For Salmonella, it’s all about being in the right place at the right time— although for a human victim, it’s more like the wrong place at the wrong time.

“Salmonella is designed to sense a variety of environmental parameters that tell the bacterium where it is in the intestine, allowing it to turn on virulence systems at the appropriate time and place,” explained James M. Slauch, head of microbiology in MCB. “It’s like a switch, turning it on, turning it off.”

For the person on the receiving end of the infection, the result can be a severe bout of stomach cramps, fever, and diarrhea.

Slauch has studied complicated Salmonella systems for 30 years, and for the past two years he has collaborated in some of his research with fellow MCB microbiologist, Cari Vanderpool. They are studying regulation of the primary virulence system required for Salmonella to invade and colonize the small intestine.

For instance, they recently identified two small RNAs that play a role in regulating Salmonella, but how they work depends on oxygen levels. If the environment in a person’s small intestine is too anaerobic—if there is not enough oxygen—then the first of these small RNAs shuts off activation of Salmonella. And if the intestinal environment has too much oxygen, the second small RNA also shuts off Salmonella virulence.

However, if oxygen levels are at a sweet spot for the bacteria—not too much or too little—then it is conducive to infection, Slauch and Vanderpool discovered.

But oxygen is only one of many factors that influence a Salmonella infection. Salt content and fatty acids also play a role in activating the virulence system, and once again, it’s all about bacteria finding the sweet spot.

“Salmonella is a major food-borne disease throughout the world, with over a million infections in the United States each year,” Slauch pointed out. “Over 500 people per year die from the infection, and in the rest of the world the death rate is much higher.”

In many cases, people don’t even realize they have been infected, as the ailment runs its course over four to seven days.

In 2018, there have been several multi-state outbreaks of Salmonella, according to the U.S. Food and Drug Administration. For instance, one outbreak may have started with tainted, pre-cut melons in fruit salad mixes, with Salmonella cases popping up across seven states, including Illinois. In this outbreak, Salmonella struck 70 people between April and June, and over half of them were hospitalized, reported the FDA.

Slauch and Vanderpool concentrate on Salmonella Typhimurium, one of the serovars most responsible for infections worldwide. Salmonella invades the cells of the small intestine, and this is required for disease, Vanderpool said. If the bacteria simply move through the middle of the intestine, they do no harm. But if they invade the epithelial cells lining the surface of the small intestine, they can wreak havoc.

What’s more, the target epithelial cells are located in the final stretch known as the distal small intestine. Once Salmonella bacteria invade the surface cells of this region, they induce an inflammatory response. It was once thought that the inflammatory response was the immune system’s way of battling the infection. But Slauch said they now know that Salmonella induces the inflammation because it helps the bacteria propagate.

“The inflammatory response gives rise to new sources of carbon and terminal electron acceptors that only Salmonella can use,” he pointed out. “The vast majority of other bacteria in the intestine cannot use these terminal electron acceptors. So Salmonella intentionally induces diarrhea to create an environment where it can propagate and outcompete the other organisms.”

Nevertheless, the inflammatory response is a two-edged sword for the bacteria. Although it helps Salmonella propagate, it is also the body’s way of flushing out the gut, “and that’s a good thing,” Slauch said. That is why doctors recommend that those suffering from Salmonella use oral rehydration as a treatment. Drink lots of water.

The collaboration between the two MCB labs can be traced back to the doctoral work of PhD student Kyungsub Kim, which began five years ago. His research in Slauch’s lab generated the preliminary data used to obtain a grant from the National Institutes of Health, and Kim continues to play a key role in the work.

Vanderpool’s laboratory has a long history of research on small RNAs, such as the ones that can influence Salmonella. But small RNAs are relative newcomers in biology. “We knew virtually nothing about small RNAs and small RNA regulation until the early 2000s,” she said.

Small RNAs, which can be as short as 100 nucleotides in length, were once called non-coding RNAs because it was believed they did not code for proteins. Although it’s true that most of them do not code for proteins, some do, as it turns out.

“It used to be that life was simple,” Slauch said. The Central Dogma of Molecular Biology was that DNA makes RNA, and RNA makes protein. But as researchers such as Vanderpool and Slauch dig deeper, it gets more complicated.

Small RNAs can base pair with messenger RNA (mRNA), which carry genetic information from the DNA to the ribosomes. However, when some small RNAs bind to regions of the mRNA, they inhibit the creation of proteins by ribosomes. Some small RNAs can even regulate the virulence response in Salmonella bacteria.

Slauch and Vanderpool have identified roughly eight small RNAs that control the Salmonella invasion system through base pairing.

“Our idea is to get a comprehensive view of the virulence signals at the molecular level,” Slauch said. “Small RNAs are a big part of that, but not the only part by any means.”

According to Slauch, so many conditions have to be just right for a Salmonella infection to occur. As he put it, “You have to have a, b, c, d, e, f, and g, and they all have to be on at the same time.”

“But if we can interfere with any one of those conditions, we can have an impact because all of those conditions are required,” Vanderpool said. “If we can stop the cells from sensing these signals—if we block the system from turning on—we block the Salmonella infection.”