Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists find genetic key to TB bacteria survival in lung cells

15.04.2003


New research led by a University of North Carolina at Chapel Hill scientist shows for the first time how Mycobacterium tuberculosis, the germ responsible for TB, uses a system for releasing proteins to help it survive the lungs’ immune defenses to spread and cause disease.



The study, published online in the April issue of Molecular Microbiology, also adds crucial new knowledge to the molecular factors that underlie the virulence of M. tuberculosis and may aid development of new, targeted treatments for the disease.

"I think this study moves us along in our understanding of TB pathogenesis," said study lead author Dr. Miriam Braunstein, assistant professor of microbiology and immunology at UNC’s School of Medicine.


In 2003, 10 years after the World Health Organization declared tuberculosis a global emergency, tuberculosis remains a severe worldwide health threat. More people die from the disease than from any other curable infectious disease. TB kills approximately 2 million people every year, 98 percent in developing countries. One-third of the world’s population is infected with the TB bacillus.

In the report, Braunstein and co-authors Drs. William R. Jacobs Jr. and John Chan from New York’s Albert Einstein College of Medicine, and Drs. Benjamin Espinosa and John T. Belisle from Colorado State University said numerous disease-causing bacteria "possess specialized protein secretion systems that are dedicated to the export of virulence factors."

The TB bacillus possesses in its genome the genes secA1 and secA2, the researchers said. In a previous report, Braunstein and others had shown that the protein SecA1 is essential for the bacillus, whereas SecA2 is not. Both of these proteins are similar to SecA, a protein that functions in the secretion process of all other bacteria.

However, the presence of multiple SecA proteins in a single bacterium is highly unusual and only shared with a few other pathogenic bacteria.

"In this study, we wanted to see if the two SecAs do the same thing or have different functions. We had a hunch that SecA2 was involved in the bacteria’s virulence, that it might be dedicated to secreting a specific subset of proteins involved in virulence," Braunstein said. To test that hypothesis, she and her colleagues genetically engineered a mutant strain of M. tuberculosis that did not have secA2. This gene deletion meant it could not produce the protein SecA2.

"We tested the strain for virulence by infecting mice with it and observed how long the mice survived over time," Braunstein said. "And we found that the mice infected with mutant TB survived longer than ’wild-type’ mice infected with TB having a functioning secA2 gene. This told us the mutant strain was not as virulent."

To further examine virulence, the researchers also examined the extent of bacterial growth in the lung, liver and spleen. "Those experiments showed the same thing," she said. "When TB is missing SecA2, it is less virulent. There is less bacterial growth, particularly in the lung."

Having demonstrated that SecA2 is required for virulence, the next step was to identify the virulence factor secreted by the protein. Two of the proteins dependent on SecA2 that were identified were antioxidant molecules: superoxide dismutase-A and catalase-peroxidase.

When M. tuberculosis is inhaled and enters the lungs via the small air sacs called alveoli, the bacteria becomes aggressively attacked and engulfed by macrophages, immune system scavenger cells. But where other bacteria succumb to the attack, TB survives in macrophage, having evolved over the millennia a mechanism to overcome the "oxidative burst" leveled at it.

"These SecA2-dependent secretions, superoxide dismutase and catalase-peroxidase are enzymes that actually scavenge the oxygen radicals that are shot at the bacteria," Braunstein said.

"All mycobacteria strains, including TB, appear to have two secA genes. So I think a long time ago the gene duplicated benignly, but one of those secAs evolved to provide a protective advantage for the pathogen. That’s why it’s still there and important to pathogen survival in macrophages."

Thus, according to the researcher, the two enzymes secreted by secA2 act as virulence factors contributing to TB’s defense against destruction in the macrophage. Moreover, this newly described virulence mechanism may apply to other types of disease-causing bacteria.

"In the last year or so, a number of Gram-positive bacterial pathogens have been identified that have two SecA proteins," Braunstein said. Important Gram-positive pathogens with two SecAs include Listeria monocytogenes, Staphylococcus aureus and Streptococcus pneumoniae.

"Gram-positive" refers to the grouping of bacteria relating to its outer structure.

"In some it has already been shown that the extra secA2 gene is required for virulence. So it might be common to certain bacterial pathogens."

Someday, drugs against TB infection could be developed aimed at blocking this secretion system, Braunstein said. "For now, the results of this study offer some new and important insights into the pathogenesis of this serious health threat."


The research was funded by the National Institute of Allergy and Infectious Diseases and the Howard Hughes Medical Institute.

Note: Contact Braunstein at (919) 966-5051 or miriam_braunstein@med.unc.edu.
School of Medicine contact: Leslie Lang, (919) 843-9687 or llang@med.unc.edu

Leslie Lang | EurekAlert!
Further information:
http://www.med.unc.edu/

More articles from Health and Medicine:

nachricht Investigators may unlock mystery of how staph cells dodge the body's immune system
22.09.2017 | Cedars-Sinai Medical Center

nachricht Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Boston Children's Hospital

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: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>