types of T cells.
B. fragilis controls the maturation of immune-suppressing regulatory T cells in the host via the PSA molecule throughout life. However, Kasper went on to show that the microbe uses yet another molecule, albeit in a time-limited fashion, to regulate early immune system development in infancy.
The molecule, a lipid called GSL-Bf717, is a fat-like substance that in the weeks and months after birth inhibits the proliferation of natural killer T (NKT) cells. NKT can trick the immune system into excessive inflammatory responses and induce it to react against its own tissues and organs.
The bacterial lipid bears structural similarity to molecules that promote NKT proliferation. Because of this resemblance, Kasper’s work showed, this bacterial fatty molecule displaces many of these NKT-promoting molecules from their binding sites and prevents the formation of an oversized NKT pool.
Research has shown that mice exposed to the bacterial lipid as newborns have a notably lower risk of developing the autoimmune disease ulcerative colitis.
The anti-inflammatory effects of B. fragilis, or similar molecules made by other bacteria, appear to extend beyond the gut. These molecules prevent not only chronic intestinal inflammation but also allergic conditions like asthma.
Kasper’s discoveries have also sparked research into the signaling axis between the gut and the brain. Emerging evidence points to the role of this bacterial sugar in counteracting the breakdown of the protective myelin sheaths that coat nerve fibers, a process that goes awry in multiple sclerosis.
Adapted from a Goethe University news release.
