To effectively fight the infection, the body must first sense that it has been invaded, and then the affected tissue signals the resources of the enclosure to fight the intruder. Must be sent. Knowing more about these early stages of pathogen recognition and response may provide scientists with important clues regarding the prevention of infections and the treatment of inflammatory diseases caused by hyperimmunity.
That was the intent behind a new study of the parasite Cryptosporidium infection, led by researchers at the University of Pennsylvania Veterinary School. When the team sought the first “danger” signal from a host infected with the parasite, they did not call them immune cells, as expected, but the epithelial cells that line the intestines where Cryptosporidium stores. Tracked up to. Infection. These cells, known as enterocytes, have been shown to take up nutrients from the intestine and warn the body of danger via the molecular receptor NLRP6, which is a component of what is known here as the inflammasome. ..
“The inflammasome can be thought of as a home alert system,” said Boris Strypen, a professor of pathology and biology at the University of Pennsylvania and the lead author of a journal article. Minutes of the National Academy of Sciences.. “There are various components such as cameras that monitor doors and windows sensors, and when triggered, they amplify the first signal to warn of danger and ask for help. The cell also has these various components. It may have provided the clearest example to date of how certain receptors in the intestine function as sensors for important intestinal infections. “
Researchers have usually focused on immune cells, such as macrophages and dendritic cells, as the first to detect foreign invaders, according to Striepen, but this new discovery is that cells are part of the immune system. The case emphasizes that the intestinal epithelium is not usually considered. Cells — play an important role in how the immune response is initiated.
“There is a growing body of literature that really understands what epithelial cells are doing to help the immune system detect pathogens,” said a postdoc in Striepen’s lab, now his own. Adam Sateriale, the first author of the paper that leads the lab, said. Francis Crick Institute in London. “They seem to be the first line of defense against infection.”
Striepen’s lab has paid considerable attention to Cryptosporidium, a major cause of diarrheal disease that can be fatal to infants in resource-poor areas of the world. Cryptosporidium is also a threat to people in resource-rich environments, causing half of all water-borne infections in the United States. In veterinary medicine, it is known to infect calves and inhibit their growth. There are no effective cures or vaccines for these infections.
In the current study, Striepen, Sateriale and colleagues utilize the recently discovered naturally occurring species of mouse cryptosporidium to mimic human infection in many ways. Researchers knew that T cells could help control parasites in the later stages of infection, but began looking for clues as to what would happen first.
One of the important clues is the unfortunate link between malnutrition and Cryptosporidium infection. Early infection with Cryptosporidium and the associated inflammation of the intestines make children more susceptible to malnutrition and stunting. At the same time, malnourished children are more susceptible to infections. This can lead to a downward spiral, increasing the risk of fatal infections in children. The mechanism behind this phenomenon is not well understood.
“It made us think that some of the risk-sensing mechanisms that can cause intestinal inflammation can also play a role in the larger situations of this infection,” Striepen adds.
Together, these connections have led the team to investigate the effects of the inflammasome and its mouse models on the infectious process. They did so by removing an enzyme called caspase-1, an important component of the inflammasome. “We found that animals lacking this had much higher levels of infection,” says Sateriale.
Further studies have shown that mice lacking caspase-1 in intestinal epithelial cells alone have as high an infection as mice that are completely deficient, demonstrating the important role of epithelial cells. It was.
Consistent with this idea, the Pennsylvanet-led team showed that, of the various candidate receptors, only the loss of the NLRP6 receptor leads to failure to control infection. NLRP6 is a receptor restricted to the epithelial barrier that was previously associated with the sensing and maintenance of the gut microbiota, a bacterium that naturally colonizes the gut. However, experiments have shown that mice have never been exposed to bacteria and therefore lack of microbiota, which also activates the inflammasome when infected with Cryptosporidium.
To track how intestinal inflammasome induction resulted in an effective response, researchers typically found some of the signaling molecules or cytokines associated with inflammasome activation. I checked. They found that the infection led to the release of IL-18. Animals that lack this cytokine or the ability to release it show a more severe infection.
“And if you add IL-18 again, you can save these mice,” says Sateriale, which almost reverses the effects of the infection.
Striepen, Sateriale, and colleagues believe there is much more to be done to find a vaccine against Cryptosporidium. However, they say their findings help clarify important aspects of the interaction between parasites, the immune system, and the inflammatory response, and the relationships that may inform these translational goals. ..
In the future, they will look to the late stages of Cryptosporidium infection and see how the host successfully eliminates Cryptosporidium. “Now that we understand how infections are detected, we want to understand the mechanisms by which infections are controlled,” says Sateriale. “After the system detects parasites, what is done to limit their growth and kill them?”
New models for studying intestinal parasites have the potential to advance vaccine development
Adam Sateriale et al. , “The intestinal parasite Cryptosporidium is regulated by NLRP6-dependent enterocyte-specific inflammasomes.” PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.2007807118
Courtesy of the University of Pennsylvania
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