Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

TB Bacterium's Outer Cell Wall Disarms the Body's Defense to Remain Infectious

05.10.2011
The bacterium that causes tuberculosis has a unique molecule on its outer cell surface that blocks a key part of the body’s defense. New research suggests this represents a novel mechanism in the microbe’s evolving efforts to remain hidden from the human immune system.

Researchers found that the TB bacterium has a molecule on its outer surface called lipomannan that can stop production of an important protein in the body’s immune cells that helps contain TB infection and maintain it in a latent state. This protein is called tumor necrosis factor (TNF). When TNF is not produced in sufficient quantities, the TB bacterium can grow unchecked and cause an uncontrolled active infection inside and outside of the lungs.

“There are several unique components on the Mycobacterium tuberculosis outer cell wall that help it sneak into the lung relatively unnoticed,” said Larry Schlesinger, professor and chair of the Department of Microbial Infection and Immunity at Ohio State University and senior author of the study. “The more we can learn about how these cell wall structures influence the human immune response, the closer we can get to developing a more effective strategy to treat or even prevent an active tuberculosis infection.”

Lipomannan resembles a tree branch sprinkled with smaller sugar molecules protruding from the outer cell wall of the bacterium. The findings show that lipomannan can block TNF production at the microRNA level. MicroRNAs are small segments of RNA that regulate – or fine-tune – a gene’s protein-building function.

To date, microRNAs have been implicated most frequently in the development of cancer. Schlesinger said this research is among the first studies to show that pathogenic bacteria can influence microRNA activation in immune cells and is the first to explore how microRNAs regulate the macrophage inflammatory response to Mycobacterium tuberculosis.

Macrophages are first-responder cells in the immune response. They eat TB bacteria at the point of infection in the lung and then normally activate molecules that make pieces of the bacteria visible to infection-fighting warriors, triggering an eventual T-cell response to come to the macrophages’ aid.

The research is published this week in the online early edition of the Proceedings of the National Academy of Sciences.

About 2 billion people worldwide are thought to be infected with TB bacteria. People who are infected can harbor the bacterium without symptoms for decades, but an estimated one in 10 will develop active disease characterized by a chronic cough and chest pain. Both active and latent infections are treated with a combination of antibiotics that patients take for at least six months, and such treatment is becoming less effective with more drug-resistant bacterial strains.

Schlesinger and colleagues conducted the study comparing lipomannans from two types of bacteria – a virulent strain of Mycobacterium tuberculosis and a harmless strain called Mycobacterium smegmatis, which is often used as a control bacterium in TB research.

Many of these same researchers, led by Schlesinger, had previously isolated the lipomannans from each type of bacterial cell’s surface and used powerful biochemical analyses to characterize the significance of the lipomannans’ structural differences. In a study published recently in the Journal of Biological Chemistry, the group reported on how the surface structures on virulent TB bacteria lowered the response of a specific T-cell that typically gets recruited to fight tuberculosis.

In this newer study, the scientists compared how the structures affected the production of TNF in primary human macrophage culture experiments.

They first established that human macrophages respond differently to the two different types of bacteria lipomannans after 24 hours of exposure. Lipomannan from the virulent TB bacterium produced significantly less TNF than lipomannan from the M. smegmatis bacterium.

Though the study showed that the harmless cells increase production of TNF through a well-known receptor pathway as expected, the virulent TB bacteria did not make use of that receptor pathway. This supported the concept that the pathogenic TB bacterium has figured out another way to block the TNF protein in its quest to keep the immune system guessing, said Schlesinger, also the director of Ohio State’s Center for Microbial Interface Biology.

A single microRNA can affect the production of hundreds of proteins, and the process of identifying those relationships is ongoing. However, two microRNAs in this study were known to be relevant for their connections to genes and proteins already established as players in the immune response to TB infection: miR-125b and miR-155.

Biochemical and genetic experiments showed that macrophages stimulated with lipomannan from TB bacteria had enhanced expression of miR-125b, effectively inhibiting the production of TNF. In contrast, the lipomannan from the harmless bacteria had enhanced expression of miR-155, which regulates other compounds in a way that stimulates TNF production.

Researchers’ experimental manipulation to lower the expression of miR-125b in macrophages increased production of TNF in response to the TB bacteria lipomannan, further confirming that this regulation of TNF occurred at the microRNA level, Schlesinger said.

“This really speaks to the power of the tuberculosis bacterium to adapt to the human host,” he said. “It has had centuries to develop a sophisticated way to deal with its encounter with the human. Fortunately, genomic technology is allowing us to identify microRNAs more and more rapidly, which might allow us to catch up with the TB bacterium and figure out a way to outsmart it.”

This work was supported by grants from the National Institutes of Health.

Co-authors of the PNAS paper, all from Ohio State, include Murugesan Rajaram, Jessica Morris, Michelle Brooks, Tracy Carlson and Jordi Torrelles of the Center for Microbial Interface Biology; Bin Ni of the Medical Scientist Training Program; and Baskar Bakthavachalu and Daniel Schoenberg of the Center for RNA Biology and Department of Molecular and Cellular Biochemistry. Brooks is also affiliated with the Department of Microbiology, Carlson with the Department of Veterinary Biosciences, and Torrelles with the departments of Internal Medicine and Microbial Infection and Immunity.

Contact: Larry Schlesinger, (614) 292-8789; larry.schlesinger@osumc.edu

Written by Emily Caldwell, (614) 292-8310; caldwell.151@osu.edu

Emily Caldwell | Newswise Science News
Further information:
http://www.osu.edu

More articles from Life Sciences:

nachricht Topologische Quantenchemie
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

nachricht Topological Quantum Chemistry
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>