August 15, 2013
Scientists Get A Closer Look At What Makes Typhoid Fever Tick
Brett Smith for redOrbit.com - Your Universe Online
In the early 20th century, Typhoid Mary became one of the iconic symbols of disease outbreak when she infected about 50 people with typhoid fever while working as a cook in and around New York City.Scientists have long wondered how a working-class Irish immigrant who appeared so healthy could have carried the Salmonella bacterium responsible for the disease, S. typhi, for so long without any symptoms.
According to a new study published in the journal Cell Host & Microbe, one reason the bacterium is able to lie dormant is by manipulating the immune systems’ macrophages to suit its own needs and enable its proliferation.
"Between 1 and 6 percent of people infected with S. typhi, the salmonella strain that causes typhoid fever, become chronic, asymptomatic carriers," said study author Denise Monack, an associate professor of immunology and microbiology at Stanford University. "That is a huge threat to public health."
In the study, Stanford and University of California, San Francisco researchers developed a mouse model of lasting salmonella infection using S. typhimurium, a related strain that can cause an infection lasting as long as two years — the average mouse lifespan.
Previous research by the same team showed that salmonella bacteria are capable of inhabiting macrophages, the immune system cells that typically engulf and destroy invading pathogens. These aggressive defenders will take on a different posture depending on their environment.
"Early in the course of an infection," Monack said, "inflammatory substances secreted by other immune cells stir macrophages into an antimicrobial frenzy. If you're not a good pathogen, you'll be wiped out after several days of causing symptoms."
However after the initial immune response, the immune system changes gears and releases anti-inflammatory factors since the body can’t take too much inflammation. These factors cause macrophages to enter a more docile phase. The less aggressive macrophages assist in wound healing and other functions instead of eating up microbes.
The more subdued macrophages are also more hospitable to invading salmonella that may have survived the initial assault, the new study found. The researchers came to this conclusion by checking gut lymph nodes and spleens of their infected mice for the presence of pro- and anti-inflammatory substances. They also recorded the ratio of inflammatory versus anti-inflammatory macrophages.
The researchers found that the ratio of anti-inflammatory substances increased and corresponded to a predominance of anti-inflammatory-macrophages in the gut lymph nodes and spleen over the course of the infection. During these later stages of infection, the scientists found that S. typhimurium preferred to inhabit anti-inflammatory macrophages due to the fact that they were more able to replicate in the anti-inflammatory type.
Researchers also found that salmonella required intracellular factors called proliferation-induced receptors, or PPARs. While S. typhimurium initially invaded the mice's spleen and gut lymph nodes regardless of PPAR-delta status, six weeks later the bacteria was undetectable in mice that had their ability to produce PPAR-delta artificially disabled. However, the bacteria were still prevalent in the tissues of PPAR-delta-producing mice.
"Salmonella is doing something to activate PPAR-delta," Monack said. "We suspect it's releasing some as-yet-unknown PPAR-delta-stimulating virulence factor into the macrophages it infects. If we can figure out what that is, it could lead to some great anti-salmonella therapeutics with relatively fewer side effects."