Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Improving the body’s ’homeland security’ against TB

24.10.2003


Immune system provides new clue to most life-threatening bacterium
The microbe that causes tuberculosis operates the way a human terrorist would. With minimal resources, the TB bacterium skillfully blends in and gains strength before lashing out unexpectedly. This microbe, which claims more human lives each year than any other bacterial pathogen, even uses its host’s defenses, hiding out in an immune cell called a macrophage.

Now, Rockefeller scientist John MacMicking, Ph.D., has discovered a unique way the immune system can disarm the bacterial offender. If this defense could be strengthened, TB could be brought to biological justice.


Reporting in the October 24 issue of the journal Science, Rockefeller researchers MacMicking and John McKinney, Ph.D., with their colleague from Duke University, Greg Taylor, Ph.D., have identified a new pathway stimulated by the soluble host protein called interferon-gamma that impairs TB’s ability to reproduce itself in mice. Interferon-gamma primarily instructs immune cells to perform different tasks by helping turn on or off certain genes. In the case of interferon-gamma, literally hundreds of genes are induced once its signal is transmitted to the nucleus of the activated cell. Of these, only a few will be responsible for controlling the replication of the TB bacterium. Finding those genes involved in antimicrobial activity against TB is the key.

"We’re looking for immune pathways which could render the TB bacillus vulnerable," says MacMicking, a research associate in the Laboratory of Infection Biology and lead author of the Science paper. "By learning more about how the immune system successfully operates during infection, we may soon be able to manipulate the host-pathogen relationship in a way which favors us, a somewhat reluctant host."

MacMicking and colleagues discovered the pathway, called LRG-47, based on clues from another TB-inhibiting pathway called NOS2 and analysis of mouse genes turned on during TB infection. MacMicking is already homing in on the human version of LRG-47. While cellular studies suggest that LRG-47 is involved in altering the bacterium’s intracellular compartment to directly prevent its growth, the precise mechanistic details remain to be worked out. However, the most powerful evidence comes from mice that no longer possess LRG-47 after removal via genetic engineering techniques; these mice become profoundly susceptible to TB infection. The researchers’ findings represent the growing trend in seeking new insights into fighting infections by studying the immune system’s signature response to specific pathogens. Information about each new pathway that is discovered could be translated into new drugs that help boost immune responses to infection.

TB, a hardy bacteria that makes its home during infection by creating its own niche inside macrophages, currently infects one third of the world’s population. Macrophages, which are cells that have specifically evolved to dispose of pathogens by engulfing and chemically destroying them, are the major front-line defense our bodies possess in trying to prevent TB from taking up residence. These cells produce the chemicals -- not unlike bleach or other household disinfectants -- which kill TB once they have received instructions from interferon-gamma to do so.

Even with interferon-gamma, however, our body doesn’t always succeed in eliminating the bacterium. But interferon-gamma stops TB from replicating, or reproducing itself, inside macrophages. Under these conditions, TB slows in growth until it is latent, or under house arrest, within the body.

"One of the reasons we study the immune response to TB," says McKinney, head of the Laboratory of Infection Biology, "is to identify better treatments than those currently in use. This will occur only as a result of scientists’ devoting more analysis to the bacteria’s weaknesses and the host’s strengths. That means studying the immune response alongside the bacteria."

Rockefeller University President Paul Nurse, Ph.D., says: "Not only have MacMicking and McKinney revealed an enticing clue that may lead to much-needed new TB treatments, they’ve carried on their research in the Rockefeller tradition. Their findings continue several aspects of earlier work conducted by Rockefeller scientists, notably James Darnell’s seminal descriptions of the interferon and Jak-STAT pathways, Zanvil Cohn’s pioneering experiments on macrophage immunobiology and Christian de Duve’s Nobel Prize-winning research on the lysosome. Others, such as current faculty members Ralph Steinman and Charles Rice, are similarly interested in finding new ways to employ the immune system in the fight against viral infection and cancer."

TB largely leads an existence based on stealth. In 90 percent of those infected, it is not life-threatening because the bacteria are under biological house arrest by the immune system. People with latent TB infections do not feel sick, have no symptoms and cannot spread TB to others. While this picture of the vast majority of those harboring the disease seems reassuring, it is misleading. The pathogen can switch from a latent state in any human host if that host’s immune system is weakened.

Normal human aging alone gives TB the possibility of reactivating, disabling and killing any of the two billion people worldwide who are latently infected. When the bug moves out of its latent stage, the person infected is not only at a high mortality risk, but can infect others with TB. An estimated 10 to 15 million people in the U.S. have latent TB.

Treatment for latent infections includes at least three potent antibiotics, but they must be taken alone or in combination, for six to nine months, and often produce toxic side effects. Even in the best health care facilities, patients with TB often balk at the lengthy and often wearying regime. In developing countries with numerous public health challenges, the long treatment and side effects of this treatment are prohibitive. As a result, TB, like staph and other bacterial infections, is becoming more threatening because of growing worldwide multi-drug resistance.

"Tuberculosis is an intractable threat to human health," says McKinney. "We will never break the chain of infection of tuberculosis the way we did with smallpox, for example. It’s a different kind of bug." For this reason, McKinney and his colleagues chip away at the sophisticated parrying between the microbe and the human host. Their latest finding puts another brick in the wall between chronic infection with TB and possible immune system-based cures.

"This discovery is exciting because it provides a much sought-after link between immune cell activation and TB inhibition," says MacMicking. "Previously we’d examined another pathway based on NOS2 but this was not the whole story. LRG-47 opens up a new way of thinking about the problem. It’s the first step in a biologic process which one day could be mimicked chemically and therapeutically through the use of small molecules."

In 2000, McKinney and his colleagues identified one of the first targets for the immune system arsenal -- a bacterial enzyme called isocitrate lyase (ICL) -- which allows TB to use fatty acids, instead of sugars, for energy. The enzyme helps keep the latent, or non-dividing microbe, alive. Drug maker GlaxoSmithKline is currently completing a high-throughput screen for ICL inhibitors. An anti-ICL drug could cut off the latent bacteria’s source of energy where the microbe is holed up inside the body.

Given that TB is so difficult to treat with the current crop of antibiotics, drugs that target processes involved during bacterial dormancy or which enhance immune responses against both replicating and non-dividing bacteria may be the best new source of intelligence in the fight against the disease.

Lynn Love | EurekAlert!
Further information:
http://www.rockefeller.edu

More articles from Health and Medicine:

nachricht NTU scientists build new ultrasound device using 3-D printing technology
07.12.2016 | Nanyang Technological University

nachricht How to turn white fat brown
07.12.2016 | University of Pennsylvania School of Medicine

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: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

NTU scientists build new ultrasound device using 3-D printing technology

07.12.2016 | Health and Medicine

The balancing act: An enzyme that links endocytosis to membrane recycling

07.12.2016 | Life Sciences

How to turn white fat brown

07.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>