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Sara Clasen of the Department of Microbiome Science at the Max Planck Institute Tübingen receives the NOSTER & Science Microbiome Prize for outstanding work on how the innate immune system can differentiate between beneficial and pathogenic gut bacteria. Clasen’s award-winning essay, now published in Science, elucidates how so-called “silent flagellins” of harmless microbes circumvent triggering a pro-inflammatory response in the host. Deepening our understanding of these flagellins may further future advances in vaccine research.
The innate immune system is the first line of defense against pathogens: it immediately reacts to antigens entering the body. To do this, it recruits immune receptors, which bind to pathogen-associated ligands. But these molecules are not only produced by disease agents, but often belong to microbes that are harmless or even beneficial to the human host. How the host immune system can tolerate ligands from non-pathogens while recognizing those from pathogens is not fully understood.
This conundrum is the topic of Clasen’s essay entitled “The sound of silence”, wherein she expounds her recent research in the Department of Microbiome Science at the Max Planck Institute for Biology Tübingen. The article won her the NOSTER & Science Microbiome Prize, which aims to reward innovative research on the functional attributes of the microbiota that has potential to contribute to our understanding of health and disease, or to guide novel therapeutic interventions.
Separating friend from foe
Although her contribution is at the interface between immunology and microbiology, Clasen emphasizes that she is a trained cell biologist. It was during her PhD studies at Johns Hopkins School of Medicine in Baltimore that she fortuitously found her love for microbiology. Joining Ruth Ley’s Department in Tübingen led to a serendipitous confluence of interests: “At that time, Ruth, a huge pillar in the microbiome community, was wondering how host immune receptors tolerate friendly microbes while defending against pathogens”, Clasen recounts. “I was able to apply methods from cell and molecular biology to figure that out.”
Ley’s lab focused on the innate immune receptor TLR5, which binds to the ligand flagellin. Flagellin is used by many bacteria – pathogens and non-pathogens alike – to build hair-like appendages for locomotion. When TLR5 recognizes this protein, it can initiate a pro-inflammatory response to stave off the putative intruder.
Clasen and her collaborators characterized the interactions between TLR5 and over 100 flagellins produced by non-pathogens that reside in the human gut. The team discovered so-called "silent flagellins", which lack a secondary TLR5 binding site. As a consequence, they still bind to TLR5, but the resulting pro-inflammatory response is very weak. Further analyzes revealed that silent flagellins are ubiquitous in the human gut, but less abundant in populations from industrialized regions.
Silence or a whisper?
While reasons for this decrease and its consequences for human health remain unclear, the discovery of silent flagellins may one day have powerful medical applications: “What’s really fascinating is that innate immunity is required to jump-start an adaptive immune response”, Clasen highlights. Highly stimulatory flagellins are often used as adjuvants in vaccines to rev up the body’s reaction to an antigen. “The microbiome is a huge pool of potential adjuvants. Identifying silent flagellins which boost an adaptive immune response without eliciting inflammation could reduce the negative side-effects of vaccination.”
As for now, Clasen will move to Georgia State University (Atlanta) to investigate the signaling response silent flagellins might cause in the host. “Maybe”, Clasen muses, “they are not silent after all – they may actually be whispering to us.”
Sara Clasen, Ph.D.
Max Planck Institute for Biology Tübingen
Department of Microbiome Science
Max-Planck-Ring 5
72076 Tübingen, Germany
sara.clasen@tuebingen.mpg.de
[1] Clasen SJ: The sound of silence. Science 381,37-38 (2023). DOI: 10.1126/science.adi6265
[2] Clasen SJ, Bell MEW, Borbón A, Lee D, Henseler ZM, De La Cuesta-Zuluaga J, Parys K, Zou J, Wang Y, Altmannova V, Youngblut ND, Weir JR, Gewirtz AT, Belkhadir Y, Ley RE: Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5. Sci. Immunol. 8 (79), 2023. DOI: 10.1126/sciimmunol.abq7001.
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