by Massachusetts Institute of Technology
researchers have identified molecules found in mucus that can block
cholera infection by interfering with the genes that cause the microbe
to switch into a harmful state.
protective molecules, known as glycans, are a major constituent of
mucins, the gel-forming polymers that make up mucus. The MIT team
identified a specific type of glycan that can prevent Vibrio cholerae
from producing the toxin that usually leads to severe diarrhea.
these glycans could be delivered to the site of infection, they could
help strengthen the mucus barrier and prevent cholera symptoms, which
affect up to 4 million people per year. Because glycans disarm bacteria
without killing them, they could be an attractive alternative to
antibiotics, the researchers say.
antibiotics, where you can evolve resistance pretty quickly, these
glycans don't actually kill the bacteria. They just seem to shut off
gene expression of its virulence toxins, so it's another way that one
could try to treat these infections," says Benjamin Wang Ph.D. '21, one
of the lead authors of the study.
Takagi Ph.D. '22 is also a lead author of the paper. Katharina Ribbeck,
the Andrew and Erna Viterbi Professor of Biological Engineering at MIT,
is the senior author of the study, which appears today in the EMBO Journal.
key members of the research team are Rachel Hevey, a research associate
at the University of Basel; Micheal Tiemeyer, a professor of
biochemistry and molecular biology at
the University of Georgia; and Fitnat Yildiz, a professor of
microbiology and environmental toxicology at the University of
California at Santa Cruz.
recent years, Ribbeck and others have discovered that mucus, which
lines much of the body, plays a key role in controlling microbes.
Ribbeck's lab has showed that glycans—complex sugar molecules found in
mucus—can disable bacteria such as Pseudomonas aeruginosa, and the yeast
Candida albicans, preventing them from causing harmful infections.
of Ribbeck's previous studies have focused on lung pathogens, but in
the new study, the researchers turned their attention to a microbe that
infects the gastrointestinal tract. Vibrio cholerae, which is often
spread through contaminated drinking water, can cause severe diarrhea
and dehydration. Vibrio cholerae comes in many strains, and previous
research has shown that the microbe becomes pathogenic only when it is
infected by a virus called CTX phage.
phage carries the genes that encode the cholera toxin, which is really
what's responsible for the symptoms of severe cholera infection," Wang
order for this "toxigenic conversion" to occur, the CTX phage must bind
to a receptor on the surface of the bacteria known as the toxin
co-regulated pilus (TCP). Working with mucin glycans purified from the
pig gastrointestinal tract, the MIT team found that glycans suppress the
bacteria's ability to produce the TCP receptor, so the CTX phage can no
longer infect it.
researchers also showed that exposure to mucin glycans dramatically
alters the expression of many other genes, including those required to
produce the cholera toxin. When the bacteria were exposed to these
glycans, they produced almost no cholera toxin.
When Vibrio cholerae infects the epithelial cells that line the gastrointestinal tract,
the cells begin overproducing a molecule called cyclic AMP. This causes
them to secrete massive amounts of water, leading to severe diarrhea.
The researchers found that when they exposed human epithelial cells to Vibrio cholerae that had been disarmed by mucin glycans, the cells did not produce cyclic AMP or start leaking water.
researchers then investigated which specific glycans might be acting on
Vibrio cholerae. To do that, they worked with Hevey's lab to create
synthetic versions of the most abundant glycans found in the naturally
occurring mucin samples they were studying. Most of the glycans they
synthesized have structures known as core 1 or core 2, which differ
slightly in the number and type of monosaccharides they contain.
researchers found that core 2 glycans played the biggest role in taming
cholera infection. It is estimated that 50 to 60 percent of people
infected with Vibrio cholerae are asymptomatic, so the researchers
hypothesize that the symptomatic cases may occur when these
cholera-blocking mucins are missing.
findings suggest that maybe infections occur when the mucus barrier is
compromised and is lacking this particular glycan structure," Ribbeck
is now working on ways to deliver synthetic mucin glycans, possibly
along with antibiotics, to infection sites. Glycans on their own cannot
attach to the mucosal linings of the body, so Ribbeck's lab is exploring
the possibility of tethering the glycans to polymers or nanoparticles,
to help them adhere to those linings. The researchers plan to begin with
lung pathogens, but also hope to apply this approach to intestinal
pathogens, including Vibrio cholerae.
want to learn how to deliver glycans by themselves, but also in
conjunction with antibiotics, where you might need a two-pronged
approach. That's our main goal now because we see so many pathogens are
affected by different glycan structures," Ribbeck says.
More information: Host-derived O-glycans inhibit toxigenic conversion by a virulence-encoding phage in Vibrio cholerae, The EMBO Journal (2022). www.embopress.org/doi/full/10. … 5252/embj.2022111562
Journal information: EMBO Journal
Provided by Massachusetts Institute of Technology