An intestinal pathogen, Salmonella Typhimurium, blocks the appetite loss response in hosts to both make the host healthier and promote the bacterium’s survival and transmission. Essentially, the pathogen controls host anorexia during infection by interfering with a gut–brain circuit, IL-1ß-mediated signaling. [Salk Institute]
The old “feed a cold, starve a fever” saying has been reexamined countless times, but always from the host’s point of view. Isn’t it time to ask what the pathogen thinks? That’s the question that occurred to a team of Salk Institute scientists. These scientists studied how an intestinal pathogen, Salmonella Typhimurium, blocks the appetite-loss response in its host, the mouse.
This “inhibition of anorexia,” the scientists decided, helps the pathogen manage a tradeoff between virulence, which is the ability of a microbe to cause disease within one host, and transmission, which is its ability to spread and establish infections between multiple hosts. Thus, as far as the pathogen is concerned, the old saying should be “starve virulence, feed transmission.”
Detailed results from the scientists’ work appeared January 26 in the journal Cell, in an article entitled, “Pathogen-Mediated Inhibition of Anorexia Promotes Host Survival and Transmission.” This article described how the Salk team took a fresh look at the connection between Salmonella and loss of appetite.
Previous studies mostly involved injecting a microbe or microbial products directly into the circulation of an animal model and studying its effect. In the current study, however, animals were infected orally—thus mimicking the bacteria's route of infection (it spreads from mouse to mouse when the animals eat each other's contaminated feces).
“Traditionally in infectious disease, we think that the stronger a pathogen's ability is to cause disease, the greater its potential is to be transmitted to other hosts,” said the Cell article’s senior author Janelle Ayres, Ph.D., an assistant professor in immunobiology and microbial pathogenesis at the Salk Institute for Biological Studies. “But we discovered a pathogen that has evolved to become less dangerous to its host. By employing this strategy, it's easier for the pathogen to spread to other hosts.”
“Host response is only half of the infectious disease equation. We wanted to understand how the bacteria's behavior is affected by the host's loss of appetite, as well,” Dr. Ayres says. “What a pathogen wants is a steady supply of nutrients, a stable niche so it can replicate, and a reliable mode of transmission.” In this case, taming the behavior of the pathogen by enabling the mice to take in more nutrition helped keep the mouse healthy, produce more feces, and then spread infection to other animals.
Further investigation revealed the mechanism by which Salmonella Typhimurium inhibits loss of appetite. Sickness behaviors are in large part mediated by a cytokine—a type of molecule involved in cell-to-cell communication—that sends a signal to the hypothalamus, a region of the brain controlling appetite. But this particular Salmonella blocks activation of the cytokine in the intestines, preventing the gut from signaling to the brain.
“Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP [Salmonella leucine rich repeat protein], prevented anorexia caused by IL-1β [interleukin-1β]-mediated signaling to the hypothalamus via the vagus nerve,” wrote the authors of the Cell article. “Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts.”
Dr. Ayres says she anticipates finding a similar strategy in other microbes, noting that genes similar to the one known to be important in blocking cytokine activation in Salmonella Typhimurium also are found in other pathogens. “But a more interesting place to look is at the components of the microbiome, especially the human microbiome,” she noted.
“When an infection in the host affects appetite, the microbiome is also potentially compromised by the loss of nutrition. I expect to find that the microbiome has evolved strategies to block this sickness response,” Dr. Ayres adds.
This is something her research group plans to study.
The researchers hope that one day their findings may lead to a better understanding of infection transmission and new ways to treat infections by supplementing patients with nutrition rather than treating them with antibiotics. The goal would be to give patients a treatment that would also prevent them from spreading their cold or fever to others.