Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Treatment for tuberculosis can be guided by patients' genetics

08.02.2012
Gene that influences inflammatory response to infection predicts effectiveness of drug therapy

A gene that influences the inflammatory response to infection may also predict the effectiveness of drug treatment for a deadly form of tuberculosis.

An international collaboration between researchers at the University of Washington in Seattle, Duke University, Harvard University, the Oxford University Clinical Research Unit in Vietnam and Kings College London reported these findings Feb. 3 in the journal Cell.

These results suggest the possibility of tailoring tuberculosis treatment, based on a patient's genetic sequence at a gene called LTA4H, which controls the balance between pro-inflammatory and anti-inflammatory substances produced during an infection.

Tuberculosis can take hold if disease-fighting inflammation is either too weak or too strong. The strength of the response is in part the result of a person's LTA4H gene sequence. Knowing whether a patient has the gene sequence for one extreme response or the other could help guide medication decisions.

Lalita Ramakrishnan, professor of microbiology, medicine and immunology at the University of Washington and the senior author of the study, said that the study suggested that that increased TB disease severity in humans can occur for fundamentally opposite reasons. "The ability to tailor therapies to these divergent inflammatory states, based on a patient's sequence at LTA4H, could improve patient outcomes."

This important observation for people began with a study of the tiny zebrafish. In these animals, the researchers linked mutations in the zebrafish version of the LTA4H gene to increased susceptibility to a TB-like infection. David Tobin, now on the faculty of the Department of Molecular Genetics and Microbiology at Duke University, is first author of the study. He performed the research while he was a postdoctoral fellow in the University of Washington laboratory of Dr. Ramakrishnan, working closely with another postdoctoral fellow Francisco Roca.

After they understood the biological basis of susceptibility to infection in the zebrafish, the researchers turned to the same gene in humans. They identified a sequence of the gene that led to higher activity and increased inflammation. They then collaborated with other researchers at the University of Washington, including Mary-Claire King, and researchers in Vietnam and the U.K., including Guy Thwaites, to study the gene among patients in Vietnam with TB. They discovered that patients carrying one copy of the high-activity sequence of the gene and one copy of the low-activity sequence were relatively protected from TB meningitis, a particularly deadly form of TB. Surprisingly, people with two copies of the high-activity sequence of the gene fared just as poorly as people with two copies of the low-activity sequence. This "heterozygous advantage," or "Goldilocks effect," is an unusual finding in human genetics.

King commented "Throughout human history, people with both forms of the LTA4H gene have probably been more likely to survive when exposed to TB than people with only one form of the LTA4H gene. This advantage may have led to both forms of the gene persisting in human populations. Selection by infectious diseases has had an enormous impact on the evolution of our species."

This surprising finding, the researchers noted, implicated both insufficient and overly abundant inflammation as different ways TB could take hold in the body. By analyzing clinical data from patients in Vietnam with a particularly severe form of TB called TB meningitis, the researchers found that anti-inflammatory therapy only benefited patients with the gene sequence that corresponds to excess inflammation. The patients with the insufficient inflammation gene sequence derived no benefit from what has been adopted as a standard therapy for TB meningitis.

Given the clinical and therapeutic implications of these findings, the researchers sought the underlying molecular mechanisms for both extremes. For this they turned back to the zebrafish.

In collaboration with Charles Serhan, of Harvard University they showed that one gene variant weakened inflammation through the overproduction of substances called lipoxins. Hyperinflammation results from a gene variant that leads to an excess of leukotriene B4. Either can interfere with the overall levels of tumor necrosis factor, a substance that, when present in normal amounts, protects against TB infection and other diseases.

Paradoxically, either a deficiency or an overkill of tumor necrosis factor can cause macrophages, the host cells that gobble up pathogens, to die by bursting and releasing the TB pathogens into a "permissive extracellular milieu where they can grow exuberantly into corded mats" the researchers said.

The researchers then discovered that corticosteroids, which are in wide clinical use, as well the active ingredient in aspirin decreased TB infection in zebrafish with the "hot responder" genotype, but increased TB infection in their "cold responder" genotype siblings.

The researchers concluded, "If patients succumb to TB for two fundamentally different reasons, then it is imperative to design therapeutic strategies that reflect this dichotomy. For example, if evaluating the treatment effects of dexamethasone on TB meningitis doesn't take into account host genotype, the very substantial benefits of the drug for the high-reactive genotype may be diluted by its neutral or possibly detrimental effects on individuals with the low-activity genotype."

A simple gene test for the high-responding variant, they said, could provide a rapid, inexpensive way to determine which patients would benefit from dexamethasone therapy added to standard infection-fighting drugs. They also believe clinical studies are urgently needed to be sure patients with the low-reactive genotype are not harmed by unnecessary dexamethasone treatment, and to find alternative treatment strategies for this group, such as agents that limit lipoxin production or boost inflammation.

Because the basic inflammatory biochemical pathways affected by the LTA4H gene are common to many infections, the researchers said TB treatment strategies suggested by their findings may hold promise for other serious infections.

The study was funded by grants from the National Institutes of Health, an American Cancer Society postdoctoral fellowship, a Mallinckrodt Scholar Award, a postdoctoral fellowship from the educational ministry of Spain, the Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases, the Burroughs Wellcome Fund, the Wellcome Trust, the American Skin Association, the Dermatology Foundation, and the Chinese Academy of Sciences.

Ramakrishnan is a recipient of the NIH Director's Pioneer Award, Tobin is a recipient of the NIH Director's New Innovator Award and King is an American Cancer Society Professor.

Others on the project team are Sungwhan F. Oh, Ross McFarland, Thad D. Vickery, John P. Ray, Dennis C. Ko, Yuxia Zou, Nguyen D. Bang, Tran T. H. Chau, Jay C. Vary, Thomas R. Hawn, Sarah J. Dunstan, and Jeremy J. Farrar.

Leila Gray | EurekAlert!
Further information:
http://www.washington.edu

More articles from Health and Medicine:

nachricht NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)

nachricht High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>