A chain reaction led by cells lining the intestines tips the system off to the presence of the parasite Cryptosporidium, consistent with a study led by researchers within the School of medicine .

To effectively combat an infection, the body first has got to sense it has been invaded, then the affected tissue must send signals to corral resources to fight the intruder. Knowing more about these early stages of pathogen recognition and response may provide scientists with crucial clues when it involves preventing infections or treating inflammatory diseases resulting from overactive immunity.

That was the intent behind a replacement study, led by researchers at the University of Pennsylvania School of medicine , examining infection with the parasite Cryptosporidium. When the team searched for the very first “danger” signals emitted by a number infected with the parasite, they traced them to not an immune cell, as may need been expected, but to epithelial cells lining the intestines, where Cryptosporidium sets up shop during an infection. referred to as enterocytes, these cells take up nutrients from the gut, and here they were shown to alert the body to danger via the molecular receptor NLRP6, which may be a component of what is referred to as the inflammasome.

“You can believe the inflammasome as an alarm during a house,” says Boris Striepen, a professor within the Department of Pathobiology at Penn Vet and senior author on the paper, which is publishing within the journal Proceedings of the National Academy of Sciences. “It has various components–like a camera that watches the door, and sensors on the windows–and once triggered it amplifies those first signals to warn of danger and send a involve help. Cells have these different components also , and now we’ve provided maybe the clearest example yet of how a specific receptor within the gut is acting as a sensor for a crucial intestinal infection.”

Typically, Striepen says, researchers have focused on immune cells, like macrophages and dendritic cells, as being the primary to detect foreign invaders, but this new finding underscores that cells not normally thought of as a part of the system –in this case intestinal epithelial cells–are playing key roles in how an immune reaction gets launched.

“There may be a growing body of literature that’s really appreciating what epithelial cells do to assist the system sense pathogens,” says Adam Sateriale, first author on the paper who was a postdoc in Striepen’s lab and now leads his own lab at the Crick Institute in London. “They seem to be the primary line of defence against infection.”

Striepen’s lab has devoted considerable attention to Cryptosporidium, which may be a leading explanation for the diarrheal disease which will be deadly in young children in resource-poor areas round the world. Cryptosporidium is additionally a threat to people in well-resourced environments, causing half all water-borne disease outbreaks within the us . In medicine , it’s known for infecting calves, stunting their growth. These infections haven’t any effective treatment and no vaccine.

In the current work, Striepen, Sateriale, and colleagues took advantage of a present species of mouse Cryptosporidium that they recently discovered mimics human infection in many respects. While the researchers knew T cells help control the parasite in later stages of infection, they began trying to find clues on what happens first.

One important clue is that the unfortunate linkage between malnutrition and Cryptosporidium infection. Early infection with Cryptosporidium and therefore the inflammation of the intestine that goes along side it predisposes children to malnutrition and stunted growth; at an equivalent time, children who are malnourished are more vulnerable to infection. this will cause a downward spiral, putting children at greater risk of deadly infections. The mechanisms behind this phenomenon aren’t well understood.

“That led us to think that perhaps a number of the danger-sensing mechanisms which will drive inflammation within the gut also play a task within the larger context of this infection,” adds Striepen.

Together these linkages inspired the research team to seem more closely at the inflammasome and its impact on the course of infection in their mouse model. They did so by removing a key component of the inflammasome, an enzyme called caspase-1. “It seems that animals that are missing this had much higher levels of infection,” Sateriale says.

Further work demonstrated that mice lacking caspase-1 just in intestinal epithelial cells suffered infections as high as those lacking it completely, demonstrating the crucial role of the somatic cell .

Consistent with this concept , the Penn Vet-led team showed that, out of a spread of candidate receptors, only loss of the NLRP6 receptor results in failure to regulate the infection. NLRP6 may be a receptor restricted to epithelial barriers previously linked to sensing and maintaining the intestinal microbiome, bacteria that naturally colonize the gut. However, experiments revealed that mice never exposed to bacteria, and thus lacked a microbiome, also activated their inflammasome upon infection with Cryptosporidium–a sign that this aspect of danger signalling occurs in direct response to parasite infection and independent of the gut bacterial community.

To trace how triggering the intestinal inflammasome led to an efficient response, the researchers checked out a number of the signalling molecules, or cytokines, typically related to inflammasome activation. They found that infection results in the discharge of IL-18, with those animals that lack this cytokine or the power to release it showing more severe infection.

“And once you add back IL-18, you’ll rescue these mice,” Sateriale says, nearly reversing the consequences of infection.

Striepen, Sateriale, and colleagues believe there is a lot more work to be done to seek out a vaccine against Cryptosporidium. But they assert their findings help illuminate important aspects of the interplay between the parasite, the immune system, and therefore the inflammatory response, relationships which will inform these translational goals.

Moving forward, they’re looking to the later stages of Cryptosporidium infection to ascertain how the host successfully tamps it down. “Now that we understand how the infection is detected, we’d wish to understand the mechanisms by which it’s controlled,” Sateriale says. “After the system senses a parasite, what’s done to limit their growth and kill them?”—ANI