Mucosal surfaces that line the body are embedded with defensive molecules that help keep microbes from causing inflammation and infections. Among these molecules are lectins, proteins that recognize microbes and other cells by binding to sugars found on cell surfaces.
Researchers headed by a team at the Massachusetts Institute of Technology (MIT) have now found that one of these lectins, known as intelectin-2 (hItln2), has broad-spectrum antimicrobial activity against bacteria found in the gastrointestinal tract. Their preclinical studies showed that this lectin binds to sugar molecules found on bacterial membranes, trapping the bacteria and hindering their growth. Additionally, the study found that intelectin-2 can crosslink molecules that make up mucus, helping to strengthen the mucus barrier.
The team suggests that this kind of broad-spectrum antimicrobial activity could make intelectin-2 useful as a potential therapeutic. It could also be harnessed to help strengthen the mucus barrier in patients with disorders such as inflammatory bowel disease. “What’s remarkable is that intelectin-2 operates in two complementary ways,” said Laura Kiessling, PhD, the Novartis Professor of Chemistry at MIT. “It helps stabilize the mucus layer, and if that barrier is compromised, it can directly neutralize or restrain bacteria that begin to escape … 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 is senior author of the researchers’ published report in Nature Communications, titled “Intelectin-2 is a broad-spectrum antimicrobial lectin,” in which they concluded, “The dual functions of Itln2 suggest it evolved to address a specific challenge in barrier immunity: the generation of antimicrobial barriers that are both structurally robust and functionally active.” The paper’s co-first authors are Amanda Dugan, PhD, a former MIT research scientist, and Deepsing Syangtan, PhD.
Current evidence suggests that the human genome encodes more than 200 lectins. These carbohydrate-binding proteins play a variety of roles in the immune system and in communication between cells. “Kiessling’s lab, which has been exploring lectin-carbohydrate interactions, recently became interested in a family of lectins called intelectins. “The intelectins, or X-type lectins, are secreted at mucosal surfaces and, though purported to play a role in host defense against microbes, aspects of their function are still unclear,” the authors wrote.
In humans, this family includes two lectins, intelectin-1 and intelectin-2. Those two proteins have very similar structures, but intelectin-1 is distinctive in that it only binds to carbohydrates found in bacteria and other microbes. “Human and mouse intelectin-1 (Itln1) are constitutively expressed in the intestines and exclusively recognize a set of microbial glycans,” the researchers continued. About 10 years ago, Kiessling and her colleagues were able to discover intelectin-1’s structure, but its functions are still not fully understood.
At that time, scientists hypothesized that intelectin-2 might play a role in immune defense, but there hadn’t been many studies to support that idea. Dugan, then a postdoc in Kiessling’s lab, set out to learn more about intelectin-2.
In humans, intelectin-2 is produced at steady levels by Paneth cells in the small intestine, but in mice, its expression from mucus-producing Goblet cells appears to be triggered by inflammation and certain types of parasitic infection. “Mouse intelectin-2 (mItln2) has been reported to be upregulated during nematode infections,” the investigators stated. “Human intelectin-2 (ITLN2, henceforth hItln2) is constitutively expressed and restricted to the small intestine.”
Through their new study, the scientists found that both human and mouse intelectin-2 bind to a sugar molecule called galactose. This sugar is commonly found in molecules called mucins that make up mucus. The studies showed that when intelectin-2 binds to these mucins, it helps to strengthen the mucus barrier. “… we find that mouse intelectin-2 (mItln2) and human intelectin-2 (hItln2) engage and crosslink mucins via carbohydrate recognition,” they stated.
Galactose is also found in carbohydrates displayed on the surfaces of some bacterial cells. The researchers showed that intelectin-2 can bind to microbes that display these sugars, including many pathogens that cause GI infections. The study results also found that over time, these trapped microbes eventually disintegrate, suggesting that the protein is able to kill them by disrupting their cell membranes. This antimicrobial activity appears to affect a wide range of bacteria, including some that are resistant to traditional antibiotics.
“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 said.
The investigators believe that these dual functions help to protect the lining of the GI tract from infection. They stated, “Our data support a model in which Itln2 protects the host against microbial threats: a defensive role in which it binds mucins to reinforce the mucosal environment and an offensive role in which it reduces bacterial burden via its antimicrobial activities.”
Because intelectin-2 can neutralize or eliminate pathogens such as Staphylococcus aureus and Klebsiella pneumoniae, which are often difficult to treat with antibiotics, it could potentially be adapted as an antimicrobial agent. “Harnessing human lectins as tools to combat antimicrobial resistance opens up a fundamentally new strategy that draws on our own innate immune defenses,” Kiessling suggested. “Taking advantage of proteins that the body already uses to protect itself against pathogens is compelling and a direction that we are pursuing.”
In patients with inflammatory bowel disease, intelectin-2 levels can become abnormally high or low. Low levels could contribute to degradation of the mucus barrier, while high levels could kill off too many beneficial bacteria that normally live in the gut. Finding ways to restore the correct levels of intelectin-2 could be beneficial for those patients, the researchers suggested. In their paper, they concluded, “These findings advance our understanding of intelectins as crucial players in host–microbe interactions, with implications for maintaining mucosal health in both homeostatic and diseased states.
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