Host genetics can contribute to lung damage in severe tuberculosis

July 3, 2014

A third of the global population is infected with the bacterial pathogen, a mycobacterium, that causes tuberculosis (TB). Most carriers control the infection and are asymptomatic, but severe forms of the disease (more common in children and immune-compromised adults, and often caused by particularly aggressive—or hypervirulent—mycobacterial strains) kill over a million people every year. An article published on July 3rd in PLOS Pathogens now identifies a factor made by the host that exacerbates lung damage in severe TB. The results also suggest why gene mutations that render the factor inactive are common.

To understand the mechanisms underlying aggressive TB, Elena Lasunskaia from the Universidade Estadual do Norte Fluminense, Rio de Janeiro, Maria Regina D'Império-Lima from the Universidade de São Paulo, Brazil, and colleagues studied mouse models which recapitulate the symptoms of severe pulmonary TB in humans. Like human patients, mice infected with two different hypervirulent mycobacterial strains develop necrotic lesions in the lung, that is, areas of dead cells that break open and release their contents. The necrotic debris contains molecules that promote an influx of from the host, and the resulting local inflammation causes further damage to the lung tissue.

One of the contents of necrotic debris is the energy-storage molecule ATP, and when it is found outside cells, it is known to stimulate immune cells through the binding to the P2X7 receptor (P2X7R). The researchers asked whether this molecular pathway plays a role in the severe forms of TB that are associated with lung necrosis. They studied mice that were lacking P2X7R and found that those mice survived otherwise deadly infections with either of the two hypervirulent mycobacterial strains.

A more detailed analysis suggested that P2X7R has a dual role in the development of aggressive TB. First, it appears to facilitate the dissemination of hypervirulent by killing infected immune cells but releasing their content, namely viable mycobacteria that have survived the process. Second, P2X7R also seems to contribute to lung inflammation and damage by promoting widespread tissue destruction.

The better outcomes in mice without P2X7R were only seen after infection with hypervirulent mycobacteria. When the researchers infected mice with a less aggressive TB strain, they found that P2X7R actually helped to control this infection. In this case, P2X7R-mediated stimulation of infected immune cells did not result in the cell death and release of viable mycobacteria, and so actually contained the infection rather than spreading it.

The observed opposite effects of P2X7R on with hypervirulent and less aggressive mycobacterial strains, respectively, could explain an epidemiological puzzle: P2X7R loss-of-function alleles (that is defective variants of the P2X7R gene) are common in humans despite the fact that they are linked to a higher risk of developing pulmonary TB. Based on their results, the researchers suggest that such variants might increase the risk of mild TB but reduce the risk of severe TB. This, they say "could explain why evolutionary pressure has maintained these gene polymorphisms at high rates in the human population."

They also state that their study "provides a perspective for the development of new therapeutic approaches in which drugs designed to inhibit P2X7R are used to ameliorate the outcomes of aggressive forms of TB".

Explore further: Scientists establish proof-of-concept for host-directed tuberculosis therapy

More information: Amaral EP, Ribeiro SCM, Lanes VR, Almeida FM, de Andrade MRM, et al. (2014) Pulmonary Infection with Hypervirulent Mycobacteria Reveals a Crucial Role for the P2X7 Receptor in Aggressive Forms of Tuberculosis. PLoS Pathog 10(7): e1004188. DOI: 10.1371/journal.ppat.1004188

Related Stories

Scientists establish proof-of-concept for host-directed tuberculosis therapy

June 27, 2014
In a new study published in Nature, scientists describe a new type of tuberculosis (TB) treatment that involves manipulating the body's response to TB bacteria rather than targeting the bacteria themselves, a concept called ...

Research says TB infection may be underestimated among people taking corticosteroid pills

June 26, 2014
Tuberculosis infection among people taking corticosteroid pills may be underestimated, new research suggests. Current guidelines for what constitutes a positive TB skin test among corticosteroid pill users may not be capturing ...

TB lung infection causes changes in the diversity of gut bacteria in mice

May 13, 2014
Johns Hopkins researchers have found evidence in mice that a tuberculosis (TB) infection in the lungs triggers immune system signaling to the gut that temporarily decreases the diversity of bacteria in that part of the digestive ...

TB dogma upended: Even uninfected cells trigger immune defenses

June 11, 2014
Experimenting with mice, infectious disease experts at NYU Langone Medical Center have found that immune system cells uninfected with the bacterium that causes tuberculosis trigger immune system T cells to fight the disease. ...

Lung lesions of TB variable, independent whether infection is active or latent

December 15, 2013
The lung lesions in an individual infected with tuberculosis (TB) are surprisingly variable and independent of each other, despite whether the patient has clinically active or latent disease, according to a new animal study ...

Team finds molecule that polices TB lung infection, could lead to vaccine

January 2, 2013
The presence of a certain molecule allows the immune system to effectively police tuberculosis (TB) of the lungs and prevent it from turning into an active and deadly infection, according to a new study led by researchers ...

Recommended for you

Data-driven malaria early warning system could predict outbreaks months in advance

October 24, 2017
A Johns Hopkins University scientist is part of a team working on a method to predict malaria outbreaks months in advance, potentially giving public health officials a chance to protect people from a disease that poses a ...

Novel therapies for multidrug-resistant bacteria

October 23, 2017
During this innovative study published in PLOS One, researchers found that novel classes of compounds, such as metal-complexes, can be used as alternatives to or to supplement traditional antibiotics, which have become ineffective ...

Key discoveries offer significant hope of reversing antibiotic resistance

October 23, 2017
Resistance to antibiotics is becoming increasingly prevalent and threatens to undermine healthcare systems across the globe. Antibiotics including penicillins, cephalosporins and carbapenems are known as β-lactams and are ...

Pneumonia vaccine under development provides 'most comprehensive coverage' to date, alleviates antimicrobial concerns

October 20, 2017
In 2004, pneumonia killed more than 2 million children worldwide, according to the World Health Organization. By 2015, the number was less than 1 million.

Newly discovered viral marker could help predict flu severity in infected patients

October 20, 2017
Flu viruses contain defective genetic material that may activate the immune system in infected patients, and new research published in PLOS Pathogens suggests that lower levels of these molecules could increase flu severity.

Migraines may be the brain's way of dealing with oxidative stress

October 19, 2017
A new perspective article highlights a compelling theory about migraine attacks: that they are an integrated mechanism by which the brain protects and repairs itself. Recent insightful findings and potential ways to use them ...

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.