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Microbiology

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

Discovered: Why so many people with schistosomiasis (there's a lot of them) are so vulnerable to bacterial co-infection

Discovered: Why so many people with schistosomiasis (there's a lot of them) are so vulnerable to bacterial co-infection

More than a billion people worldwide – almost all of them in developing countries – are infected by worm-like parasitic organisms called helminths. Organisms making up just a single genus of helminth, Schistosoma, account for one-quarter of those infections, which damage different body parts depending on what schistosomal species is doing the infecting. Some go for the lung. Others (card-carrying members of the species Schistosoma haematobium) head for the urinary tract, with one in ten infected patients suffering severe physical consequences.

People with schistosomiasis of the urinary tract are especially vulnerable to bacterial co-infections. Worse, these co-infections exacerbate an already heightened risk of bladder cancer in infected individuals, it’s believed. Unfortunately, considering the massive numbers of cases, surprisingly little is understood about the molecular aspects of the infection’s course.

A big reason for that relative ignorance has been the absence of an effective animal model enabling the detailed study of urinary-tract schistosomiasis. A couple of years ago, Stanford schistosomiasis expert Mike Hsieh, MD, PhD, developed the world’s first decent mouse model for the disease, allowing him to explore the molecular pathology that occurs early in the course of infection. Now, in a just-published study in Infection and Immunity, Hsieh has put that mouse model to work in coaxing out the cause of the curious collegiality of S. haematobium and co-infecting bacteria.

The secret, the scientists learned, is that S. haemotobium infection induces a spike in levels of a circulating immune-system signaling protein, or cytokine, called IL-4. That excess, in turn, results in a drop in the number and potency of a subset of immune cells that are important in fighting off bacterial infections. The discovery opens a pathway toward the development of new, non-antibiotic drug treatments for co-infected patients that won’t wreak havoc with their microbiomes, as antibiotics typically do.

Previously: Is the worm turning? Early stages of schistosomiasis bladder infection charted, Neglected story of schistosomiasis in Ghana, as told in a  sand animation and A good mouse model for a bad worm

Immunology, Mental Health, Microbiology, Public Health

Examining how microbes may affect mental health

Examining how microbes may affect mental health

Over on the NIH Director’s Blog today, there’s an interesting post about research efforts aimed at determining how the colonies of bacteria in our gut could play a role in mental health. As described in the piece, past research has shown there are a number of ways microbes can influence our thoughts, behavior and mood:

First of all, and perhaps most obviously, gut bacteria are engaged in a wide range of biochemical activities, producing metabolites that are absorbed into the human bloodstream. But there are other connections. One species of bacterium, for example, sends messages that are carried via the vagus nerve, which links the intestinal lining to the brain. When this species is present, the mice demonstrate fewer depressive behaviors than when it’s absent. Another bacterium plays an enormous role in shaping the immune system, which goes awry in many neurological diseases. This species of bacterium interacts directly with the immune system’s regulatory T-cells to provide resistance against a mouse version of multiple sclerosis, a progressive disease in which the immune cells damage the central nervous system by stripping away the insulating covers of nerve cells.

As Stanford microbiologist and immunologist Justin Sonnenburg, PhD, commented in a past entry on Scope, “There’s no doubt about it. These microbes are influencing every aspect of our neurobiology. There’s a direct connection between the microbes inside our gut and the central nervous system. They’re influencing our behavior, our moods, even our decisions.”

Previously: Could gut bacteria play a role in mental health?Study shows probiotic foods may alter metabolism, but can they boost your health? and Study shows intestinal microbes may fall into three distinct categories

Applied Biotechnology, Microbiology, Patient Care, Research, Stanford News, Surgery

Staphylococcus aureus holes up in upper nasal cavity, study shows

Staphylococcus aureus holes up in upper nasal cavity, study shows

nostrilsA posse led by Stanford microbe sleuth and microbiologist David Relman, MD, has apprehended Staphylococcus aureus, one of the most notorious sources of serious infections, lurking in formerly unsuspected nasal hideaways. The discovery may explain why attempts to expunge S. aureus from the bodies of hospitalized patients being readied for surgery often meet with less than perfect results.

About one in three of us are persistent S. aureus carriers, and another third of us are occasional carriers. This bacterial shadow, which abounds on skin (especially the groin and armpits) and is quite at home in the nose, does us no harm most of the time. But if it gets into the bloodstream or internal organs, it can cause life-threatening problems such as sepsis, pneumonia and endocarditis (infection of heart valves). That makes S. aureus not such a good thing to be coated with if you’re about to have your skin punctured by a catheter or pierced by a scalpel.

This is exacerbated by the all-too-frequent presence, particularly in hospital settings, of S. aureus strains resistant to an entire family of antibiotics related to methicillin. In 2011, more than 80,000 severe methicillin-resistant S. aureus infections and more than 11,000 related deaths occurred in the U.S. alone, along with a much higher number of less-severe such infections.

In a study just published in Cell Host & Microbe, Relman – who pioneered the use of ultra-high-volume gene-sequencing techniques to sort out the thousands of species of microbes that communally inhabit our skin, orifices and innards – and his team used this method to show that mucosal sites way up high in our nose, where standard S. aureus-elimination techniques may not reach, can serve as reservoirs for S. aureus. That may, at least in part, explain why efforts to rid patients of this potentially nasty bug have so often fallen short of the mark, as I noted in my news release about the new findings:

Rigorous and somewhat tedious regimens for eliminating S. aureus residing on people’s skin or in their noses do exist, but it’s typically a matter of weeks or months before the bacteria repopulate those who are susceptible. The new study offers a possible reason why this is the case.

Previously: Cultivating the human microbiome, Anti-plaque bacteria: Coming soon to your toothpaste? and Eat a germ, fight an allergy
Photo by OakleyOriginals

Genetics, Microbiology, Research, Stanford News, Transplants

Stanford study in transplant patients could lead to better treatment

Stanford study in transplant patients could lead to better treatment

To keep a patient healthy following an organ transplant, doctors must prescribe the right balance of immune-system-supressing drugs: The medications need to be strong enough to prevent rejection of the foreign body but not leave the immune system at risk for infection. Now, a study by Stanford scientists has pinpointed a little-known virus that spreads when these immunosuppressant drugs take effect. The anellovirus, first identified in 1997, could be a barometer of immune system strength, thereby informing more precise and less reactive treatment for transplant recipients.

Lead author Stephen Quake, PhD, and collaborators isolated specific DNA fragments floating in the blood plasma of 96 heart and lung transplant patients using a technique of genomics, of which Quake is a pioneer. The team studied how the drugs affected the body’s microbiome, or collection of bacteria, fungi and viruses.

As described in a release, the researchers found that “lower levels of anellovirus suggest a stronger immune system and an elevated risk of organ rejection, while higher levels of anellovirus suggest a weaker immune system with a corresponding shift in risk toward vulnerability to infection.”

Hannah Valentine, MD, professor of cardiovascular medicine and senior associate dean for diversity and leadership at the School of Medicine, remarked, “These findings suggest an effective tool to individualize the monitoring and, ultimately, the treatment of rejection. In the future, this could allow us to safely lower the doses of immunosuppressive drugs patients receive, thereby avoiding devastating side effects.”

Previously: Extracting signal from noise to combat organ rejectionWhole-genome fetal sequencing recognized as one of the year’s “10 Breakthrough Technologies” and New techniques to diagnose disease in a fetus

Microbiology, Research

Microbes in your mouth could be a distinguishing characteristic

smile2Oral hygiene still matters (keep your floss handy), but did you know that your mouth’s microbial signature may also play a role in your dental and gum health? That’s according to a recent study that found that among hundreds of species of microbes present in a person’s mouth, only two percent were shared among the four ethnic groups studied.

What’s more, the researchers found ethnicity-distinctive mouth microbial communities among the non-Hispanic black, white, Chinese and Latino populations who participated in the study.

From a release:

[Purnima Kumar, PhD, associate professor of periodontology at The Ohio State University and senior author of the study] used a DNA deep sequencing methodology to obtain an unprecedented in-depth view of these microbial communities in their natural setting.

When the scientists trained a machine to classify each assortment of microbes from under the gums according to ethnicity, a given bacterial community predicted an individual’s ethnicity with 62 percent accuracy. The classifier identified African Americans according to their microbial signature correctly 100 percent of the time.

The findings could help explain why people in some ethnic groups, especially African Americans and Latinos, are more susceptible than others to develop gum disease. The research also confirms that one type of dental treatment is not appropriate for all, and could contribute to a more personalized approach to care of the mouth.

The study was published in PLOS ONE.

Previously: “Mountain Dew mouth” rots teeth, costs taxpayersExploring the microbes that inhabit our bodies and Stanford researchers examine microbial communities of the mouth
Photo by manduhsaurus

Infectious Disease, Microbiology, Nutrition, Research, Stanford News

Joyride: Brief post-antibiotic sugar spike gives pathogens a lift

Joyride: Brief post-antibiotic sugar spike gives pathogens a lift

candy shackLet’s be clear: Antibiotics are a modern miracle. They’re also ancient history: During ancient times, moldy bread was traditionally used in Greece and Serbia to treat wounds and infections. Russian peasants used warm soil to cure infected wounds. Sumerian doctors gave patients beer soup mixed with turtle shells and snake skins. Babylonian doctors healed the eyes using a mixture of frog bile and sour milk. You get the drift.

At the same time, it’s not exactly breaking news that a course of antibiotics can wreak havoc with your gastrointestinal tract, where infamous intestinal pathogens such as salmonella and C. difficile can run amok.

“Antibiotics open the door for these pathogens to take hold,” according to Stanford microbiologist Justin Sonnenburg, PhD.

As I wrote in my press release about some exciting recent work by Sonnenburg, a healthy person’s large intestine is a menagerie teeming with miniature lifeforms:

The thousands of distinct bacterial strains that normally inhabit this challenging but nutrient-rich niche have adapted to it so well that we have difficulty living without them. They manufacture vitamins, provide critical training to our immune systems and even guide the development of our own tissues.

In return, our gut pays these industrious Oompa-Loompas salaries made of sugar – not common table sugar, but more exotic types, with names like fucose and sialic acid. Cells lining the intestine extrude long chains of such sugar varieties (these chains go by a familiar name: “mucus”) to feed its one-celled workhorses – as well as to keep them at arm’s length, so that they don’t get into the bloodstream and cause sepsis.

Everybody’s having fun until along come antibiotics and somebody gets hurt. The decimated gut-microbe ecosystem begins bouncing back within a few days, but  for as much as a month after a round of antibiotics we’re at heightened risk for infection by some bad, bad bugs.

In a new study, Sonnenburg and his colleagues snared some clues about how that works. They found that antibiotics’ inadvertent but inevitable gut-bugicide generates a transient surplus of sugars, including sialic acid and fucose, that have been liberated from gut mucus by good bugs who bit the dust before they got a chance to munch their lunch.

Salmonella lacks the equipment for carving sialic acid and fucose loose from the intestine’s extruded mucus, but it knows how to eat them. The bonanza, Sonnenburg’s team found, gives the pathogen the energy it needs to gain a toehold and launch a toxic takeover, leaving our gut in its hands.

Sonnenburg thinks there may be ways to slam the door that antibiotics open for unwanted intruders. For example, specialized probiotics with big appetites for fucose or sialic acid could be co-administered along with the antibiotics, cutting off the the nasty bugs’ stash until the nice ones repopulate the gut.

Sonnenburg’s work appears online in Nature.

Previously: The future of probiotics, Eat a germ, fight an allergy, What if gut-bacteria communities “remember” past antibiotic exposures? and Researchers manipulate microbes in gut
Photo by Lee Cannon

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

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