A recently uncovered protein in the gastrointestinal (GI) tract has the potential to neutralize a wide variety of bacteria, representing an exciting breakthrough in our understanding of immune defense mechanisms. Researchers at the Massachusetts Institute of Technology (MIT) have discovered that the mucosal surfaces lining our body contain special molecules designed to protect against inflammation and infections. Among these protective molecules are lectins, which are proteins that identify and bind to specific sugars on the surfaces of cells, including those of microbes.
One particular lectin, known as intelectin-2, exhibits a remarkable ability to combat bacteria present in the GI tract. This protein attaches to sugar molecules on bacterial membranes, effectively trapping these harmful microorganisms and inhibiting their growth. In addition, intelectin-2 can interact with components of mucus, which helps strengthen the protective mucus barrier that lines our intestines.
Laura Kiessling, the Novartis Professor of Chemistry at MIT and senior author of the study, explains, "What’s truly impressive about intelectin-2 is its dual functionality. It not only stabilizes the mucus layer, but if that barrier is compromised, it can directly neutralize or restrict bacteria that manage to escape." This broad-spectrum antimicrobial activity presents a promising avenue for future therapies, potentially offering a new way to enhance the mucus barrier in individuals suffering from conditions like inflammatory bowel disease.
The paper, co-authored by Amanda Dugan, a former MIT research scientist, and Deepsing Syangtan, a PhD student, was published today in Nature Communications.
A Multifunctional Protein
Current research indicates that humans possess over 200 different lectins, which are carbohydrate-binding proteins involved in various immune functions and cellular communication. Kiessling’s lab has focused on a family of lectins known as intelectins, which includes two members: intelectin-1 and intelectin-2. Both of these proteins possess similar structures; however, intelectin-1 is unique in that it binds exclusively to carbohydrates found in microbes. Approximately a decade ago, Kiessling and her team determined the structure of intelectin-1, but many of its functions remain a mystery.
At that time, scientists speculated that intelectin-2 might play a critical role in immune defense, yet there was limited research to substantiate this claim. Dugan, then a postdoctoral researcher in Kiessling's lab, took the initiative to investigate the functions of intelectin-2 more thoroughly.
In humans, intelectin-2 is consistently produced by Paneth cells located in the small intestine. In contrast, its expression in mice appears to be influenced by inflammation and certain parasitic infections, originating from mucus-producing Goblet cells.
In their latest study, the researchers discovered that both human and mouse intelectin-2 can bind to a sugar molecule known as galactose, which is prevalent in mucin molecules that constitute mucus. By binding to these mucins, intelectin-2 aids in bolstering the mucus barrier. Additionally, galactose is commonly found on the surfaces of some bacterial cells, and the researchers demonstrated that intelectin-2 could attach to microbial strains that express these sugars, including several pathogens responsible for gastrointestinal infections.
Remarkably, the researchers observed that over time, the trapped bacteria would eventually break down, indicating that intelectin-2 can effectively kill these pathogens by disrupting their cell membranes. This antimicrobial action appears to target a diverse range of bacteria, including those resistant to conventional antibiotics.
These two functions work synergistically to safeguard the GI tract lining from infections. As Kiessling summarizes, "Intelectin-2 first reinforces the mucus barrier itself, and then if that barrier is breached, it can manage the bacteria and limit their proliferation."
Fighting Off Infection
In individuals with inflammatory bowel disease, levels of intelectin-2 may fluctuate significantly, either becoming too low, which could lead to the breakdown of the mucus barrier, or too high, risking the elimination of beneficial gut bacteria. The researchers suggest that finding methods to adjust and restore optimal levels of intelectin-2 could greatly benefit these patients.
Kiessling emphasizes the importance of stabilizing the mucus barrier by stating, "Our findings highlight how crucial it is to maintain the integrity of the mucus barrier. Looking forward, we can envision utilizing lectin properties to develop proteins that actively strengthen that protective layer."
Given that intelectin-2 can neutralize challenging pathogens like Staphylococcus aureus and Klebsiella pneumoniae, which are often tough to treat with existing antibiotics, there’s potential for it to be adapted into a novel antimicrobial agent.
"Leveraging human lectins as tools to counteract antimicrobial resistance introduces a fundamentally innovative strategy that taps into our innate immune defenses," Kiessling states. "Utilizing proteins that our body already employs to fend off pathogens is a compelling direction we are pursuing."
This research received funding from several prestigious organizations, including the National Institutes of Health Glycoscience Common Fund, the National Institute of Allergy and Infectious Diseases, 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, Davis; Ramnik Xavier, a professor of medicine at Harvard Medical School and the Broad Institute; and Katharina Ribbeck, the Andrew and Erna Viterbi Professor of Biological Engineering at MIT.
