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 “danger” signals emitted by a host called the parasite, they found them not to be immune cells, as might be expected, but to lining epithelial cells. inside, 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 – like a camera that looks at the door, and sensors on the windows – and once it is triggered it will extend these first signals to warn of danger and alert. Cells also have these different parts, and we have now given the clearest example of how a specific receptor in the gut acts as a sensory device for an important infectious disease. . “
As always, Striepen says, researchers have focused on immune cells, such as macrophages and dendritic cells, as the first to be discovered by foreign invaders, but this new finding confirms that thinking of cells as part of the immune system – in this case. epithelial cells – play key roles in how the immune response is triggered.
“There is a growing body of literature that greatly values what epithelial cells do to help the immune system detect pathogens,” says Adam Sateriale, the first author of the paper which was emailed in Striepen ‘s laboratory and now runs 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 notorious for suffering 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 species of Cryptosporidium mouse that they naturally discovered that resembles human disease in many ways. While the researchers knew that T cells were helping to 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 abdominal inflammation predict children 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 miracle are not well understood.
“That led us to think that some of the risk-sensing devices that may be moving inflammation in the gut may play a role in a larger context of this disease,” Striepen notes. add.
Taken together, these links prompted the research team to take a closer look at the flu 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 turns out that animals that lose this had much higher disease rates,” Sateriale says.
Further work showed that mice lacking caspase-1 directly in intestinal epithelial cells suffered as high infections as those not at all, demonstrating the importance 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 infection.
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 a disease is detected, we want to understand the ways in which it is controlled,” says Sateriale. “After the system senses a parasite, what are they done to limit their growth and kill them? “
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Striepen and Sateriale coauthors on the paper were Jodi A. Gullicksrud at Penn Vet, Julie B. Engiles, Briana McLeod, Emily Dugler, Jorge Henao-Mejia, Igor E. Brodsky, and Christopher Hunter, and Ting Zhou at Yale University and Aaron M. Ring.
Boris Striepen is a professor in the Department of Pathobiology at the University of Pennsylvania School of Medicine.
Adam Sateriale is a group director at the Francis Crick Institute. He completed a postdoctoral fellowship at Striepen’s laboratory.
The study was supported by the Bill and Melinda Gates Foundation (Grant 1183177) and the National Institutes of Health (grants AI148249, AI137442, and AI055400).