UC Davis researchers have shown how the innate immune system distinguishes between dangerous pathogens and friendly microbes.
Like burglars entering a house, hostile bacteria give themselves away by breaking into cells. However, sensing proteins instantly detect the invasion, triggering an alarm that mobilizes the innate immune response.
This new understanding of immunity ultimately could help researchers find new targets to treat inflammatory disorders. The paper was published in Nature on March 31.
The immune system has a number of difficult tasks, including differentiating between cells and microbes. However, the body, particularly the digestive tract, contains trillions of beneficial microbes, which must be distinguished from dangerous pathogens.
“We are colonized by microbes. In fact, there are more bacteria in the body than cells,” said senior author Andreas Bäumler, professor and vice chair of research in the department of medical microbiogy and immunology.
“The immune system must not overreact to these beneficial microbes. On the other hand, it must react viciously when a pathogen invades.”
The key to distinguishing between pathogenic and beneficial bacteria are their differing goals. Ordinary digestive bacteria are content to colonize the gut, while their more virulent cousins must break into cells to survive.
Salmonella achieves this by activating enzymes that rearrange the actin in a cell’s cytoskeleton. Fortunately, cellular proteins sense the active enzymes, leading to a rapid immune response.
In the study, the researchers investigated a strain of salmonella, in both cell lines and animal models, to determine how the innate immune system singles out the bacteria for attack.
Salmonella uses a secretion system, a type of molecular syringe, to inject pathogenic proteins, such as SopE, into the cell. SopE activates enzymes which break down the surrounding actin, allowing the bacterium inside.
But breaking and entering has consequences. Sensing the active enzymes, and recognizing their pathogenic nature, a protein called NOD1 sends the alarm, signaling other proteins that the cell is in danger.
Ultimately, this signaling pathway reaches the protein NF-κB, a transcription factor that instructs the genome to mount an immune response, activating genes associated with inflammation, neutrophils and other immune functions.
These results could help researchers find new targets to combat inflammatory diseases. For example, NF-κB is known to be involved in a variety of conditions, such as inflammatory bowel disease, arthritis, sepsis and others. By understanding the pathways that activate inflammation, scientists and clinicians can develop ways to inhibit it.
“These pathways might be triggered erroneously because the host thinks there’s an infection,” said Bäumler. “Knowing the pathways and how they are activated is critical to controlling them.”
— UC Davis Health News Office