by Elise Wachspress
Staphylococcus aureus (commonly called Staph) is found on the skin and in the nose, throat, and gastrointestinal tract of about a third of the human population. Staph is one of the many “commensal” bacteria that routinely make their homes in our bodies, usually without incident.
But if Staph grows unchecked, it can cause problems. Staph infections on skin and other soft tissues account for about 14 million outpatient or emergency visits in the U.S. each year, and some populations, especially those in military training, experience significantly greater risks.
Staph can also become more invasive, infecting deep tissues, the lungs, blood stream, skeletal structures and joints, urinary tract, or heart lining. It can even cause sepsis, an especially dangerous systemic condition. Low-birth-weight babies, nursing homes residents, surgical patients, diabetics, cancer patients, or anyone with “foreign” appliances in their bodies (like implants, catheters, or ventilators) are more vulnerable to these kinds of Staph infections.
Generally, our bodies are quite adept at building weaponry—antibodies—against bacteria and viruses. Once the body produces these defenders, they tend to become part of a lifelong arsenal, effective deterrents against future infection by that specific interloper. But although healthy people from infant to adults carry Staph antibodies, these often fail to keep this particular bacteria from re-establishing itself. In fact, once you’ve had a Staph infection, you are more likely to get the infection again, even if you’ve been effectively treated with surgery or antibiotics.
The rise of antibiotic-resistant strains—namely methicillin-resistant Staph aureus, commonly known as MRSA—makes this problem especially worrisome. We are running out of antibacterial armaments to stop MRSA infections, and the cost of the fight is astronomical, estimated at over $10 billion per year in the U.S. alone. Finding a new way to reduce MRSA infections is critical.
University of Chicago microbiologists Olaf Schneewind, MD, PhD, and Dominique Missiakas, PhD, have found that a protein, SpA, which rides on the surface of the Staph bacterium blocks the development of effective antibodies. The Schneewind/Missiakas team cleverly generated mutant proteins, with new chemical groups at the binding sites of SpA, disordering the bacterium’s ability to block the development of antibodies. Early studies show these new proteins are effective in helping the immune system respond much more effectively to Staph colonization, and now the team is tweaking the molecules to find the most powerful version.
With the support of the Polsky Center for Entrepreneurship and Innovation, they have now launched a new company, ImmunArtes, to move their discovery toward commercialization. In December, the team won a $175,000 investment from the University of Chicago Innovation Fund.
In theory, the modified molecule could be a twofer: the basis for a vaccine against MRSA and a potential treatment for those already infected. The team recognizes the problem implicit in the latter strategy: MRSA can become lethal so quickly that the patient might die before the body can make enough antibodies.
The vaccine strategy also presents challenges. Several pharmaceutical companies (Merck, GlaxoSmithKline, and Novartis) have tried in vain to develop Staph vaccines or immune therapeutics; others (Pfizer and MedImmune), are still trying. What makes the prospect of a successful vaccine or antibody therapy so daunting is the multitude of evasive mechanisms deployed by Staph. Nevertheless, Schneewind and Missiakas are confident their vaccine strategy can overcome these obstacles, help decolonize Staph in humans, and reduce the risk of new Staph infection. The team is launching an aggressive development plan, producing clinical grade vaccine, generating preclinical data, and launching a human trial within the next three years.
The value of an effective vaccine would be tremendous. The nursing home industry is already taking note, and gyms, schools, and daycare centers will certainly be important beneficiaries of a MRSA vaccine.
Success will put the world one tool closer in the battle against antibiotic-resistant superbugs.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office
by Katya Frazier
Graduate student in the Committee on Molecular Metabolism and Nutrition
If you’ve had strep throat or an ear infection, you likely have deep respect for antibiotics. They powerfully fight off bacteria—by damaging their DNA, disarming their protein-making machinery, or causing their cell walls to explode.
But what happens if antibiotics inadvertently target the “good” bacteria in our bodies? These are the micro-organisms that help us digest our food, make our vitamins, keep our skin moisturized, tune our immune system, and so much more.
For over a decade, scientists and physicians have noticed a connection between early use of antibiotics and inflammatory bowel diseases (IBD)—chronic, painful gastrointestinal conditions that are growing in incidence at an alarming rate. IBD, the umbrella term for Crohn’s disease and ulcerative colitis, affects over 1.5 million in the U.S. alone. As many people can attest, there are few effective therapies that provide lasting relief.
Recently, Eugene Chang, MD, and his team at the University of Chicago published a study aiming to understand the connection between antibiotics and IBD development. In this study, Jun Miyoshi, MD, PhD, and Alexandria Bobe, PhD, treated pregnant, genetically susceptible mice with antibiotics and then observed both the mothers and their new pups over time.
Mouse pups whose mothers were treated with antibiotics did, indeed, tend to develop IBD-like symptoms, but the evidence showed a more complicated story. Since the antibiotics were not transmitted from mother to pups, Miyoshi and Bobe could determine that it wasn’t the antibiotics themselves that triggered the IBD symptoms. Instead, the antibiotics disrupted the bacterial community in the mothers, and this unbalanced microbiota (dysbiosis) was transferred to the pups during pregnancy, delivery, and nursing. The gut dysbiosis skewed the pups’ immune system, priming them for inflammation and increased development of IBD-like symptoms, as compared to non-treated mice.
Interestingly, the mothers of these pups, as well as other adult mice given the same antibiotic exposure, tended not to develop symptoms, which include weight loss and diarrhea. It was as if their immune systems, which were fully mature before they were exposed to the antibiotics, kept them from developing symptoms—even though they were genetically primed.
These experiments seem to indicate a direct, causal link between gut dysbiosis—an imbalance of bacteria in the gut, which can be caused by antibiotic use—and later development of IBD, especially in those with both immature immune systems and a background of genetic susceptibility. This is not to say that we should stop using antibiotics, as they can be crucial, life-saving treatments. What this study does show is the powerful, complex effects of gut bacteria during early life on our health. And this may be true not just for IBD, but other inflammatory diseases as well, from allergies to certain types of arthritis.
This research and others suggest promising new avenues to improve health. What if the balance of bacteria in our gut could be used as a biomarker to diagnose or even predict IBD? And what if we could find a way to reset the microbiota in the gut and tame the inflammation that results in IBD?
Diving into the complex mechanisms of the gut microbiome
Although research has revealed so much, the mechanisms by which the microbes in our bodies affect disease are still cloudy. Microbial communities in the gut are not only complex, but thrive only in an air-free environment, which makes them particularly difficult to study. But the more we discover about the dynamics of the microbiome—in both healthy and sick individuals—the better chance we have to turn the dial towards health. The Duchossois Family Institute was established to advance these discoveries.
But that is only part of the Duchossois Family Institute mission. It will also drive translation of bench research on the microbiome more efficiently into the clinic and back again to the lab. We need to better understand how our current lifestyles and treatments affect the bacteria living within us, so we can help countless other people achieve a lifetime of vigor and good health.
Photo by Seweryn Olkowicz/WIKIMEDIA COMMONS
by Renée de Pooter, PhD
Staff scientist in the Department of Pathology
Every year as the days get shorter and kids head back to school, we are reminded of both the vulnerability and the importance of our immune systems. Your doctor, your family and friends, maybe even your employer asks if you’ve had your flu shot yet.
It’s an important question. The CDC estimates that the 2015-2016 flu season cost the US economy $7 billion in lost productivity and contributed to 12,000 deaths. And those who have survived the flu aren’t likely to forget the cough, high fever, muscle pain and sheer debilitating exhaustion.
Every year, vaccine manufacturers churn out 179 million doses of vaccine, an estimated $1.6 billion/year industry. That’s a lot of money for something that does not always work well.
Every year, flu vaccine manufacturers have to make an educated guess about which strains of flu to include in their vaccine, based on the recommendations of the World Health Organization. In the northern hemisphere, the guessing game starts in spring, to assure there are stockpiles of that year’s vaccine ready before the December-to-March flu season.
There is no sure way to predict how the flu will mutate from year to year. Like an errant monk distracted by worldly thoughts, the flu virus is a poor copyist: every time it replicates it makes little mistakes that cause small changes, called “antigenic drift.” More dramatically, because some types of flu can infect pigs or fowl as well as humans, these animals can pick up a completely different version of a gene from another virus that infects the same animal. Those viruses can undergo an even more profound “antigenic shift,” as if the befuddled monk started one day by copying from an entirely different book.
The 2015-2016 flu vaccine was pretty successful, with an estimated vaccine effectiveness (VE) of 48 percent. The 2014-2015 vaccine was less effective and had an overall VE of just 19 percent. More worryingly, it’s hard to predict real wild-card events, like the antigenic shift that created the 1918 pandemic.
By tapping into our immune system’s memories, Patrick Wilson, PhD, associate professor of medicine at the University of Chicago, hopes his research will lead to a universal flu vaccine, one that will protect everyone, perhaps for a lifetime.
The best vaccine targets are the proteins that stud the outside of the virus particle like sprinkles on a cupcake. If the vaccine can goad the body into making antibodies that lock onto the sprinkles, the virus can’t infect human cells. Over time, scientists have learned that the most protective antibodies tend to focus on a protein called hemagglutinin.
Hemagglutinin is shaped like a lollipop, a slender stalk with a big blob—the head region—at the end. While the stalks of different flu strains are pretty similar, the head regions are highly mutable, changing every year. Unfortunately, immune-soldier cells—the B cells—tend to get fixated on the sugary ball of the lollipop and ignore the blander stalk. In doing so, they miss the chance to create an immune memory that would offer broad protection against multiple strains of flu.
Viruses have evolved to use this sneaky distraction technique to elude the host’s immune system.
To better understand how vaccines and the flu shape our immune system, Wilson and his group looked at individual B cells in people vaccinated against the flu. They found that the B cells that produced antibodies against the stalk were hold-overs from previous immunizations/infections, multiple-tour soldiers called memory B cells. They went on to prove that the antibodies made by these stalk-specific memory B cells could protect people against new strains of flu they’d never encountered, confirming that immunity to the stalk confers broad protection against the flu.
Wilson’s group is now working to better understand which vaccination strategy would get the body’s B cells to ignore the tempting head region and make more antibodies against the stalk. If they can figure this out, we could design vaccines that protect against the flu year after year, saving thousands of lives and billions of dollars.
Read about how evolution helps to forecast the flu in the University of Chicago Medicine’s ScienceLife.