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History, Infectious Disease, Microbiology, Public Health, Research, Stanford News

Did microbes mess with Typhoid Mary’s macrophages?

Did microbes mess with Typhoid Mary's macrophages?

macrophage with salmonella insideMary 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?
Previously: TB organism’s secret life revealed in a hail of systems-biology measurements
Photo by AJC1

Global Health, Infectious Disease, Microbiology, Research, Stanford News

Cat guts, car crashes, and warp-speed Toxoplasma infections

Cat guts, car crashes, and warp-speed Toxoplasma infections

cute kittyBetween one-quarter and half of the people on Earth are infected with Toxoplasma gondii. This is one widespread parasite: The versatile protozoan can infect most warm-blooded creatures. Yet it can sexually reproduce only within the intestines of members of the cat family. (Toss that fact off at your next dinner party.)

It gets weirder. Strangely, T. gondii-infected rats seem to have an altered sense of… well, something. Instead of experiencing dread at the smell of cat feces, as would any rat in its right senses, infected rats experience something akin to falling in love, in a manner Stanford biologist Robert Sapolsky, PhD, has described.

Apparently, evolution has favored T. gondii over rats, because the latter’s newfound fondness for feline feces increases their risk of being devoured – and of their microbial manipulators’ scoring a five-star honeymoon hotel room inside a cat gut.

As for us people, immune-compromised individuals can suffer great harm from a T. gondii infection but the vast majority of those infected experience no obvious symptoms – although people with T. gondii residing in them are 2.5 times as likely to get into car accidents, and pregnant women probably should be screened for the pest’s presence. There are also indications that T. gondii infection is associated with an increased risk for schizophrenia.

This, then, is a bug deserving of some serious study. Speaking of which, in a study published in Nature Chemical Biology, Stanford microbiologists Matt Bogyo, PhD, and John Boothroyd, PhD, and their colleagues have revealed another item in the bag of burglar tools the pathogen uses to invade cells.

They found a small molecule (so, a good candidate drug) that causes the parasite to invade victims’ cells more efficiently. Yep, I said that correctly: A dose of this stuff enhances the parasite’s invasion capacity.

“Hmmmm,” you may be thinking. “Okayyyy … so why should I get excited about a compound that increases the number of parasites that are invading a person’s or animal’s cells?”

Bogyo gave me an answer in the form of an analogy. “It’s easy to find ways to make a car go slower. But a lot of those ways of slowing it down don’t tell you much of anything about how the car works. If you find something that makes the car go faster, you’re on the road to cracking that car’s operating system.”

There are other reasons, Bogyo theorized, why the compound Bogyo, Boothroyd and company identified could prove useful. Here’s one:

Inducing increased invasion of the host may actually result in poorer overall fitness for the parasite. Increasing the speed of the invasion process will prevent [T. gondii] from being able to disseminate away from the point of exit from a previously infected host cell. This will prevent the spread of the parasite throughout the body and actually reduce the productivity of the infection. So, ultimately, compounds that stimulate the parasite invasion pathway might be viable therapeutic agents.

Previously: Patrick House discusses Toxoplasma gondii, parasitic mind control and zombies, Compound clogs Plasmodium’s in-house garbage disposal, hitting malaria parasite where it hurts and NIH study supports screening pregnant women for toxoplasmosis
Photo by flackjack

Global Health, Infectious Disease, Microbiology, Public Health, Research, Science, Stanford News

TB organism’s secret life exposed in hail of systems-biology measurements

TB organism's secret life exposed in hail of systems-biology measurements

paparazziIf you want to track a criminal, it’s not enough to have a high-resolution photo of one nostril. Much better to have a mug shot of the malefactor’s entire face – or better yet, a video that shows how that face’s  expressions change with shifting situations. Call it a “systems approach.”

A number of scientists from several institutions, spearheaded by Stanford infectious-disease sleuth Gary Schoolnik, MD, have done something like that with tuberculosis. Their investigation’s results were just published in Nature.

Technically speaking, TB is on the decline globally. But that’s not saying much. Roughly one out of every three people on Earth today is infected by the microbe responsible for the disease. Fortunately, fewer than one in 10 of those so infected will develop symptoms in their lifetimes. But that still leaves tuberculosis in second place among the world’s current most lethal infectious diseases – close to 1.5 million deaths annually. An estimated billion souls have succumbed to TB in the past 200 years. Meanwhile, drug resistant TB strains are becoming increasingly common.

Yet the organism’s modus operandi remains poorly understood. So, rather than conducting a narrow study of how changes in a given gene’s or protein’s activity level correlates with disease-relevant characteristics of M. tuberculosis (the TB agent’s formal name), the Schoolnik-led team took a systems approach. They went about assembling a global profile of the agent’s changing features as it adapts to low oxygen levels – in other words, to life inside its preferred host in the human body, an immune cell called a macrophage. The researchers’ objective: an accounting of the extensive regulatory network that determines which genes are active and which are quiet under differing environmental conditions (for example, when oxygen is scarce, versus abundant).

Key to the coordinated activation of numerous genes are proteins called transcription factors, which bind selectively to patches of DNA and instigate the production of proteins specified by the genes in these local regions. Out of the TB agent’s 180-plus already-known transcription factors, the team was able to map the activities and interactions of 50 that are involved in, among other things, coordinating the switching on of genes helpful in the breakdown of fatty substances in the macrophage’s outer membrane as well as the generation of microbial energy-storage molecules, cell wall components, and substances that increase the crafty organism’s virulence and help it outwit an infected person’s immune system.

So, still a rough sketch. But look out, bug. The cameras are blazing, there’s no place to hide.

Updated 07-04-13: My original post stated, falsely, that tuberculosis has felled more people in the past 200 years than any other infectious disease. In fact, smallpox has been a comparable killer. How quickly we (I) forget. Now eradicated, smallpox took hundreds of millions of lives in the 20th century alone. I hope the size of TB’s toll will someday be similarly forgettable. (Kudos to RealClearScience‘s Alex Berezow for catching my error.)

Previously: Stanford TB project bridges U.S.-North Korea divide, Researchers show way to reduce prevalence, spread of TB in former Soviet Union and Coming soon: A faster, cheaper, more accurate tuberculosis test
Photo by drukelly

Global Health, Health Disparities, In the News, Media, Microbiology, Public Health

A journalist’s experience with tuberculosis, the “greatest infectious killer in human history”

I’m a bit late in finding it, but The Global Mail published a fascinating and sobering feature article last week about the  heartbreaking toll of drug-resistant tuberculosis in parts of the developing world. Journalist Jo Chandler traveled to Papua New Guinea in 2011 to tell the personal stories of those affected with the disease, which is rampant in the country, including a woman named Edna who lost her 19-year-old daughter, Susan:

Tuberculosis retains the distinction of being the greatest infectious killer in human history, claiming an estimated billion lives in the past 200 years. Its toll today is still second only to HIV (and it is the major killer of people with HIV). In 2011, 8.7 million people fell sick with TB. Edna’s daughter was one of 1.4 million who died of it that year.

The story is illustrated with beautiful, disturbing photographs of villagers with the disease that alone are enough to keep me reading. But then Chandler’s narrative takes a riveting, disturbing turn:

Sometime in those few days, somewhere, someone coughed or sneezed or sang or laughed, spraying a cloud of invisible Mycobacterium tuberculosis into the air, and I inhaled. By the time my ride out finally materialises on the tarmac and I click my heels for home, it seems I have a stowaway. Eighteen months later, in March 2013, I am diagnosed with multidrug-resistant tuberculosis (MDR TB). Let’s call it accidental immersion journalism.

I digest all this as I recover at home, still a little shocked when I hear the phrase “I’ve got TB” come from my mouth – and still adjusting to the horrified response it often elicits. My body is sore from surgery, and weakened and assailed by the mindblowing volume and variety of drugs coursing through unhappy veins. My partner is gentle and my children attentive and my parents worried. I’m profoundly grateful to every doctor, every nurse, and for every jab and tablet and almost every bloody cannula.

I have notebooks full of stories of TB patients who die seeing none of it.

Chandler’s story first attracted my interest because of an article I wrote early this year about how the bacterium hides out in the bone marrow of patients, only to resurface years or decades later. But I found I couldn’t tear myself away from Chandler’s comparison of the treatment that she’s receiving at home in Australia (including four months of IV drugs) with that available to infected people in neighboring Papua New Guinea. And like most readers, I suspect, I found myself deeply embarrassed of my lack of awareness of this killer.

Previously: Tuberculosis may remain dormant in bone marrow stem cells of infected patients, Researchers show way to reduce prevalence, spread of TB in former Soviet Union and Coming soon: a faster, cheaper more accurate tuberculosis test

In the News, Microbiology, Research

Could “breathprints” one day be used to diagnose disease?

Could "breathprints" one day be used to diagnose disease?

Your “breathprint,” the chemical composition of each exhale, may hold potential as a new medical diagnostic tool, according to research recently published in PLOS ONE.

In the small study, Swiss researchers used a technique known as mass spectrometry to analyze the molecules in participants’ breath samples. As reported in the New Scientist:

The team was interested in metabolites, compounds produced by the body’s metabolism. The molecules are volatile and small enough to pass from the blood into airways via the alveoli in our lungs, so are present in our breath – albeit in miniscule amounts, sometimes less than one molecule per billion molecules of air.

The team found that metabolites in individuals’ breath remained “constant and clear”, says Swiss Federal Institute of Technology professor [Renato Zenobi, PhD].

Zenobi’s team can identify compounds in breath immediately, so our breathprint could be used to detect signature metabolites associated with disease, giving an instant diagnosis. In a preliminary study, Zenobi has shown that breath samples can reveal whether people have chronic obstructive pulmonary disease.

While more research is needed to understand how breathprints might be used in a clinical setting, the research is noteworthy in light of the growing body of scientific showing a variety of unique biological identifiers, including microscopic ecosystems that exist in the human body, could offer insights into our personal health.

Photo by Sean Friend

Bioengineering, Humor, Immunology, In the News, Infectious Disease, Microbiology, Research

Gutnik? NASA to launch colon-inhabiting bacteria into space

You’ve heard of Sputnik, that little tiny antenna-clad chunk of metal heaved into low orbit on October 4, 1957, effectively kicking off the Space Age?

Well, make way for Gutnik. A news release issued by NASA’s Ames Research Center foretells the launch into space of a satellite inhabited by a bunch of nano-mariners who, left to their own devices, would no doubt rather curl up inside a bowel.

Sometime in the next one to three years, according to the release, a so-called “nanosatellite” weighing about 30 pounds and peopled by the intestinal bug E. coli will streak into the sky, with the mission of amassing data on whether the zero-gravity environment that cloaks our planet might increase microbes’ resistance to antibiotics. That’s important, because, as the release states:

Bacterial antibiotic resistance may pose a danger to astronauts in microgravity, where the immune response is weakened. Scientist believe that the results of this experiment could help design effective countermeasures to protect astronauts’ health during long-duration human space missions.

E. coli is probably the most-studied micro-organism in all of science. While most strains are harmless and actually quite friendly (producing vitamin K for us, just to name one of the nice things they do), some of them can cause food poisoning, urinary-tract infections and more.

Gutnik (whose real name is EcAMSat) is the brainchild of Stanford microbiologist A.C. Matin, PhD, the principal investigator for the joint NASA/Stanford University School of Medicine project. Matin’s previous inventions include microbes capable of gobbling up environmental toxins like uranium and chromium, as well as magnetic-field-seeking bacteria that can increase the contrast of magnetic-resonance imaging. So this new satellite caper is just one more in a series of wild but potentially very useful feats of imagination.

The thing that really knocks me out, though, is how all these scientists and engineers will manage to get those billions of little tiny bugs to sit still while the chin straps on their little tiny space helmets are being fastened.

Previously: Space: A new frontier for doctors and patients and Outer-space ultrasound technologies land on Earth
Photo by Per Olof Forsberg

Microbiology, Videos

Touring the microscopic worlds of the human body

Touring the microscopic worlds of the human body

Scientific illustrator Dee Breger specializes in creating images using a scanning electron microscope (SEM), which has an incredible level of magnification. In this recently posted TEDEducation video, Breger takes viewers on a tour of the hidden world inside the human body and offers close-up shots of a blood clot, the thyroid gland and neurons involved in memory. It’s worth taking a moment to watch. (The dental plaque image alone will motivate you to take better care of your teeth.)

Previously: Cool video of the intestinal immune system, Exploring the microbes that inhabit our bodies and Video of innate immune reaction in the lymph node

Microbiology, NIH, Research, Videos

Exploring the role of extracellular RNA communication in human disease

Exploring the role of extracellular RNA communication in human disease

DNA may be the main building blocks of the body, but researches are starting to discover that RNA, which transports genetic information within a specific cell, could hold greater potential in understanding a wide range of diseases and developing novel therapeutics.

This recently posted National Institutes of Health video offers a great primer explaining how some RNA, known as extracellular RNAs (exRNA), can travel through bodily fluids and alter cells at a distance. The NIH Common Fund’s Extracellular RNA Communication program is currently investigating how exRNAs control cell behavior. By doing so, researchers hope to develop methods for detecting disease earlier and to create new treatment options, such as harnessing exRNAs’ communication power to turn a diseased cell into a healthy one.

Previously: Slicing and dicing small RNA molecules can better combat viruses, enhance gene therapies, say Stanford researchers and The RNA insurrection: Genes’ “humble servant” rules from behind the scenes

Microbiology, Nutrition, Public Health, Research

How food may influence our cells and overall health

Here’s something to contemplate post lunch: In addition to delivering carbohydrates, fats and proteins to your body, the food you gobbled down midday contains nutrients and chemicals that may communicate instructions to your cells. A piece published today in Scientific American offers insights into how our diets may affect overall health:

Cells talk to each other in a complex language of chemical messages. They instruct each other to grow, to move and to respond to threats. Problems in cell communication lead to diseases such as diabetes and cancer. The messages take many forms, including hormones and charged molecules called ions. Cells also listen to signals that come from outside the body.

Recent findings show that molecules found in food can change cell chatter. For example, in 2010 a team of researchers in California and Japan found that omega-3 fatty acids from food bind to a specialized protein studding cell surfaces. That protein, called GPR120, is found in adipose and muscle tissues. When omega-3 fatty acid attaches to the protein, fitting like a key in a lock, GPR120 sets off a chain reaction of cellular events that ultimately protect against weight gain and inflammation.

Understanding the influence of food on cells could offer a better way to design diets, says Randy J. Seeley, the director of the Cincinnati Diabetes Center at the University of Cincinnati. A special diet to tone down inflammation might also combat weight gain or protect against diabetes.

Previously: Nature/nurture study of type 2 diabetes risk unearths carrots as potential risk reducers
Photo by Jeremy Keith

Global Health, Microbiology, Stanford News

President Obama awards National Medal of Science to Stanford’s Lucy Shapiro

President Obama awards National Medal of Science to Stanford's Lucy Shapiro

Today, President Barack Obama presented 23 innovators and researchers, including Stanford developmental biologist Lucy Shapiro, PhD, with national medals for their contributions to science, technology and innovation.

As reported by my colleague, Shapiro arrived in the nation’s capitol on Wednesday to attend a whirlwind of events commemorating her accomplishment. At a press conference this afternoon in the East Room at the White House, she and eleven other researchers were awarded the National Medal of Science alongside eleven inventors who received the National Medal of Technology and Innovation.

During the event, Obama joked that “this is the most collection of brainpower we’ve had under this roof in a long time” and lauded honorees for their hard work and commitment to their field. He said:

Thanks to the sacrifices they’ve made, the chances they’ve taken, the gallons of coffee they’ve consumed, we now have batteries that power everything from cell phones to electric cars. We have a map of the human genome and new ways to produce renewable energy. We’re learning to grow organs in the lab and better understand what’s happening in our deepest oceans. And if that’s not enough, the people on this stage are also going to be responsible for devising a formula to tame frizzy hair as well as inspiring the game Tetris.

But what also makes these individuals unique is how they’ve gotten here – the obstacles they’ve overcome and the commitments they’ve made to push the boundaries of our understanding.

Shapiro was honored for “the pioneering discovery that the bacterial cell is controlled by an integrated genetic circuit functioning in time and space that serves as a systems engineering paradigm underlying cell differentiation and ultimately the generation of diversity in all organisms.”

In addition to Shapiro, Sidney Drell, PhD, a senior fellow at the Hoover Institution, was also named a recipient of the National Medal of Science. He received the award for his contributions “to quantum field theory and quantum chromodynamics, application of science to inform national policies in security and intelligence, and distinguished contributions as an advisor to the United States government.”

Previously: Stanford’s Lucy Shapiro receives National Medal of Science

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