Tuberculosis virulence factor identified, may be target for new drug

December 14, 2016 by Brian Wallheimer, Purdue University
This photomicrograph reveals Mycobacterium tuberculosis bacteria using acid-fast Ziehl-Neelsen stain; Magnified 1000 X. The acid-fast stains depend on the ability of mycobacteria to retain dye when treated with mineral acid or an acid-alcohol solution such as the Ziehl-Neelsen, or the Kinyoun stains that are carbolfuchsin methods specific for M. tuberculosis. Credit: public domain

Scientists have discovered the mechanism that hijacks the immune system's response to tuberculosis, revealing an important new drug target for the disease that kills more than 1 million people each year.

Herman Sintim, Purdue University's Drug Discovery Professor of Chemistry, collaborated with scientists at Johns Hopkins University to determine how tuberculosis turns off a human cell's signal to mount an to the . Their findings were published in the journal Nature Chemical Biology.

Tuberculosis is a bacterial disease that results in coughing, fever, night sweats, weight loss and sometimes death.

When Mycobacterium tuberculosis enters a human cell, the presence of its DNA and a molecule that it makes called c-di-AMP alert the cell to the bacteria's presence. The human cell responds by creating a messenger molecule, cGAMP, which signals nearby cells to mount an immune response to kill the tuberculosis bacteria.

The also produces another molecule, ENPP1, which degrades the cGAMP. That key step turns off the call for an immune response.

"Immune response can involve reactive oxygen and nitrogen species, which can kill the bacteria but at the same time cause collateral damage and also damage or kill the host cells as well," Sintim said. "There is a very delicate response to bacteria and stopping that response once bacteria have been taken care of."

But the has found a way to turn off the call for help. By producing a protein called cyclic dinucleotide phosphodiesterase (CdnP), the bacterium reduces the concentration of the cell's messenger molecule, cGAMP, a nucleic acid. This accentuates the effect of the human phosphodiesterase ENPP1, an enzyme that cleaves nucleic acids, to quickly degrade any already-made cGAMP and turn off the immune response early.

"The host cGAMP never gets to a high enough concentration to activate the immune response," Sintim said. "This is a very effective strategy the bacteria have developed to suppress an immune response."

Sintim and colleagues tested their hypothesis by creating a mutant of Mycobacterium tuberculosis that lacked the CdnP protein and tested it in a mouse model. On average, the mice with the mutant bacteria lived more than two times longer than mice with the wild type, suggesting that CdnP played a role in suppressing immune response.

They then artificially synthesized the cGAMP molecule and investigated if it was a substrate for CdnP. The CdnP degraded the human molecule as predicted.

Sintim said the CdnP protein in the now becomes an attractive target for a new drug. If a molecule could be developed that would inactivate or inhibit CdnP, it would improve immune response in patients.

Sintim's team identified several that would bind with and inhibit CdnP, but they have not reached the potency level needed to create drugs. They will continue looking for new compounds that could potently inhibit this newly discovered CdnP drug target.

Explore further: New compound targets TB bacterium's defense against the immune system

More information: Ruchi Jain Dey et al. Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase, Nature Chemical Biology (2016). DOI: 10.1038/nchembio.2254

Related Stories

Curcumin may help overcome drug-resistant tuberculosis

March 24, 2016

New research indicates that curcumin—a substance in turmeric that is best known as one of the main components of curry powder—may help fight drug-resistant tuberculosis. In Asia, turmeric is used to treat many health ...

Researchers discover immune system's 'Trojan Horse'

July 31, 2015

Oxford University researchers have found that human cells use viruses as Trojan horses, transporting a messenger that encourages the immune system to fight the very virus that carries it. The discovery could have implications ...

Tuberculosis and HIV co-infection

October 18, 2016

The HIV virus increases the potency of the tuberculosis bacterium (Mtb) by affecting a central function of the immune system. This is the conclusion of a study carried out by researchers at Linköping University in Sweden. ...

Team finds key to tuberculosis resistance

March 2, 2015

The cascade of events leading to bacterial infection and the immune response is mostly understood. However, the molecular mechanisms underlying the immune response to the bacteria that causes tuberculosis have remained a ...

Recommended for you

New theory shows how strain makes for better catalysts

April 20, 2018

Brown University researchers have developed a new theory to explain why stretching or compressing metal catalysts can make them perform better. The theory, described in the journal Nature Catalysis, could open new design ...

Machine-learning software predicts behavior of bacteria

April 19, 2018

In a first for machine-learning algorithms, a new piece of software developed at Caltech can predict behavior of bacteria by reading the content of a gene. The breakthrough could have significant implications for our understanding ...

Spider silk key to new bone-fixing composite

April 19, 2018

UConn researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

GLUT5 fluorescent probe fingerprints cancer cells

April 19, 2018

Determining the presence of cancer, as well as its type and malignancy, is a stressful process for patients that can take up to two weeks to get a diagnosis. With a new bit of technology—a sugar-transporting biosensor—researchers ...

0 comments

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.