The intestinal cells sound the alarm when parasites enter

To effectively fight an infection, the body must first sense that it has been invaded, and then the affected tissue must send out signals to maternity sources to fight the invader. To learn more about these early stages of pathogen recognition and response, scientists can provide important clues when it comes to preventing infections or treating inflammatory diseases due to overactive immunity.

It was the intention behind a new study, led by researchers at the University of Pennsylvania School of Veterinary Science, to investigate infection with the parasite Cryptosporidium. When the team was looking for the very first hazard signal signals emitted by a host infected with the parasite, they did not detect it to an immune cell, as might be expected, but to epithelial cells in the intestines lies, where Cryptosporidium during an infection. These cells, known as enterocytes, take up nutrients from the intestines, and here they are shown to inform the body through the molecular receptor NLRP6, which is a component of what is known as inflammation.

“You can think of inflammation as an alarm system in a home,” says Boris Striepen, a professor in the Department of Pathobiology at Penn Vet and senior author of the article that appeared in the journal. Proceedings of the National Academy of Sciences. “It has different components – such as a camera that monitors the door and sensors on the windows – and once activated, it amplifies the first signals to warn of danger and to call for help. Cells also have these different components, and now we have given perhaps the clearest example of how a particular receptor in the gut acts as a sensor for a major intestinal infection. ‘

Striepen says that researchers have usually focused on immune cells, such as macrophages and dendritic cells, as the first to detect foreign invaders, but this new finding emphasizes that cells are not normally considered part of the immune system – in this case intestinal epithelial cells – plays key roles in how an immune response is initiated.

“There is a growing body of literature that really appreciates what epithelial cells do to help the immune system feel pathogens,” says Adam Sateriale, first author of the paper who was a postdoctoral fellow in Striepen’s laboratory and now runs his own laboratory. . Francis Crick Institute in London. “They seem to be a first line of defense against infection.”

Striepen’s laboratory has devoted considerable attention to Cryptosporidium, which is a major cause of diarrheal diseases that can be fatal in young children in areas poor in resources around the world. Cryptosporidium is also a threat to people in well-resource environments, causing half of all outbreaks of waterborne diseases in the United States. In veterinary medicine it is known that calves become infected, which slows down their growth. These infections have no effective treatment and no vaccine.

In the present work, Stripes, Saterials, and colleagues have used a naturally occurring species of mouse Cryptosporidium, which has recently been discovered to mimic human infection in many respects. While the researchers knew that T cells help control the parasite in later stages of infection, they began looking for clues as to what happens first.

One important clue is the unfortunate link between malnutrition and Cryptosporidium infection. Early infection with Cryptosporidium and the accompanying inflammatory bowel disease expose children to malnutrition and stunted growth; at the same time, malnourished children are more susceptible to infection. This can lead to a downward spiral, which puts children at greater risk for fatal infections. The mechanisms behind this phenomenon are not well understood.

“This has led us to think that some of the hazard detection mechanisms that can cause inflammation in the gut also play a role in the larger context of this infection,” Striepen adds.

These links together inspired the research team to take a closer look at the inflammatory atom and its impact on the course of infection in their mouse model. They did this by removing a key component of the inflammation, an enzyme called caspase-1. “It seems that animals that are missing it have had much higher infection levels,” says Sateriale.

Further work has shown that mice without caspase-1 only suffered infections in intestinal epithelial cells as high as those that did not have them, showing the crucial role of the epithelial cell.

Consistent with this idea, the Penn Vet-led team showed that only the loss of the NLRP6 receptor from a variety of candidate receptors leads to the failure to control the infection. NLRP6 is a receptor restricted to epithelial barriers that were previously linked to the observation and maintenance of the gut microbiome, bacteria that naturally colonize the gut. However, experiments have revealed that mice that were never exposed to bacteria and therefore did not have a microbiome also activated their inflammation during infection with Cryptosporidium – a sign that this aspect of danger is taking place in direct response to parasite infection. and independent of the intestinal bacterial community.

To find out how inflammation of the intestinal tract led to an effective response, the researchers looked at some of the signaling molecules, or cytokines, commonly associated with inflammation of inflammation. They found that infection leads to the release of IL-18, with animals lacking this cytokine, or the ability to release it, showing more serious infection.

“And if you add IL-18 again, you can save these mice,” says Sateriale, which almost reverses the effects of infection.

Stripes, Saterials and colleagues believe that much work still needs to be done to find a vaccine against Cryptosporidium. But they say their findings help shed light on important aspects of the interaction between the parasite, the immune system and the inflammatory response, the relationships that can inform these translation goals.

Looking ahead, they look at the later stages of Cryptosporidium infection to see how the host successfully dismantles it. “Now that we understand how infection is detected, we want to understand the mechanisms by which it is controlled,” says Sateriale. “After the system detects a parasite, what is being done to limit and kill their growth?”