In order for the body to fight off an infection, it must first become aware of an invading pathogen. A new study led by the University of Pennsylvania has revealed that the very first “danger” signals that are transmitted upon pathogen recognition can be traced to gut cells that line the intestines called enterocytes.
The researchers found that when a host is first infected by the parasite Cryptosporidium, the gut cells trigger a series of reactions that alert the immune system. The enterocytes alert the body to danger through the molecular receptor NLRP6, which is a component of the inflammasome.
“You can think about the inflammasome as an alarm system in a house. 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 call for help,” said study senior author Professor Boris Striepen.
“Cells have these different components as well, and now we’ve provided maybe the clearest example yet of how a particular receptor in the gut is acting as a sensor for an important intestinal infection.”
Typically, researchers have focused on immune cells, like macrophages and dendritic cells, as being the first to detect foreign invaders, but this new finding underscores that cells not normally thought of as part of the immune system are playing key roles in how an immune response gets launched, explained Professor Striepen.
“There is a growing body of literature that is really appreciating what epithelial cells are doing to help the immune system sense pathogens,” said study first author Adam Sateriale. “They seem to be a first line of defense against infection.”
A team in Professor Striepen’s lab has extensively studied Cryptosporidium, which is a leading cause of diarrheal disease that can be deadly in young children in resource-poor regions. Cryptosporidium also causes half of all water-borne disease outbreaks in the United States.
The current study was focused on a naturally occurring species of mouse Cryptosporidium that mimics human infection in many ways. The experts already knew that T cells help control the parasite in the later stages of infection, but they wanted to know more about the body’s initial response.
Early infection with Cryptosporidium, as well as the intestinal inflammation that it causes, predisposes children to malnutrition and stunted growth. At the same time, children who are malnourished are more susceptible to infection.
“That led us to think that maybe some of the danger-sensing mechanisms that can drive inflammation in the gut also play a role in the larger context of this infection,” said Professor Striepen.
Using the mouse model, the research team took a closer look at the inflammasome and its impact on the course of infection. They removed a key component of the inflammasome, an enzyme called caspase-1. “It turns out that animals that are missing this had much higher levels of infection,” said Sateriale.
Further analysis showed that mice lacking caspase-1 in their gut cells suffered infections as high as those lacking it completely, which demonstrates the critical role of the enterocytes.
The experts determined that out of various receptors, only the loss of the NLRP6 receptor compromised the body’s ability to control the parasitic infection. The NLRP6 receptor was previously linked to maintaining the intestinal microbiome.
To understand how triggering the intestinal inflammasome led to an effective response, the researchers looked at some of the signaling molecules, or cytokines, typically associated with inflammasome activation. They found that infection leads to release of IL-18, and animals that lacked this cytokine experienced more severe infection.
Next, the team plans to investigate the later stages of Cryptosporidium infection. “Now that we understand how infection is detected, we’d like to understand the mechanisms by which it is controlled,” said Sateriale. “After the system senses a parasite, what is done to restrict their growth and kill them?”
The study is published in the journal Proceedings of the National Academy of Sciences.