Study finds possible 'persistence' switch for tuberculosis

Sep 17, 2010

(PhysOrg.com) -- An examination of a portion of the tuberculosis genome that responds to stress has allowed Rice University bioengineers Oleg Igoshin and Abhinav Tiwari to zero in on a network of genes that may "switch" the disease into dormancy.

The bacteria that cause (TB), Mycobacterium tuberculosis, can transition into a dormant state to ward off attacks from antibiotics and the immune system. A new report from Igoshin and Tiwari in this month's issue of Physical Biology examines a network of genes that may make this possible. A computer model of the network showed it can act as a "persistence" switch that toggles the organism from a fast-growing to a slow-growing state.

"The that allow Mycobacterium tuberculosis to switch into this slow-growing, persistent state have been associated with genes that are activated when the microorganism is under stress," said Igoshin, senior author of the study and an assistant professor in bioengineering at Rice.

Tiwari, lead author of the study and a graduate student in Igoshin's lab, said, "We examined a stress-response network of genes that are found in both the TB bacterium and other closely related mycobacteria. We analyzed the role of multiple feedback loops in this network, and were eventually able to identify an ultrasensitive mechanism that works in combination with the feedback loops to form a switch. This switch can possibly activate transition to the persistent state."

The study was a collaborative effort between Igoshin's laboratory at Rice's BioScience Research Collaborative and the research groups of Gabor Balazsi at the University of Texas M.D. Anderson Cancer Center and Maria Laura Gennaro at the Public Health Research Institute of the New Jersey Medical School.

Scientists have long known that the has the ability to "hunker down" and go dormant under stressful conditions. Previous studies have confirmed that both the slow-growing and fast-growing forms of the bacteria have identical genes.

"The fact that the same organism can exist in two states at the same time in the same environment raises many questions," Igoshin said. "What is the basis for this bistability? What are the environmental cues that activate the switch?"

Other bacteria can switch between stable states as well, but Mycobacterium tuberculosis' ability to make this transition is one reason TB is such a widespread disease. As much as 30 percent of the world's population is believed to be infected with TB, which causes about 2 million deaths every year.

Igoshin said advances in molecular microbiology have allowed researchers to identify networks of mycobacterial genes that become activated when the organism is stressed. One of these networks contains genes that make mycobacterial transcription factor (MprA) and another protein called sigma factor E (SigE).

"Our collaborative team developed an approach that allowed us to formulate general conclusions about the properties of the mycobacterial stress-response network, even though we had limited knowledge of the underlying parameter values," Igoshin said.

Tiwari said, "Using this approach, we systematically examined the different modules, or subsets, of the full network. We found that bistability was linked to a positive feedback loop between MprA and SigE, a protein that binds to RNA polymerase to promote the production of both MprA and SigE."

Igoshin and Tiwari believe their modular approach to investigate the role of multiple feedback loops could also be used to unravel mechanisms that other bacteria use to control bistability.

"There are many outstanding questions regarding the specific ways that gene regulatory networks operate in bacteria," Igoshin said. "The generality of this modular approach opens up a promising avenue for answering some of those questions because it can be readily adapted to other networks."

And that is precisely what Igoshin's lab and its collaborators are preparing to do thanks to a recently awarded five-year, $1.35 million grant from the National Institutes of Health (NIH).

"We want to understand -- at a network-level -- how different organisms mount these types of responses," Igoshin said. "We need this to better understand how cells function and to build better computer models of pathogenic bacteria that cannot be easily manipulated in the laboratory."

Explore further: Recorded Ebola deaths top 7,000

Related Stories

Are sacrificial bacteria altruistic or just unlucky?

Apr 15, 2008

An investigation of the genes that govern spore formation in the bacteria B. subtilis shows that chance plays a significant role in determining which of the microbes sacrifice themselves for the colony and which go on to ...

Experts say Toronto unprepared for TB

Feb 24, 2008

Health experts warn there could be an outbreak of tuberculosis in Toronto, which reportedly lacks a centralized system of TB clinics.

Scientists discover bacteria that can cause bone infections

Oct 17, 2008

Scientists have discovered that a bone infection is caused by a newly described species of bacteria that is related to the tuberculosis pathogen. The discovery may help improve the diagnosis and treatment of similar infections, ...

Road mapping could be key to curing TB

Feb 05, 2010

The complex chain of metabolic events in bacteria that lead to fatal diseases such as tuberculosis (TB) may be better understood using mathematical models, according to an article published in the February issue of Microbiology To ...

Recommended for you

Recorded Ebola deaths top 7,000

13 hours ago

The worst Ebola outbreak on record has now killed more than 7,000 people, with many of the latest deaths reported in Sierra Leone, the World Health Organization said as United Nations Secretary-General Ban ...

Liberia holds Senate vote amid Ebola fears (Update)

17 hours ago

Health workers manned polling stations across Liberia on Saturday as voters cast their ballots in a twice-delayed Senate election that has been criticized for its potential to spread the deadly Ebola disease.

Evidence-based recs issued for systemic care in psoriasis

Dec 19, 2014

(HealthDay)—For appropriately selected patients with psoriasis, combining biologics with other systemic treatments, including phototherapy, oral medications, or other biologic, may result in greater efficacy ...

Bacteria in caramel apples kills at least four in US

Dec 19, 2014

A listeria outbreak believed to originate from commercially packaged caramel apples has killed at least four people in the United States and sickened 28 people since November, officials said Friday.

Steroid-based treatment may answer needs of pediatric EoE patients

Dec 19, 2014

A new formulation of oral budesonide suspension, a steroid-based treatment, is safe and effective in treating pediatric patients with eosinophilic esophagitis (EoE), according to a new study in Clinical Gastroenterology and Hepatology, the official clinical practice journal ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.