How exactly was the Irish immigrant known as Typhoid Mary able to infect about 50 people in New York City in the early 1900s without succumbing to the illness herself? Scientists say they are now close to cracking the case. 
 
 In a new study, they were able to solve the mystery of how a dangerous bacterial pathogen can, in some people, manage to persist without causing symptoms and find a way to survive for decades. 
 
 For the salmonella bacteria that causes typhoid fever, the researchers said it manages to hide in immune cells known as macrophages and "hacks" their metabolism to their own benefit. If the germs are successful in pulling that off, then an infected person can unknowingly spread the pathogen without falling ill herself -- like in Typhoid Mary, whose real name was Mary Mallon. Just watch the video above. 
 
 “To all outward appearances, she was perfectly healthy,” study co-author Dr. Denise Monack, associate professor of immunology and microbiology at Stanford University, said in a written statement. 
 
 Monack and her research team infected mice with a strain of salmonella, and found that, the bacteria were able to "wait out" the body's aggressive immune response before they then positioned themselves in the immune cells that became less aggressive at later stages of infection. 
 
 “There aren’t a ton of pathogens that hang out in macrophages,” Monack told the Los Angeles Times, adding that the bacterium behind tuberculosis is another. 
 
 So if that's where the nasty germ hangs out, how does it survive and go unnoticed? The researchers found that a protein known as PPAR-delta was required for salmonella to replicate inside the macrophages and "hack" them. 
 
 “Salmonella is doing something to activate PPAR-delta,” Monack said in the statement. “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.” ||||| Stanford University School of Medicine scientists have shown how salmonella—a bacterial menace responsible for hundreds of thousands of deaths each year from typhoid fever and food poisoning—manages to hide out in immune cells, altering their metabolism to its own benefit, much as someone might remodel a newly rented home to suit his own comfort. 
 
 Salmonella's ability to position itself inside infected people's cells for the long haul can turn them into chronic, asymptomatic carriers who, unknown to themselves or others, spread the infectious organism far and wide. 
 
 The findings, which will be published Aug. 14 in Cell Host & Microbe, could lead to new and better treatments for typhoid fever. Worldwide, there are 16 million to 20 million cases each year, resulting in about 200,000 deaths, although the disease is no longer common in developed countries. Scientists further estimate that there are close to 100 million cases of salmonella-induced gastrointestinal infections each year, the majority from food poisoning, resulting in more than 150,000 deaths. 
 
 "Between 1 and 6 percent of people infected with S. typhi, the salmonella strain that causes typhoid fever, become chronic, asymptomatic carriers," said Denise Monack, PhD, associate professor of immunology and microbiology and the study's senior author. "That is a huge threat to public health." 
 
 A classic case of a chronic, symptom-free carrier is the infamous Typhoid Mary, an Irish immigrant who made her living as a cook in and around New York City in the early 1900s. She infected about 50 people with typhoid fever. "To all outward appearances, she was perfectly healthy," Monack said. 
 
 Monack and others have sought to learn how a microbe that causes such profound acute symptoms in most people can lie dormant in symptom-free carriers' bodies for long stretches of time. To address this, Monack has developed a mouse model of persistent salmonella infection. S. typhi—the typhoid-inducing salmonella strain—infects only humans. But S. typhimurium, a closely related strain that commonly causes food poisoning in people, can infect both humans and mice. Monack's experimental mice can harbor an S. typhimurium infection for as long as two years—an entire mouse lifetime. 
 
 Previous work by Monack's team has shown that salmonella bacteria are able to take up residence inside voracious attack cells called macrophages (from the Greek words for "big eater"). These cells, which are called to the front lines of an immune assault against invading microbes, reside in tissues throughout the body and are known for their ability to engulf and digest pathogens. 
 
 Ornery critters that they are, macrophages would seem an unlikely hostel for bacteria bent on long-term survival. But, said Monack, a macrophage has two faces, depending on its biochemical environment. "Early in the course of an infection," she 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." 
 
 But salmonella is one tough bug. And our bodies can't tolerate lots of inflammation. So, after several days of inflammatory overdrive, the immune system starts switching to the secretion of anti-inflammatory factors. This shifts macrophages into a kinder, gentler mode. Thus defanged, anti-inflammatory macrophages are more suited to peaceful activities, such as wound healing, than to devouring microbes. 
 
 A key finding in the new study was that salmonella that survive the inflammatory assault seem to have ways of turning the subdued, anti-inflammatory macrophages into hospitable housing. Monack and her colleagues infected the experimental mice with Salmonella typhimurium and inspected their gut lymph nodes and spleen at 0, 5, 15, and 42 days post-infection for the presence of pro- and anti-inflammatory substances. They also examined the ratio of inflammatory versus anti-inflammatory macrophages, which have distinguishing surface and intracellular features. 
 
 Over time, the ratio of anti-inflammatory substances in the macrophage's surrounding environment increased, with a corresponding shift to a predominance, in the gut lymph nodes and spleen, of anti-inflammatory-macrophages. Experiments proved that at later stages of infection, S. typhimurium preferentially hung out in the anti-inflammatory macrophages. It wasn't that inflammatory macrophages were invulnerable to infection, but rather that, having infected a macrophage, S. typhimurium was much more able to replicate in the anti-inflammatory type. 
 
 After more experimentation, Monack and her colleagues came up with the probable mechanism. Salmonella apparently has a way of manipulating macrophages to expedite the switch from an inflammatory to anti-inflammatory state and, in the process, push their metabolism in a direction favorable to the bacteria. 
 
 It's known that an inflammatory macrophage gets a lot of its energy from anaerobic glucose metabolism, whereas an anti-inflammatory macrophage can get fuel from the aerobic oxidation of fatty acids, which ultimately increases the supply of glucose within the cell. A major determinant of glucose production within the macrophage is a family of intracellular receptors that, when bound by specific fatty acids from outside the cell, head to the nucleus and switch on or off numerous genes, including ones responsible for fat metabolism. These roaming genetic switches, called peroxide-proliferation-induced receptors, or PPARs, have been intensely studied. An important set of drugs—including rosiglitazone (Avandia) and pioglitazone (Actos), both licensed in the United States to treat type-2 diabetes—activate PPARs. 
 
 Other bacteria are known to hole up inside macrophages, and there have been suggestions in the literature that PPARs somehow contribute to intracellular pathogens' ability to persist in macrophages. But nobody has known why, Monack said. So, when activation levels of one of those PPAR family members, designated PPAR-delta, proved higher in her lab's S. typhimurium-infected test mice, she and her team conducted experiments to find out why, some of them involving a strain of lab mouse whose ability to produce PPAR-delta had been disabled. 
 
 The investigators found that PPAR-delta was required for salmonella to replicate inside macrophages. Even though S. typhimurium initially colonized the mice's spleen and gut lymph nodes regardless of PPAR-delta status, six weeks later it was undetectable in the PPAR-delta-deficient mice's tissues—but present to a substantial degree, as expected, in the PPAR-delta-producing mice. Additionally, the deficient mice had far fewer anti-inflammatory macrophages, and these mice's macrophages had significantly lower glucose levels. 
 
 PPAR-delta is known for sustaining fatty-acid metabolism in cells when activated, leading to increased glucose levels in cells. Intriguingly, PPAR-delta mRNA and protein levels, as well as those of a gene regulated by PPAR-delta, rose significantly in S. typhimurium-infected macrophages, suggesting that salmonella has a way of manipulating macrophages to boost PPAR-delta activity and, commensurately, glucose levels in the cell. 
 
 "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." 
 
 Explore further: Salmonella infection, but not as we know it ||||| Share 
 
 Mary Mallon (a.k.a. “Typhoid Mary“) didn’t mean any harm to anybody. An Irish immigrant, she made her living for several years about a century ago by cooking for better-off families in the New York City area. Strangely, the people she cooked for kept on coming down with typhoid fever – but not Mary. 
 
 Mallon, alas, turned out to be a chronic asymptomatic carrier of Salmonella typhi, the bacterial strain that causes typhoid fever. Typhoid is a deadly disease that, while no longer a huge problem in the United States, infects tens of millions – and kills hundreds of thousands – of people around the world every year. 
 
 “She didn’t know she had it,” says Stanford microbiologist Denise Monack, PhD. “To all outward appearances, she was perfectly healthy.” 
 
 Salmonella strains, including one called S. typhimurium, also cause food poisoning in people and pets, taking an annual human toll of 150,000 globally. While S. typhi infects only humans, closely related S. typhimurium can infect lots of mammals. 
 
 Between 1 and 6 percent of people infected with S. typhi become chronic, asymptomatic typhoid fever carriers. Nobody has known why this happens, but it’s a serious public-health issue. To address this, Monack has developed an experimental mouse model that mimicks asymptomatic typhoid carriers. In a new study published in Cell Host & Microbe, she and her colleagues put that model to good effect, showing that Salmonella has a sophisticated way of messing with our immune systems. The bacteria set up house inside voracious attack cells called macrophages (from the Greek words for “big eater”). Macrophages, are known for their ability to engulf and digest pathogens and are called to the front lines of an immune assault against invading microbes. Ornery critters that they are, macrophages would seem like the last thing bacteria bent on long-term survival would want to meet. 
 
 But, as I wrote in my release about this study, a macrophage has two faces, depending on its biochemical 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.” But salmonella is one tough bug. And our bodies can’t tolerate lots of inflammation. So, after several days of inflammatory overdrive, the immune system starts switching to the secretion of anti-inflammatory factors. This shifts macrophages into a kinder, gentler mode. Thus defanged, anti-inflammatory macrophages are more suited to peaceful activities, such as wound healing, than to devouring microbes. 
 
 And, sure enough, Monack and her colleagues showed that salmonella germs have a way (still mysterious, but stay tuned) of taming macrophages, flipping an intercellular switch inside of these thug-like cells that not only expedites their champ-to-chump shift but induces them to pump out tons of glucose, the bug’s favorite food. What better place to hide than in the belly of the beast?
– A new Stanford University study solves part of the mystery surrounding Typhoid Mary, the New York Times reports. Scientists have long wondered how Mary Mallon could have infected so many people as a carrier of typhoid fever in the early 1900s, yet appear perfectly healthy for decades. The study offers clues as to how the bacteria that cause the illness, Salmonella typhi, hide out: They invade macrophages, cells in the immune system that typically attack invading bacteria, and then manipulate the metabolism of those macrophages. Stanford's Scope blog says the bacteria "mess with our immune systems"; the Huffington Post describes the bacteria as 'hacking" the macrophages; Phys.org goes with an analogy, comparing the bacteria to renters who remodel a home. Basically, the bacteria are tough enough that they can survive the first few days of an inflammatory response from the immune system, after which the macrophages go into a "kinder, gentler" anti-inflammatory mode because the body can't handle too much inflammation, and then the bacteria are safe. It's not yet known how the bacteria are able to successfully "flip the switch" on the macrophages, but they also manage to get the macrophages to produce glucose, which the bacteria then feed on—and they can then survive in their new hiding place for decades. The Times notes another mystery: While Mallon's samples were often rife with Salmonella typhi bacteria, at other times they were perfectly clean. (Click for another fascinating health discovery that links our mental health to our gut.)