The moist surfaces that line the body contain specialized molecules that help defend against microbes and prevent infections and inflammation. Among these protective molecules are lectins, a group of proteins that identify microbes and other cells by attaching to sugars on their surfaces.
Researchers at MIT have now identified one lectin with particularly strong antimicrobial effects against bacteria living in the gastrointestinal (GI) tract. The protein, called intelectin-2, attaches to sugar molecules on bacterial membranes. This interaction traps the bacteria and slows their growth. The protein can also link together components of mucus, reinforcing the mucus layer that protects 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,” says Laura Kiessling, the Novartis Professor of Chemistry at MIT and the senior author of the study.
Because of its broad antimicrobial activity, intelectin-2 may have potential as a therapeutic tool, the researchers say. It could also help reinforce the mucus barrier in people with conditions such as inflammatory bowel disease.
Amanda Dugan, a former MIT research scientist, and Deepsing Syangtan PhD ’24 are the lead authors of the study, which appears in Nature Communications.
A Multifunctional Immune Protein
Evidence suggests that the human genome encodes more than 200 lectins, which are carbohydrate-binding proteins involved in immune defense and communication between cells. Kiessling’s lab has been studying how lectins interact with carbohydrates and recently focused on a group known as intelectins. In humans, this family includes two proteins, intelectin-1 and intelectin-2.
Although these two lectins share a similar structure, intelectin-1 has a unique feature. It binds only to carbohydrates found on bacteria and other microbes. About a decade ago, Kiessling and her colleagues determined the structure of intelectin-1, but its precise biological functions are still not fully understood.
At that time, researchers suspected that intelectin-2 might also contribute to immune defense, although there was limited experimental evidence. Dugan, who was then a postdoctoral researcher in Kiessling’s lab, began investigating the role of intelectin-2 in more detail.
In humans, intelectin-2 is consistently produced by Paneth cells in the small intestine. In mice, however, the protein appears to be produced by mucus-secreting Goblet cells in response to inflammation or certain parasitic infections.
How Intelectin-2 Strengthens the Gut Barrier
The researchers discovered that intelectin-2 from both humans and mice can bind to a sugar molecule called galactose. This sugar is commonly found in mucins, the molecules that form mucus. When intelectin-2 attaches to these mucins, it links them together and strengthens the mucus barrier that protects the intestinal lining.
Galactose also appears in carbohydrates displayed on the surface of some bacterial cells. The team showed that intelectin-2 can attach to microbes carrying these sugars, including several pathogens known to cause gastrointestinal infections.
Over time, the trapped microbes begin to break apart, suggesting that intelectin-2 disrupts their cell membranes and ultimately kills them. This antimicrobial effect works against many different bacteria, including some that are resistant to conventional antibiotics.
The researchers believe these two functions help shield the GI tract from infection.
“Intelectin-2 first reinforces the mucus barrier itself, and then if that barrier is breached, it can control the bacteria and restrict their growth,” Kiessling says.
Potential for Treating Gut Diseases and Resistant Bacteria
In people with inflammatory bowel disease, levels of intelectin-2 can become either unusually low or unusually high. Reduced levels may weaken the mucus barrier, while excessive amounts could eliminate beneficial bacteria that normally inhabit the gut. The researchers suggest that therapies designed to restore balanced levels of intelectin-2 could help these patients.
“Our findings show just how critical it is to stabilize the mucus barrier. Looking ahead, we can imagine exploiting lectin properties to design proteins that actively reinforce that protective layer,” Kiessling says.
Intelectin-2 can also neutralize or eliminate pathogens such as Staphylococcus aureus and Klebsiella pneumoniae, which are often difficult to treat with antibiotics. Because of this ability, the protein may one day be developed into a new antimicrobial treatment.
“Harnessing human lectins as tools to combat antimicrobial resistance opens up a fundamentally new strategy that draws on our own innate immune defenses,” Kiessling says. “Taking advantage of proteins that the body already uses to protect itself against pathogens is compelling and a direction that we are pursuing.”
The research was funded by 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, a professor of medical microbiology and immunology at the University of California at Davis School of Medicine; Ramnik Xavier, a professor of medicine at Harvard Medical School and the Broad Institute of MIT and Harvard; and Katharina Ribbeck, the Andrew and Erna Viterbi Professor of Biological Engineering at MIT.