This suite of cells circulating in your blood has to detect and respond to hundreds of different possible infections that could attack your body, distinguishing them from your own cells and from safe bacteria like those in your gut microbiome.

A new study from researchers at the Allen Discovery Center at Stanford University has found that the innate immune system, our first line of defense against dangerous invaders, has an even more fine-tuned sensory system than previously realized. Macrophages, the type of immune cell that detect and destroy invading bacteria, can distinguish very subtle differences about the infectious bacteria salmonella. The researchers describe their findings in a study published Wednesday in the journal Cell Systems.

“The way that our immune system works to alert the body to the presence of an infection is of critical interest,” said Markus Covert, Ph.D., director of the Allen Discovery Center and a lead author on the study. “If we can figure out ways to stimulate those signals, we can get in to help the immune system do its job and fight off agents like salmonella.”

Salmonella is a common food-borne bacterium that afflicts more than 100 million people around the world every year, killing approximately half a million. The bacteria breach the walls of the intestines, which causes diarrhea or more serious infections like typhoid fever. Salmonella then infect macrophages in the gut and other parts of the body. Most salmonella strains are resistant to common antibiotics. A better understanding of how the bacteria and our immune systems interact could point to future targets for better therapies, Covert said.

The Stanford research team looked at mouse macrophage cells infected with salmonella in the lab and found that the immune cells can sense several important distinctions about the level of infection or danger of infection. The cells can tell the difference between bacterial debris and live bacteria in their vicinity, and between dangerous bacteria like salmonella and safe bacteria like E. coli. They can also sense if there’s a bacterium nearby versus inside themselves, and if they are infected with actively growing or dormant bacteria.

A cellular Morse code

The team was able to track these subtle differences by studying the macrophages over time and one cell at a time, thanks to a special fluorescent reporter system that reads out cellular responses to infection. That system, which the researchers developed as part of their work within the Allen Discovery Center, a program under The Paul G. Allen Frontiers Group, a division of the Allen Institute, enabled them to understand the individual differences in immune cell-bacterial cell interactions. Previous studies looked just at the average response among a large group of macrophages.

“By doing this dynamic live imaging over time, what you see is that there’s significant variation at the single-cell level,” said Denise Monack, Ph.D., an investigator at the Allen Discovery Center and co-lead author on the study.

The immune cells switch on two different internal response systems in response to salmonella; the research team created colored readouts of those systems. They saw that the macrophages flashed different patterns of fluorescence depending on the bacterial threat level — switching on one or both response systems for different lengths of time — like a cellular Morse code.

The next steps will be to figure out how other immune cells read and respond to these coded signals, and to ask how salmonella slips through these defenses when infection leads to disease. They’re trying to address the latter by infecting macrophages with salmonella missing certain genes to ask which pieces of the bacteria trigger specific responses from the immune cells.

“We’d like to watch the chess games between these two,” Covert said. “Right now, we’re just seeing the moves that are made by the immune cells, and we also want to watch the moves the bacterium makes in response.”