Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene mutation leads to super-virulent strain of TB

09.12.2003


Disabling a set of genes in a strain of the tuberculosis bacteria surprisingly led to a mutant form of the pathogen that multiplied more quickly and was more lethal than its natural counterpart, according to a new study led by researchers at the University of California, Berkeley.



As early as two weeks after infection, researchers found significantly more bacteria from the organs of mice infected with the mutated tuberculosis (TB) bacteria than for mice infected with the unmodified, or "wild-type," strain. By 27 weeks, the mutant-infected mice started to die, while their counterparts infected with the wild-type strain survived until the end of the experiment at 41 weeks.

"These findings came as a complete surprise to us," said Dr. Lee Riley, professor of epidemiology and infectious diseases at UC Berkeley’s School of Public Health and principal investigator of the study. "We thought we had made a mistake, so we repeated the test several times, and we always got the same result."


The researchers say the study, to be published Dec. 8 in Proceedings of the National Academy of Sciences, sheds light on the mechanisms used by a pathogen that now infects one-third of the world’s population and kills 2 million people per year. According to the World Health Organization, which in 1993 declared TB a global emergency, an estimated 36 million people could die of TB by 2020 if the disease is not controlled.

The results were unexpected because prior studies pointed to the mce1 operon, the collection of genes that researchers disabled in the TB bacteria, as an important virulence factor that helped the organism invade cells. Researchers expected that mutating the mce1 genes would impair the pathogen’s ability to infect the mice. Instead, the bacteria became more deadly.

"This is one of the very few hypervirulent organisms ever created," said Lisa Morici, a lead author of the study who received her Ph.D. in infectious diseases from UC Berkeley in May. "This breaks a long-standing assumption among scientists that disabling a potential virulence gene weakens a pathogen."

Morici and Nobuyuki Shimono, assistant professor of medicine at Kyushu University’s Graduate School of Medical Sciences in Japan, are co-lead authors of the paper.

The researchers point out that even though the virulent strain of TB bacteria can be grown in a lab, it is not a likely candidate for use as a biological weapon. "Mycobacterium tuberculosis grows extremely slowly, is hard to aerosolize and, if it is not in a dormant stage, can be treated with antibiotics," said Morici, who is now a post-doctoral fellow at Tulane University’s School of Medicine. "There are several other virulent organisms out there that are easier to manipulate than TB."

The researchers compared the spleens, livers and lungs of mice at various time points throughout the experiment, from 24 hours to 41 weeks after infection. They found that the progression of the unmodified TB strain hit a plateau about 17 weeks after infection, while the mce1 mutated TB strain didn’t stop spreading until it killed its host.

The researchers also compared the reactions to normal and mutated forms of bacillus Calmette-Guérin (BCG), a weakened version of the TB bacteria that triggers an immune response but does not lead to disease.

They found that in the unmodified strains of both the TB bacteria and the BCG groups, there were well-defined granulomas, clusters of immune cells that surround TB bacteria to keep it in check. The researchers noticed that granulomas had not formed properly in the mutated strains of both the TB bacteria and the BCG groups.

The differences suggest that the mce1 gene mutations led to changes in the TB bacteria that impacted the host’s own immune response. "It appears that the host immune system does not recognize the mutated TB organisms, so the bacteria are left to grow unchecked," said Morici.

While the body typically summons granulomas to keep the TB bacteria from spreading and developing into an active infection, it does not completely eliminate the bug. When encased by granulomas, the bacteria move into a dormant, asymptomatic stage. It is when they sense a change in the host’s immune system, caused by such factors as the onset of diseases including AIDS, diabetes or cancer, that they begin to multiply again and cause the active TB disease.

"What we have learned is that the granuloma shield not only protects the host, it also protects the TB bacteria from the host’s other immune cells and antibiotic drugs that may otherwise kill the bacteria," said Shimono.

"The hallmark of the TB bacterium is its ability to stay dormant in a person’s body for years, making it one of the most successful bacteria around," said Riley. "Even if we could treat all the people now with active infection, we’d never be able to wipe out TB entirely because 60 percent of the people exposed to TB develop latent infections. TB is very difficult to treat not because it kills people rapidly, but because it stays dormant. By understanding the mechanism behind latency, we may also be able to develop new diagnostic tests to predict who will develop the active disease."

Other co-authors of the paper are Nicola Casali, Sally Cantrell and Ben Sidders at UC Berkeley’s School of Public Health; and Sabine Ehrt at Cornell University’s Weill Medical College.


The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, supported this study.

Sarah Yang | UC Berkeley
Further information:
http://www.berkeley.edu/news/media/releases/2003/12/08_mutation.shtml

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

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...

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

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>