“Shock Medicine”: The “Inflammatory Reflex”

27 04 2015

We’re all familiar with the normal reflexes that are triggered when we are struck with a mallet in just the right spot, touch a hot stove, or flinch at an unexpected noise. What most of us don’t realize is that many reflexes are occurring beyond our perception. One of the most important reflexes is our body’s natural response to infection or injury. When a signal travels the neural pathways between the organs and the brain, it can sometimes result in what Dr. Kevin Tracey has dubbed the “inflammatory reflex”.

Our growing understanding of this critical “reflex” is pioneering a revolutionary new therapeutic strategy called bioelectronic medicine, which unlike treatments with pills and injections, takes advantage of the body’s natural control mechanisms to treat inflammation and other diseases. Dr. Tracey, a brain surgeon, has devoted his career to researching molecules that cause inflammation; in the 1980’s, he was part of the team that discovered the critical role of tumor necrosis factor (TNF) in infection and sepsis.

The immune system normally protects the body against infection and injury, and the inflammatory reflex is a biological mechanism that regulates the immune response. Failure of this protective mechanism can lead to diseases such as rheumatoid arthritis and lupus, which are caused by an overactive immune response. Tracey’s research on TNF unexpectedly led to the discovery that the nervous system plays a key role in regulating the immune response. He showed that injecting a small amount of a drug that inhibits TNF into the brain actually blocked production of TNF throughout the body. He determined this effect was dependent on the vagus nerve, which transmits nerve impulses to and from several organs and the brain.

Dr. Tracey has developed an electrical device that stimulates the vagus nerve and prevents production of TNF by a type of immune cell called a macrophage, effectively inhibiting inflammation. Use of this device has dramatically improved symptoms in patients with rheumatoid arthritis. Studies in numerous other diseases are underway, and there are many additional potential applications.

 

Read more about Dr. Tracey’s discoveries, and his vision for the future of medicine in Scientific American.

 

 

Feinsteininstitute.org [en línea] Manhasset, NY (USA): feinsteininstitute.org, 27 de abril de 2015 [ref. 18 de febrero de 2015] Disponible en Internet: http://www.feinsteininstitute.org/programs-researchers/featured-programs/bioelectronic-medicine/tapping-reflexes-treat-disease/



Chronic Fatigue Syndrome Is a Biological Illness

2 03 2015

Scientists Discover Robust Evidence That Chronic Fatigue Syndrome Is a Biological Illness.

Immune Signatures in Blood Point to Distinct Disease Stages, Open Door to Better Diagnosis and Treatment

 

Mady Hornig, MD

Researchers at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health identified distinct immune changes in patients diagnosed with chronic fatigue syndrome, known medically as myalgic encephalomyelitis (ME/CFS) or systemic exertion intolerance disease. The findings could help improve diagnosis and identify treatment options for the disabling disorder, in which symptoms range from extreme fatigue and difficulty concentrating to headaches and muscle pain.

These immune signatures represent the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages. Results appear online in the new American Association for the Advancement of Science journal, Science Advances.

With funding to support studies of immune and infectious mechanisms of disease from the Chronic Fatigue Initiative of the Hutchins Family Foundation, the researchers used immunoassay testing methods to determine the levels of 51 immune biomarkers in blood plasma samples collected through two multicenter studies that represented a total of 298 ME/CFS patients and 348 healthy controls. They found specific patterns in patients who had the disease three years or less that were not present in controls or in patients who had the disease for more than three years. Short duration patients had increased amounts of many different types of immune molecules called cytokines. The association was unusually strong with a cytokine called interferon gamma that has been linked to the fatigue that follows many viral infections, including Epstein-Barr virus (the cause of infectious mononucleosis). Cytokine levels were not explained by symptom severity.

“We now have evidence confirming what millions of people with this disease already know, that ME/CFS isn’t psychological,” states lead author Mady Hornig, MD, director of translational research at the Center for Infection and Immunity and associate professor of Epidemiology at Columbia’s Mailman School. “Our results should accelerate the process of establishing the diagnosis after individuals first fall ill as well as discovery of new treatment strategies focusing on these early blood markers.”

There are already human monoclonal antibodies on the market that can dampen levels of a cytokine called interleukin-17A that is among those the study shows were elevated in early-stage patients. Before any drugs can be tested in a clinical trial, Dr. Hornig and colleagues hope to replicate the current, cross-sectional results in a longitudinal study that follows patients for a year to see how cytokine levels, including interleukin-17A, differ within individual patients over time, depending on how long they have had the disease.

 

Stuck in High Gear

The study supports the idea that ME/CFS may reflect an infectious “hit-and-run” event. Patients often report getting sick, sometimes from something as common as infectious mononucleosis (Epstein-Barr virus), and never fully recover. The new research suggests that these infections throw a wrench in the immune system’s ability to quiet itself after the acute infection, to return to a homeostatic balance; the immune response becomes like a car stuck in high gear. “It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop,” says Dr. Hornig. “Early diagnosis may provide unique opportunities for treatment that likely differ from those that would be appropriate in later phases of the illness.”

The investigators went to great lengths to carefully screen participants to make sure they had the disease. The researchers also recruited greater numbers of patients whose diagnosis was of relatively recent onset. Patients’ stress levels were standardized; before each blood draw, patients were asked to complete standardized paperwork, in part to engender fatigue. The scientists also controlled for factors known to affect the immune system, including the time of day, season and geographic location where the samples were taken, as well as age, sex and ethnicity/race.

In 2012, W. Ian Lipkin, MD, director of the Center for Infection and Immunity, and colleagues reported the results of a multicenter study that definitively ruled out two viruses thought to be implicated in ME/CFS: XMRV (xenotropic murine leukemia virus [MLV]-related virus) and murine retrovirus-like sequences (designated pMLV: polytropic MLV). In the coming weeks, Drs. Hornig and Lipkin expect to report the results of a second study of cerebrospinal fluid from ME/CFS patients. In separate ongoing studies, they are looking for “molecular footprints” of the specific agents behind the disease—be they viral, bacterial, or fungal—as well as the longitudinal look at how plasma cytokine patterns change within ME/CFS patients and controls across a one-year period, as noted above.

“This study delivers what has eluded us for so long: unequivocal evidence of immunological dysfunction in ME/CFS and diagnostic biomarkers for disease,” says Dr. Lipkin, senior author of the current study and the John Snow Professor of Epidemiology at Columbia’s Mailman School. “The question we are trying to address in a parallel microbiome project is what triggers this dysfunction.”

Co-authors include Andrew F. Schultz, Xiaoyu Che, and Meredith L. Eddy at the Center for Infection and Immunity; Jose G. Montoya at Stanford University; Anthony L. Komaroff at Harvard Medical School; Nancy G. Klimas at Nova Southeastern University; Susan Levine at Levine Clinic; Donna Felsenstein at Massachusetts General Hospital; Lucinda Bateman at Fatigue Consultation Clinic; and Daniel L. Peterson and Gunnar Gottschalk at Sierra Internal Medicine. The authors report no competing interests.

Support for the study was provided by the Chronic Fatigue Initiative of the Hutchins Family Foundation and the National Institutes of Health (AI057158; Northeast Biodefense Center-Lipkin).

 

 

About Columbia University’s Mailman School of Public Health
 
Founded in 1922, Columbia University’s Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 450 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,300 graduate students from more than 40 nations pursuing a variety of master’s and doctoral degree programs. For more information, please visit www.mailman.columbia.edu.

 

Mailman.columbia.edu [en línea] New York, NY (USA): mailman.columbia.edu, 02 de marzo de 2015 [ref. 27 de febrero de 2015] Disponible en Internet: http://www.mailman.columbia.edu/news/scientists-discover-robust-evidence-chronic-fatigue-syndrome-biological-illness

 



Epidemic Proportions

3 10 2013

The fight against infectious diseases increasingly links discovery with care

 

A WAR WITH LITTLE PEACE: The incidence of extensively drug-resistant tuberculosis continues to grow in Russia. This young man is a patient in a tuberculosis ward in a psychiatric hospital in the North Caucasus region of that nation.

 

 When Mycobacterium tuberculosis invades a person’s body, it doesn’t just settle into the lungs and look for a spot from which to eke out a living. It hijacks that person’s macrophages—cells that attack invading bacteria—and uses the mechanisms of inflammation to manipulate the environment around it, remodeling its new home to suit its needs.

 

Salmaan Keshavjee knew about Mycobacterium’s penchant for makeovers, and thought that this knowledge might be useful in the fight against tuberculosis. So he was intrigued when he learned of an unusual approach that researchers at Sweden’s Karolinska Institutet were taking to control these bacteria-orchestrated renovations.

To understand this twist in the body’s normal path of self-defense, and to find ways to get the immune response back on track, the Sweden-based team, led by Markus Maeurer, a professor of clinical immunology at the institute, had cultured the mesenchymal stem cells from patients with extensively drug-resistant tuberculosis (XDR TB), then reinfused the patients with those cultured stem cells. Because mesenchymal stem cells help suppress inflammation, the researchers wanted to see if they could safely dampen and refocus the inflammatory response without  compromising immune function.

“Their preliminary data suggested that the stem cells didn’t suppress immunity in an adverse way, and surprisingly, the patients who received the transplanted cells did much better on their XDR TB treatment than typical patients in their condition,” says Keshavjee, an HMS associate professor in the Department of Global Health and Social Medicine and a physician in the Division of Global Health Equity at Brigham and Women’s Hospital. With the treatments now in use, fewer than a third of patients with XDR TB recover, but in this small initial study, all the participants appeared to recover.

Keshavjee is developing a partnership with the institute’s team, laying a foundation for more-extensive trials of the treatment in Russia and Peru. “Saving lives from a disease that’s killing people—that’s always good,” Keshavjee says. “But this work also opens the door to thinking about tuberculosis differently. If the mycobacterium is manipulating its environment by modulating T cells and other immune cells, we need to ask, ‘What if we unmodulate that environment?’ ”

“Inside our bodies, the bugs are living in an ecosystem,” he adds. “As humans, we also have our own ecology, which plays out in society. Recognizing the complex biosocial nature of infectious diseases moves you toward some crucial insights about how these diseases work and how to fight them.”

To fight infectious diseases worldwide, biomedical researchers and clinicians are joining efforts to apply laboratory-based discoveries to the challenge of saving the lives of people with tuberculosis, cholera, and other age-old ravages. These international collaborations are increasingly considering such diseases in context, as integrated parts of complex interconnected systems that involve humans.

 

“We now have genomic and proteomic platforms that are beginning to have immediate relevance to the challenges of diagnosing and treating infectious disease in poor communities,” says Paul Farmer ’90, the Kolokotrones University Professor at Harvard, head of the Department of Global Health and Social Medicine at HMS, and a cofounder of Partners In Health, an international nonprofit that brings health care to the poor. “Many of these new technologies are more portable, scalable, and affordable than ever before.”

 

In Black and White

Tuberculosis is a global public health issue that is unevenly distributed: the burden of the disease is highest in Asia and Africa, with India and China accounting for almost 40 percent of cases. Africa has 24 percent of the world’s cases and the highest rates of disease and death per capita. In the Russian Federation, XDR TB is a particular concern: it has rapidly spread through prison populations. In Peru, while the incidence of tuberculosis is decreasing, the incidence of multidrug-resistant tuberculosis is on the rise. Overall, according to a 2012 report from the World Health Organization, there were an estimated 8.7 million new cases of tuberculosis and 1.4 million deaths worldwide from the disease in 2011.

Similar sobering statistics can be found for cholera. Although up to 80 percent of cholera cases can be successfully treated with low-cost oral rehydration salts, the WHO estimates that annually more than 100,000 people succumb to the disease.The impact of cholera is most acute in regions with poor sanitation and unsafe supplies of drinking water, conditions that annually spawn three to five million cases worldwide. The entire country of Bangladesh is considered at high risk for this disease, the only country with this designation from the WHO.

 

Delete Buttons

Like tuberculosis, cholera elicits a complex immune response. The infection takes place in the mucosal membrane of the small intestine, where billions of beneficial bacteria live. Our gut microbiota perform welcome chores such as fermenting carbohydrates to release their useful energy. Although our gut mucosa is always on the alert for foreign bacteria, killing every newcomer would be imprudent, as some may be useful in maintaining the health of their human host. Yet when a pathogen is identified, the mucosal cells mount a vigorous immune response.

 

Unfortunately, the basic mechanisms of that response are still poorly understood. This knowledge gap has hindered the development of effective, durable vaccines for diseases such as cholera. In fact, current vaccines offer only partial protection that lasts for just a few years.

To extend this protection, or perhaps even block the disease permanently, researchers, including John Mekalanos, the Adele H. Lehman Professor of Microbiology and Molecular Genetics and head of the Department of Microbiology and Immunobiology at HMS, are tweaking the genetic makeup of Vibrio cholerae. The trick has been determining how to eliminate the genes that turn off the disease without disturbing the ones that elicit an immune reaction. Mekalanos, along with Mike Levine at the University of Maryland, has pioneered the use of a live oral cholera vaccine. This vaccine uses a genetically altered version of the organism that is unable to cause disease.

In addition to learning which genes halt the cholera bacterium, it is necessary to understand which ones are activated during its transmission and infection. Stephen Calderwood ’75, the Morton N. Swartz, M.D. Academy Professor of Medicine (Microbiology and Immunobiology) at HMS and Massachusetts General Hospital, is looking at gene expression at different points in V. cholerae’s life cycle to determine which genes are expressed by the pathogen during infection, as well as which trigger immune responses in the human host.

For this research, Calderwood is collaborating with clinicians and researchers at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh. Calderwood’s team has collected thousands of samples from patients who have been hospitalized with severe cholera.

 

The Sniff Test

The insights from such molecular biology studies can also lead to some surprising diagnostic tools for infectious disease. The tubercle bacterium, for example, can be insidious; it can lurk in the lungs of a mildly infected patient for years. Active infections of the bacterium, however, release a detectable signature of volatile organic compounds. This airborne fingerprint may be useful in diagnosing the disease, particularly in children; not only is it difficult for them to produce sufficient sputum for analysis, their sputum contains relatively few of the organisms.

“A baby’s exhalation could be captured,” says Ed Nardell, an HMS associate professor of medicine at Brigham and Women’s, “so she wouldn’t need to produce a sputum sample.”

 

Nardell is part of a team that’s investigating the effectiveness of a new gas chromatography technology that can detect the chemical signature of M. tuberculosis in a few puffs of human breath. In some parts of the world, giant Gambian rats, trained to sniff out the bacterium’s signature compounds, are already being used to detect M. tuberculosis in sputum samples. Unlike humans using microscopes, these trained rats accurately examine specimen after specimen without fatigue—and all for the fee of a sweet treat.

 

Phase Shifts

Another complicating factor in the fight against these diseases is that the causal agents change throughout their life cycles. The tubercle bacterium modifies its environment to suit its needs. By contrast, the cholera bacterium acclimates itself to the environment it inhabits. Many cholera microbes spend their lives in water, feeding on plankton to derive energy. During this aquatic phase, the adaptations that help them survive in water make them much less infectious in humans. Calderwood and his team, however, have discovered that the cholera microbes found in the fecal matter of infected humans—before the microbes adapt to the aquatic environment—are hyperinfectious for a brief period following their evacuation from the host.

Because this human ecology is important to the transmission of the disease, Calderwood’s collaborators in Bangladesh dispatch research teams to patients’ homes. To study disease transmission in a household, the team invites all family members, sick or well, to participate. While visiting, the team can survey a patient’s living conditions and, if needed, provide medical care to other family members.

 

“These diseases are perfect examples of how knowing the social context of an infection can be crucial,” says Mercedes Becerra, an HMS associate professor of global health and social medicine. “It’s not some vague notion of social context; it’s actually seeing the physical setting where people live and testing the strains that have infected different members of a family or community. The household is a really important unit for analysis and for medical interaction.”

Just as it is crucial to see how the bacteria operate—at the chemical and genetic levels—in human hosts, it is important to understand how the illness plays out in the context of specific human populations, according to Becerra.

 

Knit One, World View

These diseases also interact in another key ecosystem: the community of HMS researchers working on global health and infectious disease. Some may be community health workers with knowledge of the lives of their neighbors. Some are social scientists measuring the clinical effectiveness of different approaches to preventing and treating these diseases, or mapping the social, political, and historical aspects of health. Geneticists, immunologists, engineers, and architects—each play a role in teasing out the intricacies of these diseases and the pathogens that cause them.

“To beat these diseases, somebody has to understand the immune system and the bugs at different levels,” Becerra says, “while others have to work on understanding the impact on patients and families. That’s why it’s so important to work together from multiple angles, linking discovery with care delivery—and then turn around to look for new discoveries.”

Jake Miller is a science writer in the HMS Office of Communications and External Relations.

 

by Jake Miller

 

 

 

Hms.harvard.edu [en línea] Cambridge, MA (USA)

hms.harvard.edu, 03 de octubre de 2013 [ref. Summer 2013] Disponible en Internet: http://hms.harvard.edu/news/harvard-medicine/harvard-medicine/how-bugs-are-built/epidemic-proportions



More than a Machine

20 12 2012

Ribosome regulates viral protein synthesis, revealing potential therapeutic target 

 

Some viruses depend on ribosomal protein L40 (rpL40), highlighted within the large (60S) subunit, for protein synthesis. Image courtesy of the Whelan Lab.

Some viruses depend on ribosomal protein L40 (rpL40), highlighted within the large (60S) subunit, for protein synthesis. Image courtesy of the Whelan Lab.

By ELIZABETH COONEY Viruses can be elusive quarry. RNA viruses are particularly adept at defeating antiviral drugs because they are so inaccurate in making copies of themselves. With at least one error in every genome they copy, viral genomes are moving targets for antiviral drugs, creating resistant mutants as they multiply. In the best-known example of success against retroviruses, it takes multiple-drug cocktails to corner HIV and narrow its escape route.

Rather than target RNA viruses themselves, aiming at the host cells they invade could hold promise, but any such strategy would have to be harmless to the host.  Now, a surprising discovery made in ribosomes may point the way to fighting fatal viral infections such as rabies.

Results were published online November 19 in Proceedings of the National Academy of Sciences.

The ribosome has traditionally been viewed as the cell’s molecular machine, automatically chugging along, synthesizing proteins the cell needs to carry out the functions of life. But Amy Lee, a former graduate student in the program of virology, and Sean Whelan, HMS professor of microbiology and immunobiology, now say the ribosome appears to take a more active role, regulating the translation of specific proteins and ultimately how some viruses replicate.

The researchers were studying differences between how viruses and the host cells they infect carry out the process of translating messenger RNAs (mRNAs) into proteins. Focusing on protein components found on the surface of the ribosome, they discovered a protein that some viruses depend on to make other proteins, but that the vast majority of cellular mRNAs do not need.

Called rpL40, this ribosomal protein could represent a target for potential treatments; blocking it would disable certain viruses while leaving normal cells largely unaffected.

“Because certain viruses are very sensitive to the presence and absence of these ribosomal proteins, it might be a useful way for us to think about targeting ribosomes for therapeutic purposes from an antiviral standpoint,” said Whelan. “This is a way to think about interfering with rabies virus infection. There are no therapeutics for rabies infection.”

The team screened protein constituents of the ribosome to see which ones might be involved in specialized protein synthesis. Studying the vesicular stomatitis virus, a rhabdovirus in the same family as the rabies virus, they found that its mRNAs depended on rpL40 but only 7 percent of host-cellular mRNAs did. Some of the cellular mRNAs that depend upon rpL40 were stress response genes.

Experiments in yeast and human cells revealed that a class of viruses, which includes rabies and measles, depended on rpL40 for replication.

“This work reveals that the ribosome is not just an automatic molecular machine but instead also acts as a translational regulator,” said first author Amy Lee, who is now a post-doctoral researcher at the University of California, Berkeley.

The concept of targeting cellular functions such as protein synthesis for antiviral therapies is being explored by a number of research groups, but there are no drugs based on this.

“We think the principle is bigger than just this single protein,” Whelan said.  “Viruses have an uncanny way of teaching us new biology all the time.”

Maria Barna, assistant professor of developmental biology and genetics at Stanford University, called the work part of an exciting area of exploration. Her own recently published findings showed that a single ribosomal protein belonging to the large ribosome subunit rpL38 is critically required for formation of the mammalian body plan and specialized translational control.
 
“It is extremely fascinating that one single ribosomal protein is required for translational control of so many viruses, while its loss does not appear to have a major consequence on general protein synthesis or for cell viability. Any means to down-regulate rpL40 may be a novel therapeutic approach for viral infections,” she said about work led by Whelan. Barna was not involved in the research. “However, a deeper understanding is critically needed to determine whether the few ribosomal proteins, such as rpL40, shown to exert ribosome-mediated translational specificity reflects a harbinger of a new layer of gene regulation.”

This work was supported by NIH grants AI059371 and AI057159. Whelan is a recipient of a Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award. Lee is supported by the Department of Defense through the National Defense Science & Engineering Graduate Fellowship Program and the National Science Foundation through the Graduate Research Fellowship Program.

 

Hms.harvard.edu [en línea] Cambridge, MA (USA): hms.harvard.edu, 20 de diciembre de 2012 [ref. 26 de noviembre de 2012] Disponible en Internet: http://hms.harvard.edu/content/more-machine