Researchers from the School of Medicine found that the cells lining the uterus are able to counteract the Cryptosporidium parasite with the help of a self-generated chain reaction.
To fight infection effectively, the body must first sense that it has been attacked, then the affected substance must send signals to corral facilities to fight the infection. attack. Finding out more about these early stages of pathogen identification and response may provide scientists with vital insights when it comes to preventing or treating inflammatory diseases. resulting from overactive immunity.
That was the intent behind a new study, led by researchers at the University of Pennsylvania School of Medicine, examining infection with the parasite Cryptosporidium. When the team looked for the first signs of “danger” sent out by a host called the parasite, they found that it was not going to an immune cell, as might be expected, but to epithelial cells that lining of the abdomen, where Cryptosporidium establishes a store during infection.
Called enterocytes, these cells take up nutrients from the gut, and here they have been shown to warn the body of danger through the molecular receptor NLRP6, which is part of the object called the inflammasome.
“You can think of the inflammasome as a home alarm system,” says Boris Striepen, professor in the Department of Pathobiology at Penn Vet and senior author of the paper, which publishes in the journal Proceedings of the National Academy of Sciences. “There are a number of components – such as a door-facing camera, and window sensors – and once triggered it will extend these first signals to warn of danger and alert. for help.
Cells also have these different components, and now we have provided the clearest example yet of how a specific receptor in the spleen acts as a sensing device for an important infectious disease. As usual, Striepen says, researchers have focused on immune cells. , such as macrophages and dendritic cells, are the first to be discovered by foreign invaders, but this new finding confirms that cells are not usually seen as part of the immune system – in this case epithelial cells intestinal – plays key roles in how the immune response is triggered.
“A growing body of literature values the contribution of epithelial cells to helping the immune system detect pathogens,” said Adam Sateriale, the paper’s first author. postdoc in the Striepen laboratory and now directs its own laboratory at the Francis Crick Institute in London. “They seem to be the first line of defense against infection. ”
Striepen’s lab has given a lot of attention to Cryptosporidium, which is a major cause of potentially fatal diarrheal disease in young children in uninhabited areas around the world. Cryptosporidium is also a threat to humans in well-resourced environments, causing half of all waterborne disease outbreaks in the United States. In veterinary medicine, it is famous for ingesting calves, stopping their growth. These diseases are not effectively treated and there is no vaccine.
In the current work, Striepen, Sateriale, and colleagues exploited a naturally occurring species of Cryptosporidium mouse that they recently discovered mimicking human disease in many ways. While the researchers knew that T cells helped control the parasite at later stages of the disease, they began to look to find out what happens first.
One important reputation is the unfortunate link between malnutrition and Cryptosporidium disease. Early infection with Cryptosporidium and accompanying inflammation of the abdomen leads to malnutrition and stunted growth; at the same time, malnourished children are more prone to diseases. This can lead to a downward spiral, putting children at greater risk of fatal diseases. The mechanisms behind this phenomenon are not fully understood.
“That led us to think that some of the risk-sensing mechanisms that may trigger inflammation in the spleen may play a role in a larger context of this disease,” Striepen said. Overall these links prompted the research team to take a closer look at the inflammasome and its impact on the course of infection in their mouse model. They did this by removing a key component of the inflammasome, an enzyme called caspase-1. “It appears that missing animals had much higher levels of disease,” Sateriale says.
Further work showed that mice lacking caspase-1 directly in intestinal epithelial cells suffered from infections as high as those not at all, revealing the vital role of the epithelial cell.
Consistent with this view, the team led by Penn Vet, out of several candidate receptors, showed that only the loss of the NLRP6 receptor leads to a failure in disease control. NLRP6 is a receptor restricted to previously bound epithelial barriers by sensitizing and maintaining the intestinal microorganism, bacteria that naturally settle on the gut. However, tests showed that mice were never exposed to germs, and therefore did not have midges, they activated their inflammasome after infection with Cryptosporidium – an indication that this aspect of risk signaling occurs as direct response to parasitic disease and independent of the gut bacterial community.
To find out how stimulation of the intestinal inflammasome stimulated an effective response, the researchers looked at some of the signaling molecules, or cytokines, usually associated with inflammasome activity. They found that infection leads to the release of IL-18, with those animals lacking this cytokine or the ability to release it showing a more severe infection. “And when you put IL-18 back, you can save those mice,” Sateriale says, almost reversing the effects of disease.
Striepen, Sateriale, and colleagues believe there is much more work to be done to find a vaccine against Cryptosporidium. But they say their findings help clarify important aspects of the interplay between the parasite, the immune system, and the inflammatory response, relationships that may inform the these translation goals.
Moving forward, they are looking forward to the later stages of Cryptosporidium infection to see how the host successfully reduces it. “Now that we understand how the disease is detected, we want to understand the ways in which it is controlled,” says Sateriale. “Once the system has become aware of a parasite, what is being done to limit their growth and kill them? ”
(This story was published from a wire group group without altering the text.)
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