Featured Research

from universities, journals, and other organizations

Cell-destroyer that fights and promotes TB reveals what's behind its split identity

April 11, 2013
University of Washington
TB can be a disease not only of failed immunity but also of excessive immune response. Tumor necrosis factor -- normally an infection-fighting substance produced by the body -- can actually heighten susceptibility to tuberculosis if its levels are too high.

Exuberant mycobacterial growth showing chains of fluorescent microbes in an infected zebrafish larva which had an excess of tumor necrosis factor.
Credit: Francisco Jose Roca Soler

Tumor necrosis factor -- normally an infection-fighting substance produced by the body -- can actually heighten susceptibility to tuberculosis if its levels are too high.

Related Articles

University of Washington TB researchers unravel this conundrum in a report this week in Cell.

Their study shows how excess production of this disease-cell destroyer at first acts as a TB germ killer. But later the opposite occurs: too much tumor necrosis factor encourages TB pathogens to multiply in the body.

In addition to figuring out some reasons behind this back-pedaling, the scientists learned that certain combinations of drugs already available for other conditions can curtail the shift from anti-TB to pro-TB.

The drug combination revealed in this study, the authors noted, "has the potential to revert some cases of hypersusceptibility to hyperresistance."

The scientists were Francisco Jose Roca Soler, of the UW Department of Microbiology, and Lalita Ramakrishnan, UW professor of microbiology, medicine and immunology. A recipient of the National Institutes of Health Director's Pioneer Award, Ramakrishnan is recognized for her work on how the TB pathogen and its hosts' cells interact to cause disease.

These studies are conducted in zebrafish, an animal model for tuberculosis. The fish's embryos and small fry are transparent. Researchers can see through their skin to observe their organs, tissues and cells and the internal appearance of some infections, for example, the bacterial cording of TB.

Roca and Ramakrishnan explained that TB had traditionally been thought of as a disease of failed immunity. However, more recent studies from their lab and other labs, both in zebrafish and in humans, have suggested that it also can result from too strong of a defensive inflammatory response.

"While tumor necrosis factor is a critical host defense against tuberculosis," Roca and Ramakrishnan noted, "an excess of this factor is also implicated in the development of the disease in zebrafish and in humans."

Variations in a specific location of the zebrafish genome can cause either too much or too little tumor necrosis factor to be produced, depending on the type of variation. In either case, deficiency or overabundance, zebrafish become prone to tuberculosis.

In both cases the scavenger cells, or macrophages, that are trying to clear away the TB pathogens by ingesting them, die and burst open. They are like torn vacuum cleaner bags spilling their dirty contents.

When the TB bacteria escape the confines of the scavenger cells, "they grow exuberantly in the extracellular environment," Roca and Ramakrishnan said.

Researchers needed to work out the differences between TB susceptibility caused by too high or too low tumor necrosis factors because the distinction is vital to treatment decisions. Only patients whose genetics made them launch a pro-inflammatory response, benefited from steroid treatment, previous studies have shown. Steroids can increase the chance of death among TB patients with a weak inflammatory response.

In the present study, Roca and Ramakrishnan elucidated the molecular pathways by which too much tumor necrosis factor at first rapidly promotes macrophages to go after TB bacteria, and then turns around and forces the hard-working macrophages to die and expel their captives.

They found that both the microbiocidal activity, and the death of the macrophages, resulted from upping the production of reactive oxygen species by the mitochondria inside the macrophages. Mitochondria are the energy-generating power plants of living cells.

Tumor necrosis factor inside of infected macrophages induces reactive oxygen species from the mitochondria. These are the chemicals responsible for cell damage from oxidative stress.

Early on, reactive oxygen species can be beneficial. Initially their presence encourages the macrophages to destroy pathogens. As they accumulate, however, they promote self-harm.

Suddenly the macrophage is programmed to self-destruct. The reactive oxygen species carry out the death sentence by modulating a pathway for a substance called cyclophilin D, which sets the stage for the demolition of mitochondria.

Reactive oxygen species also play a role in acid sphingomyelinase-mediated ceramide production. This waxy substance occurs in cell membranes. One of its many roles is regulating signals for cell death.

The researchers were able to convert the high tumor necrosis factor state to become resistant to tuberculosis. They did so by genetically blockading both cyclophilin D and acid sphingomyelinase in previously susceptible zebrafish.

Similarly, they discovered that the drug combination of alisporivir, a cyclophilin D-inhibiting drug, and desipramine, an antidepressant that inactivates acid sphingomyelinase, also reverses susceptibility to TB in zebrafish prone to tumor necrosis factor excess.

Essentially, the experiments suggest that preventing cell death in TB infected macrophages can prolong their capacity to attack TB pathogens.

A longer-living army of macrophages, filled with the microbiocidal reactive oxygen species, will destroy the TB pathogens inside them and make the host highly resistant to tuberculosis.

Because excessive amounts of tumor necrosis factor are implicated in several inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, sarcoidosis, and Crohn's, the authors noted, "The findings may be useful for understanding diseases in addition to tuberculosis."

Grants from the National Institutes of Health and the Northwest Research Center of Excellence for Biodefense and Emerging Diseases, and a postdoctoral fellowship from the educational ministry of Spain, funded this research project.

Story Source:

The above story is based on materials provided by University of Washington. The original article was written by Leila Gray. Note: Materials may be edited for content and length.

Journal Reference:

  1. Francisco J. Roca, Lalita Ramakrishnan. "Tumor necrosis factor dually mediates resistance and susceptibility to mycobacteria through induction of mitochondrial reactive oxygen species. Cell, 2013 DOI: 10.1016/j.cell.2013.03.022

Cite This Page:

University of Washington. "Cell-destroyer that fights and promotes TB reveals what's behind its split identity." ScienceDaily. ScienceDaily, 11 April 2013. <www.sciencedaily.com/releases/2013/04/130411123858.htm>.
University of Washington. (2013, April 11). Cell-destroyer that fights and promotes TB reveals what's behind its split identity. ScienceDaily. Retrieved March 31, 2015 from www.sciencedaily.com/releases/2013/04/130411123858.htm
University of Washington. "Cell-destroyer that fights and promotes TB reveals what's behind its split identity." ScienceDaily. www.sciencedaily.com/releases/2013/04/130411123858.htm (accessed March 31, 2015).

Share This

More From ScienceDaily

More Health & Medicine News

Tuesday, March 31, 2015

Featured Research

from universities, journals, and other organizations

Featured Videos

from AP, Reuters, AFP, and other news services

Solitair Device Aims to Takes Guesswork out of Sun Safety

Solitair Device Aims to Takes Guesswork out of Sun Safety

Reuters - Innovations Video Online (Mar. 31, 2015) — The Solitair device aims to take the confusion out of how much sunlight we should expose our skin to. Small enough to be worn as a tie or hair clip, it monitors the user&apos;s sun exposure by taking into account their skin pigment, location and schedule. Matthew Stock reports. Video provided by Reuters
Powered by NewsLook.com
Soda, Salt and Sugar: The Next Generation of Taxes

Soda, Salt and Sugar: The Next Generation of Taxes

Washington Post (Mar. 30, 2015) — Denisa Livingston, a health advocate for the Dinι Community Advocacy Alliance, and the Post&apos;s Abby Phillip discuss efforts around the country to make unhealthy food choices hurt your wallet as much as your waistline. Video provided by Washington Post
Powered by NewsLook.com
UnitedHealth Buys Catamaran

UnitedHealth Buys Catamaran

Reuters - Business Video Online (Mar. 30, 2015) — The $12.8 billion merger will combine the U.S.&apos; third and fourth largest pharmacy benefit managers. Analysts say smaller PBMs could also merge. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
S. Leone in New Anti-Ebola Lockdown

S. Leone in New Anti-Ebola Lockdown

AFP (Mar. 28, 2015) — Sierra Leone imposed a three-day nationwide lockdown Friday for the second time in six months in a bid to prevent a resurgence of the deadly Ebola virus. Duration: 01:17 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.


Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News


Free Subscriptions

Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile

Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?

Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins