World News – AU – Gut cells sound the alarm when parasites enter: Study

A chain reaction triggered by cells in the intestine alerts the immune system to the presence of the parasite Cryptosporidium, according to a study by researchers at the School of Veterinary Medicine.

To effectively fight an infection, the body must first sense that it has invaded, and then the affected tissue must send signals to the appropriate resources to fight the invader. Knowing more about these early stages of pathogen detection and response may provide important clues to scientists when it comes to preventing infections or treating inflammatory diseases that result from overactive immunity.

This was the intent of a new study conducted by researchers from the University of Pennsylvania School of Veterinary Medicine that looked at infection with the parasite Cryptosporidium. When the team looked for the first « danger signals » emitted by a host infected with the parasite, they did not attribute them to an immune cell, as expected, but to epithelial cells in the intestine, in which Cryptosporidium settles during an infection. These cells, known as enterocytes, take nutrients from the intestines. It was shown here that they alert the body to dangers via the molecular receptor NLRP6, which is part of the so-called inflammasome.

« You can think of the inflammasome as an alarm system in a house, » says Boris Striepen, professor in the Department of Pathobiology at Penn Vet and senior author of the paper, which is published in the journal Proceedings of the National Academy of Sciences. “It has various components – such as a camera that monitors the door and sensors on the windows – and, once triggered, amplifies these initial signals to warn of dangers and send a call for help. Cells have these different components too, and now we have perhaps the clearest example of how a particular receptor in the gut acts as a sensor for a major gut infection. ”

According to Striepen, researchers have typically focused on immune cells like macrophages and dendritic cells, which are the first to recognize foreign invaders. However, this new finding underscores that cells are usually not considered part of the immune system, in which case gut epithelial cells play a key role in triggering an immune response.

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

Striepen’s laboratory has paid close attention to Cryptosporidium, a leading cause of diarrheal disease which can be fatal in young children in resource-poor areas around the world. Cryptosporidium is also a threat to people in well-resourced settings, causing half of all water-borne disease outbreaks in the United States. In veterinary medicine, it is known to infect calves and stunt their growth. These infections have no effective treatment or vaccine.

In the current work, Striepen, Sateriale, and colleagues used a naturally occurring species of mouse Cryptosporidium that they recently discovered to mimic infection in humans in many ways. While the researchers knew that T cells help control the parasite in later stages of the infection, they looked for clues as to what happened first.

One important note is the unfortunate link between malnutrition and Cryptosporidium infection. An early infection with Cryptosporidium and the accompanying inflammation of the intestines predispose children to malnutrition and stunted growth. At the same time, malnourished children are more prone to infections. This can lead to a downward spiral, putting children at higher risk of fatal infections. The mechanisms behind this phenomenon are not well understood.

« This led us to believe that some of the hazard detection mechanisms that can trigger inflammation in the gut may also play a role in the larger context of this infection, » adds Striepen.

Together, these links inspired the research team to study the inflammasome and its effects 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 lacking this had a much higher rate of infection, » says Sateriale.

Further work showed that mice lacking caspase-1 only in intestinal epithelial cells suffered as much infections as mice completely lacking caspase-1, which shows the crucial role of the epithelial cell.

Consistent with this idea, the Penn Vet-led team showed that, of a large number of candidate receptors, only the loss of the NLRP6 receptor makes the infection uncontrollable. NLRP6 is a receptor that is restricted to epithelial barriers previously associated with capturing and maintaining the gut microbiome, bacteria that naturally colonize the gut. However, experiments showed that mice that were never exposed to bacteria and therefore had no microbiome activated their inflammasome even when infected with Cryptosporidium – a sign that this aspect of hazard signaling occurs as a direct reaction to a parasite infection and independently of the intestinal bacterial community.

To determine how triggering the intestinal inflammasome resulted in an effective response, the researchers examined some of the signaling molecules, or cytokines, typically associated with inflammasome activation. 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 if you add back IL-18 you can save these mice, » says Sateriale, almost reversing the effects of infection.

Striepen, Sateriale and colleagues believe that there is still much to be done to find a vaccine against Cryptosporidium. However, they say their findings help shed light on important aspects of the interplay between the parasite, immune system, and inflammatory response, relationships that can influence these translational targets.

In the future, look at the later stages of Cryptosporidium infection to see how the host successfully suppresses them. « Now that we understand how the 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 its growth and kill it? »

(This story was posted by a wire agency feed with no changes to the text. Only the heading was changed. )

Cell, Cryptosporidium, Parasitism, Small Intestine, Inflammation, Enterocytes, Research, Boris Striepen