One secret to how TB sticks with you

Jul 09, 2009

Mycobacterium tuberculosis is arguably the world's most successful infectious agent because it knows how to avoid elimination by slowing its own growth to a crawl. Now, a report in the July 10 issue of the journal Cell, a Cell Press publication, offers new insight into the bugs' talent for meager living.

"Tuberculosis can resist the host immune system and remain latent for decades," said Michael Glickman of the Memorial Sloan-Kettering Cancer Center. To do so, the mycobacterium responsible must resist an arsenal of DNA-damaging mutagens produced within the macrophage, the immune cell in which it lives. "It's incompletely understood how it can do that. We've identified one such mechanism."

The discovery could lead to new drugs that might eliminate strains of TB that have grown resistant to those that are currently available.

A whopping 30% of the world's population is infected with latent TB, the researchers said. In some people, the will reactivate, causing an estimated 1.3 million deaths a year, according to the World Health Organization.

One secret to TB's success is a protein that the researchers call CarD, the new study shows. That protein ratchets down transcription of the genes encoding ribosomal RNA (rRNA) by directly binding , the cellular machinery that transcribes DNA into RNA. rRNA is the central component of the ribosomes that serve as the cell's factories, and, Glickman explained, its production accounts for some 90 percent of all transcription.

"The mycobacterium tailors its translational machinery in response to stress within the host and we have identified CarD as a critical mediator of this response" he said.

Loss of CarD is fatal to M. tuberculosis living in cell culture, Glickman and his colleague Christina Stallings show. CarD depletion leaves the pathogen sensitive to killing by oxidative stress, starvation, and as it fails to cut its transcription of rRNA.

Importantly, Glickman said, they were able to show in infected mice that the mycobacterium depends on CarD not just when it is in its early, most active phase of growth, but also later in the course of infection. Drugs that target CarD's interaction with RNA polymerase could therefore lead to sorely needed, new TB drugs, the researchers said.

"The TB health crisis is exacerbated by the alarming emergence of multidrug- and extensively drug-resistant strains," Glickman said. "The development of new chemotherapeutic strategies is imperative, which requires insight into the pathways involved in M. tuberculosis infection, persistence, and drug resistance. CarD is one such pathway that we plan on targeting for therapeutic development. "

The findings might also prove to be clinically important for other disease-causing microbes.

Scientists knew before how some bacteria adapted to stress by limiting rRNA transcription, Glickman said. But the new study is the first to show how this is done in a mycobacterium, which lack a key gene responsible in other bugs like E. coli.

CarD is widely distributed in the bacterial world, he said, for instance it is found in Bacillus anthracis, the bacterium that causes anthrax. "This finding may have broader application to other important pathogens," he said.

Source: Cell Press (news : web)

Explore further: Blocking a fork in the road to DNA replication

add to favorites email to friend print save as pdf

Related Stories

Smoking increases risk of TB infection, study finds

Feb 27, 2007

People who smoke have a greater risk of becoming infected with tuberculosis (TB) and of having that infection turn into active TB disease, according to an analysis by researchers at the University of California, Berkeley.

Tuberculosis drug shows promise against latent bacteria

Sep 12, 2008

A new study has shown that an investigational drug (R207910, currently in clinical trials against multi-drug resistant tuberculosis strains) is quite effective at killing latent bacteria. This revelation suggests that R207910 ...

Potential treatment for TB solves puzzle

Jul 04, 2008

Scientists have uncovered a new target for the potential treatment of TB, finally resolving a long-running debate about how the bacterial cell wall is built. The research, published in the July issue of Microbiology reveal ...

Recommended for you

Blocking a fork in the road to DNA replication

1 hour ago

A team of Whitehead Institute scientists has discovered the surprising manner in which an enigmatic protein known as SUUR acts to control gene copy number during DNA replication. It's a finding that could shed new light on ...

Cell division, minus the cells

4 hours ago

(Phys.org) —The process of cell division is central to life. The last stage, when two daughter cells split from each other, has fascinated scientists since the dawn of cell biology in the Victorian era. ...

A new method simplifies the analysis of RNA structure

4 hours ago

To understand the function of an RNA molecule, similar to the better-known DNA and vital for cell metabolism, we need to know its three-dimensional structure. Unfortunately, establishing the shape of an RNA ...

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.