Researchers at MIT have made a significant breakthrough by identifying a lectin with potent antimicrobial properties against bacteria residing in the gastrointestinal (GI) tract. Known as intelectin-2, this protein binds to sugar molecules on bacterial membranes, effectively trapping the bacteria and inhibiting their growth. Additionally, intelectin-2 can connect components of mucus, enhancing the protective mucus layer of the gut lining.
"What's remarkable is that intelectin-2 operates in two complementary ways. It helps stabilize the mucus layer, and if that barrier is compromised, it can directly neutralize or restrain bacteria that begin to escape," explains Laura Kiessling, the Novartis Professor of Chemistry at MIT and the study's senior author.
Given its extensive antimicrobial activity, intelectin-2 shows promise as a therapeutic agent, particularly for individuals suffering from conditions like inflammatory bowel disease.
The study's lead authors, Amanda Dugan, a former MIT research scientist, and Deepsing Syangtan, a PhD candidate, published their findings in Nature Communications.
A Multifunctional Immune Protein
Research indicates that the human genome encodes over 200 lectins, carbohydrate-binding proteins integral to immune defense and cellular communication. Kiessling's lab has been exploring how lectins interact with carbohydrates, focusing on a subgroup known as intelectins, which includes intelectin-1 and intelectin-2.
While both lectins share a similar structure, intelectin-1 uniquely binds only to carbohydrates found on bacteria and other microbes. A decade ago, Kiessling's team determined the structure of intelectin-1, but its specific biological roles remain largely elusive.
At the time, researchers suspected that intelectin-2 might play a role in immune defense, though experimental evidence was scarce. Dugan, then a postdoctoral researcher, began a detailed investigation into intelectin-2's function.
In humans, intelectin-2 is produced by Paneth cells in the small intestine, while in mice, it is generated by mucus-secreting Goblet cells in response to inflammation or parasitic infections.
How Intelectin-2 Strengthens the Gut Barrier
The team discovered that both human and mouse intelectin-2 can bind to galactose, a sugar commonly found in mucins, the molecules that constitute mucus. When intelectin-2 binds to these mucins, it links them together, thereby fortifying the mucus barrier that safeguards the intestinal lining.
Furthermore, galactose also appears on the surface of certain bacterial cells. The research demonstrated that intelectin-2 can attach to these microbes, including various pathogens known to cause gastrointestinal infections.
Over time, the trapped bacteria begin to disintegrate, indicating that intelectin-2 disrupts their cell membranes and ultimately eliminates them. This antimicrobial action is effective against a range of bacteria, including those resistant to conventional antibiotics.
According to Kiessling, "Intelectin-2 first reinforces the mucus barrier itself, and then if that barrier is breached, it can control the bacteria and restrict their growth."
Potential for Treating Gut Diseases and Resistant Bacteria
In individuals with inflammatory bowel disease, levels of intelectin-2 can fluctuate significantly. Low levels may compromise the mucus barrier, while excessive levels could eradicate beneficial gut bacteria. Therapies aimed at restoring balanced intelectin-2 levels could be beneficial for these patients.
"Our findings underscore the importance of stabilizing the mucus barrier. Looking ahead, we envision utilizing lectin properties to engineer proteins that actively reinforce this protective layer," Kiessling notes.
Intelectin-2 also has the potential to neutralize pathogens like Staphylococcus aureus and Klebsiella pneumoniae, which are often challenging to treat with antibiotics. This capability suggests that the protein may evolve into a new antimicrobial treatment.
"Leveraging human lectins as tools against antimicrobial resistance represents a groundbreaking strategy that taps into our innate immune defenses," Kiessling concludes. "Utilizing proteins that the body naturally employs for pathogen protection is an exciting direction for future research."
This research received funding from the National Institutes of Health Glycoscience Common Fund, the National Institute of Allergy and Infectious Disease, the National Institute of General Medical Sciences, and the National Science Foundation.
Other contributors to the study include Charles Bevins from the University of California at Davis, Ramnik Xavier from Harvard Medical School, and Katharina Ribbeck from MIT.
