Anne-Catrin Uhlemann, MD, PhD, came to Columbia University intending to study drug-resistant malaria, after completing her doctorate on the topic at University College London. But a few months into her clinical fellowship in infectious diseases, an encounter with a patient set her on a different path.
The patient was in his 50s and quite ill, with diabetes as well as end-stage renal disease, and he was admitted with a Staphylococcus aureus infection so severe that it had plunged him into septic shock. Blood cultures revealed that the strain had a low-level resistance to vancomycin, an antibiotic commonly used for blood infections. When she and her team later conducted molecular analysis on the bacteria, they found that all but the first of the patient’s 12 previous Staph infections had come from the same strain of methicillin-resistant Staph aureus, or MRSA, suggesting that somehow, either at home or in the hospital, he was getting reinfected.
That strain was USA300, a MRSA “superbug” that emerged in epidemic waves in schools, sports teams, prisons, and other community environments outside the United States in the 1990s. In most cases the infection only involves the skin and is treatable, but severe pneumonia, blood infection, or a rare but life-threatening flesh-eating infection occurs in about one in every 10 people with staphylococcal infections. “While these types of infections are described everywhere, there’s no place except the United States where one clone accounts for so many cases,” says Dr. Uhlemann. “The numbers really went up staggeringly in about 2000.”
“Our study of a community of drug users in Brooklyn was among the first large community-based studies looking at Staph transmission.”
In 2005, just two years before Dr. Uhlemann encountered her patient, the CDC reported almost 19,000 U.S. deaths after a MRSA infection. And though USA300 first emerged in the community, it is now one of the most common causes of hospital-acquired infections as well. Hospital-acquired infection rates have decreased considerably, but even so the pathogen is still present and very much considered a public health menace.
Dr. Uhlemann and her colleagues were able to treat the patient and finally cure his infection, but she was left with a question she felt compelled to answer: How was Staph’s changing genetic makeup making this strain so virulent and propelling its spread? She grabbed the chance to apply what she knew about drug resistance from her studies of malaria to a disease she was encountering so frequently right in front of her eyes. “I saw endless numbers of terrible, invasive Staph aureus infections during my fellowship. It made me appreciate what a powerful pathogen S. aureus is,” Dr. Uhlemann says.
Tracking Down the Source of Infections
When some of the first community-associated USA300 outbreaks began, Franklin D. Lowy, MD, found himself right in the middle of them. He first encountered Staph in the 1970s, during his medical training at Harlem Hospital and his infectious disease fellowship at the Albert Einstein College of Medicine in the Bronx. The neighborhoods around both hospitals were plagued with a high rate of injection drug use, so many of his patients had Staph infections. Staph was the single most important bacterial pathogen among these patients, causing skin infections around the injection site or more serious systemic infections that traveled into their heart, joints, or lungs.
As Staph infections became common in the ’90s, Dr. Lowy wondered how the bacteria spread through this population and he suspected that drug users served as reservoirs, potentially seeding others in the community with these bacteria. Techniques for understanding transmission pathways of infection were just being developed at the time, and so-called “hidden populations”—people on the margins of society—were especially hard to track. Dr. Lowy set out to compare isolates of Staph aureus in a group of drug users in Yonkers, N.Y. Working with a local drug counselor, the team swabbed people’s noses and their drug paraphernalia, then used a DNA analysis technique called pulsed field gel electrophoresis—the state of the art at the time—to characterize the strains each person carried. By mapping the molecular features of the strains people carried, the group was able to re-create the social network in the group with startling precision. “This was just a remarkable finding that surprised us all in terms of how clean the data were,” Dr. Lowy says. “It really provided a method for looking at linkages that were not otherwise detectable.”
Researchers aim to use genomic data to track infections and maybe even identify hotspots of risk before outbreaks take off.
Using these same techniques, he teamed up with Maureen Miller, PhD, an epidemiologist at the Mailman School and an expert in social networks, to examine transmission in a broader community. “Our study of a community of drug users in Brooklyn was among the first large community-based studies looking at Staph transmission,” Dr. Lowy says.
Drs. Lowy and Miller expected to find MRSA spreading through high-risk social networks—injection drug users and people who knew lots of users—but to their surprise, the molecular epidemiology showed that many strains were spread widely within the entire community. That suggested that people were picking up infections from common environmental sources like homes, workplaces, and schools. Subsequent studies in households and businesses of northern Manhattan and in the New York state prison system supported the notion that a strain could establish itself in a particular environment. But the research still did not reveal how the strains passed from person to person.
As whole genome sequencing became cheaper and more accessible toward the end of the last decade, the researchers embraced its ability to track transmission more precisely; Drs. Lowy and Uhlemann used it essentially to reconstruct the evolutionary history of USA300 in northern Manhattan and the Bronx. At first, the work was slow-going: Sequencing methods were still clunky and it took more than two years to sequence the first eight isolates. But then things took off: In the subsequent four years, the group sequenced some 400 samples of MRSA from 161 people from these local communities who had experienced community-associated infections between 2009 and 2011. To map the strain’s transmission, each sample was characterized with information on participants’ medical histories, antibiotic use, and where they lived.
By looking at differences between strains in both sick people and healthy control subjects, the researchers concluded that community-associated MRSA first arose in 1993 in these neighborhoods and that it was re-introduced into the geographical area multiple times. The genomic diversity among the strains was surprising, Dr. Uhlemann says. Almost every household harbored its own unique strain. “We were able to provide genetic proof, based on the similarity of isolates within a household, that they sort of ping-pong around between individuals, either as colonizers or sometimes causing infections,” she explains. There were only a few cases of a single clone being found in multiple households, and the mechanism for this wider-spread transmission is unknown.
Dr. Uhlemann is now working with Dr. Lowy on his prison studies to determine whether the movement of inmates from one state prison to another accounts for the spread of strains.
A promising technology selectively kills bacteria but not human cells in a petri dish and has the potential to disinfect surgical theaters by bathing them in ultraviolet light.
Ultimately, says Dr. Lowy, the aim is to use genomic data to track infections and maybe even identify hotspots of risk before outbreaks take off. “In order to disrupt the ongoing epidemic of community-acquired MRSA infections, it’s critical that we identify the sources and reservoirs of transmission,” say the researchers. Dr. Lowy and Dr. Uhlemann have begun collecting pilot data for creating what they call the New York City “antibiotic resistome,” a map of all antibiotic resistance genes across the city, including those found in MRSA. Researchers would sample people’s homes, their bodies, and fast food restaurant toilets. The researchers plan to overlay this map with the locations of pharmacies, bodegas, hospitals, day care facilities, and other places where infections often strike in the hope that it will pinpoint variables that might predict where hotspots of antibiotic resistance might turn up. Classically, awareness of an epidemic begins after individuals with infections are identified. “That’s already pretty late in the game,” says Dr. Lowy. This geographically based analysis, however, might be able to flag an increased risk of an antibiotic-resistant epidemic such as MRSA before people get sick. “It’s a very different approach to surveillance,” he adds.
David Brenner, PhD, the Higgins Professor of Radiation Biophysics (in Radiation Oncology) and director, Center for Radiological Research
Franklin Lowy, MD, professor of medicine and of pathology & cell biology (in epidemiology) at CUMC
Maureen Miller, PhD, adjunct associate professor of epidemiology, Mailman School of Public Health
Dane Parker, PhD, assistant professor of microbial pathogenesis (in pediatrics)
Alice Prince, MD, the John M. Driscoll Jr. MD and Yvonne Driscoll MD Professor of Pediatrics in the Division of Infectious Diseases
Gerhard Randers-Pehrson, PhD, senior research scientist, Center for Radiological Research
Anne-Catrin Uhlemann, MD, PhD, the Florence Irving Assistant Professor of Medicine
In the hospital, too, genomics should play a larger role in pinpointing and containing infections. For example, sequencing and comparing every bacterial isolate that is found can reveal patterns—did all the patients with the same clone see the same respiratory therapist or undergo the same procedure?—that could allow researchers to root out the cause of infections in real time, Dr. Uhlemann says. “This technology really has to become an integral part of delivering care.”
Why is MRSA So Destructive?
Methicillin resistance itself is not the scary part of MRSA, explains Alice Prince, MD, who has spent decades investigating how the bacterium activates a damaging immune response in the host. Apart from rare cases—like Dr. Uhlemann’s patient—clinicians do have antibiotics in their armament that can treat it. “What is a big deal is that in addition to that one gene, USA300 has a whole bunch of other virulence factors that make it especially destructive,” says Dr. Prince.
Staph colonizes the noses and mouths of about one-third of the population, but only some people get sick. Understanding this differential response requires looking past the microbe itself, says Dr. Prince. People can die from Staph and other infections even when bacteria do respond to antibiotics, she adds. “That suggests to me that there’s something other than being able to kill the organism with antibiotics that’s important.” This other factor is the host response to infection. “With complicated organisms like MRSA, we want to identify what it is about the immune response that is aberrant or dysregulated in some people that causes them to get sick or even die.”
Dr. Prince began her career studying why children with cystic fibrosis experience so many respiratory infections. She set out to understand the protective and destructive cell signaling pathways that microbial pathogens could spark. At first, she focused on the bacterium Pseudomonas aeruginosa, but in the mid-1990s, a lab member’s interest in Staph infections, which are also an issue for kids with CF, broadened her scope.
Basic questions about bacterial infections of the lung were unknown, including how the lung first detected the presence of bacteria and initiated a response. A few years later, a PhD student in the lab and his fiancée, who was studying calcium signaling in neurons, were tinkering in the lab late one night and found that infections with both pathogens activated changes in calcium concentration in airway epithelial cells in the lung. Calcium signaling is a major way that cells communicate. It turned out, as the group’s study showed, that cells used it to tell their neighbors that they were infected with these pathogens.
Gradually, the group is learning how these and other signals amplify or limit the intensity of an infection. In 2004, researchers identified one central mechanism through which Staph turns on inflammatory cytokines. A protein on its cell surface called Protein A, they found, plugs into a major immune signaling molecule, tumor necrosis factor, to turn on the spigot of inflammatory molecules in the host’s body. This pathway turned out to drive the development of pneumonia after Staph infections. “You need a little bit of inflammation to fight infection,” says Dr. Prince, “but a recurring theme of our work is that Staph causes too much inflammation, which turns out to be destructive.”
The Prince lab is also looking into why some people are more prone to MRSA infections, including people who have just had influenza. To fight flu, the body activates an immune response mediated by molecules called interferons. The group’s studies showed that interferons activated by influenza were helpful for battling the flu, explains Dane Parker, PhD, who led the work while he was a postdoc in the Prince lab. But mice that were genetically engineered to lack specific interferons actually recovered better from Staph infections than normal mice.
Not only does the body’s reaction to influenza hamper its response to Staph, the viral response also seems to invite Staph in. In a study published this year, Drs. Parker and Prince and others in the lab found that when the virus activates type 3 interferons, the bacterial community in a person’s nose changes and colonization by Staph increases. That, in turn, means a significantly greater risk of a full-blown infection.
People with diabetes are more prone to Staph and MRSA infections in their skin. “I’ve got some preliminary evidence suggesting that high glucose levels dampen cells’ ability to kill Staph aureus, so I’d like to look more at how glucose manipulates the physiology of the bacterium,” Dr. Parker says.
Studying Staph in the lab is difficult, though, compared with some other bacteria, because mice lack receptors for some of the key toxins that the infection produces, particularly those caused by MRSA. Dr. Parker has recently begun using the Columbia Center for Translational Immunology’s humanized mouse core, which develops humanized mouse models with functional human hematopoietic and lymphoid systems, including novel humanized mouse models with robust, functional human immune systems.
Ultimately, the immune signaling molecules identified in the host response could provide therapeutic targets to help treat MRSA infections, say Drs. Parker and Prince. “It won’t replace antibiotics, but it could be synergistic,” Dr. Parker explains. “Modulating these inflammatory cascades could give the host immune system a better fighting chance to do its job, while the antibiotics work on killing the bacteria.”
Preventing Surgical Site Infections
Targeting the immune system, either with antibiotics or immune modulators, deals with infections after they happen. Other researchers at Columbia are working on new ways to prevent them from occurring in the first place.
In the hospital, one major route of hospital-acquired infections is surgery. Every year, some 650,000 people in the United States get sick from infections they develop in the hospital, and 75,000 of them die, according to the Centers for Disease Control and Prevention. MRSA is a particular scourge, causing a quarter of all postsurgical cases.
About three years ago, scientists and physicians at P&S started looking for a solution to the vexing problem of surgical site infections. David Brenner, PhD, who directs Columbia’s Center for Radiological Research, immediately thought of a widely used method of disinfecting surgical theaters: bathing them in ultraviolet light.
“We knew that UV light was very good at killing all sorts of microbes, be they bacteria or viruses,” he says. “UV light doesn’t care whether the bacteria are drug-resistant or drug-sensitive; it kills bacteria by a completely different mechanism.”
Conventional germicidal lamps, however, use 254-nanometer (nm) light, a wavelength that kills human cells as well as microbial ones and causes cancer and cataracts in exposed people. Dr. Brenner’s collaborator, Gerhard Randers-Pehrson, PhD, had a solution. He suspected that UV wavelengths between 200 and 225 nanometers could penetrate and kill small cells, like bacteria and viruses, but leave human cells, which are much larger, unharmed. The duo set out to build a device that delivers this so-called narrow-spectrum farUVC light.
Dr. Lowy provided the radiologists with MRSA and trained them how to work with the pathogen. The team’s first study on the approach, published in 2013, showed that their technology, which they call the differential UV sterilizer (DUVS), selectively killed bacteria but not human cells in a petri dish. “That was the first indication that the idea was maybe not a bad one,” Dr. Brenner says. More recently, the group examined the device’s MRSA-zapping abilities on 3-D sheets of human skin as well as in a mouse model. Both tests showed that DUVS killed MRSA without causing any harm to the human skin or the mouse tissues.
The next step is to determine whether the device helps patients in the real world of the operating room. Those tests are still to come, but Columbia has signed an agreement with the Japanese lighting company Ushio to manufacture the light sources if all goes as planned. Dr. Brenner envisions integrating DUVS light sources into the illumination lamp above the operating table, or perhaps into surgical headlamps that surgeons often wear. The applications potentially go well beyond the operating room, Dr. Brenner says. “Imagine any room, like a doctor’s waiting room or a classroom in a school,” he says, where it could kill not just MRSA but also influenza virus or tuberculosis bacteria. “You might even think of it in airports, to stop the spread of global pandemics.”
Despite progress on multiple fronts, much work remains to be done. Researchers have only just begun to tap the potential of genome sequencing to create more precise systems of surveillance and to identify people at the highest risk of infection, says Dr. Uhlemann. Ideas on developing interventions, too—from effectively eradicating the bug from a host individual to interfering with the inflammatory processes it switches on—are just dawning.
“There is still a lot we need to understand about how these organisms cause disease,” says Dr. Prince.