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Published On April 28, 2021

BASIC RESEARCH

Made to Be Invaded

Mini gut models give scientists a front row seat to some of the most puzzling pathogen behaviors.

The foodborne bacteria Salmonella enterica begins its reproductive journey by hitching a ride on a tainted meal. After being swallowed it coasts to the hollow tube of the digestive tract, where it will grow and divide. But the bacterium must first propel itself through a 50-micron thick layer of viscous mucus in the walls of the intestines, using a whip-like flagellum as a kind of corkscrew. Once near the lining of the gut, it deploys a syringe-like protein to inject itself into a cell, where it can at last make copies of itself.

Despite Salmonella being one of the most common food-borne illnesses in the United States, the entire life cycle of the bacterium that causes it has been remarkably tricky to map. But by using organoids—tiny, lab-grown, three-dimensional tissues—researchers have at last been able to tease out this and other mysteries of infectious disease.

For Salmonella, researchers used an enteroid, a type of organoid grown from human intestinal cells. The detailed journey of Salmonella was caught on camera for the first time and published in the journal mBio in January. This deeper understanding of its life cycle could lead to smarter, more targeted treatments.

“Enteroids provide an excellent platform where you can test pathogenesis, immunity and response to therapeutics in something that looks much more like a human gut environment,” says Marcela Pasetti, immunologist at the University of Maryland School of Medicine.

For infectious disease researchers, these mini intestines and other organoids are quickly replacing cell culture and animal models. They have been especially helpful in studying intestinal diarrheal diseases, which are the second leading cause of death worldwide in children under the age of five. Because this model system is made from primary human cells, it provides a much more accurate picture for pathogens that reproduce within that specific kind of host cell.

Take the poliovirus, which generally infects gut cells in humans. In mouse models, however, the gut is not used as the main route of infection. “This is a huge discrepancy,” says Adithya Sridhar, a senior scientist in virology at Amsterdam University Medical Center in the Netherlands. “It means that in animal models you’re not studying the actual disease that is being caused by the virus.”

In a 2018 paper, a research team used enteroids to reveal a previously unknown protein that helps in poliovirus infection, a discovery that overturned long held beliefs about polio’s infection strategy.

Prior to using enteroids, Sridhar favored other techniques that used cell lines. But those presented other, troubling issues. Cell cultures are generally made from immortalized cancer cells, and viruses infecting them tend to accumulate mutations more quickly than they would in the outside world—perhaps because the virus is adapting to an unusual environment. According to Sridhar, this phenomenon calls into question whether cell cultures are a suitable model to observe normal human infection. Petra Geiser, infection biologist at Uppsala University in Sweden and co-author of the Salmonella study, agrees. “Cell cultures are made to survive so we can culture them easily,” Geiser says. “But that also means they are much more resistant to infection, because they don't die quickly. Their response is not natural.”

Geiser is excited about using enteroids to study infections caused by other enteropathogens. Shigella, for example, causes more than half a million deaths each year and is currently treated with antibiotics, though the emergence of resistant strains calls for new strategies. In 2019, an experiment by Christina Faherty, a molecular biologist at Massachusetts General Hospital, used enteroids to highlight how the bacteria adhere to epithelial cells (an important first step in infection). It also helped researchers test a novel therapy using phages—“good” viruses that can be targeted to attack harmful pathogens.

The next frontier will be to pair lab-grown human host cells with immune cells to more closely mimic actual infections. Efforts are already underway to combine immune cells such as human macrophages with enteroid cultures.

Pasetti’s lab has shown how immune cells extend projections into the hollow of the gut and how white blood cells called neutrophils move from one compartment of the gut to another. Work in her lab has also shed light on how dendritic cells, a first line of defense in the gut, make the gut lining stronger and scout between cells for pathogen threats.

According to Pasetti, who has authored several research papers on this subject, “these systems can tell us how the antibodies are working, what elements help to protect against pathogen and how could we identify effective therapeutics.”

As the organoid models evolve, she and others are eager for a front row seat as the battles between host and pathogen play out. “The system is becoming more sophisticated and generating more information,” says Pasetti. “That can ultimately be used to help develop good therapeutics and vaccines.”