Featured Research

from universities, journals, and other organizations

New therapies for bad infections based on finding on classic suppressor of immunity

Date:
January 7, 2014
Source:
Medical College of Georgia at Georgia Regents University
Summary:
A well-documented suppressor of immunity that's used by fetuses and tumors alike just may be able to change its spots, researchers report. In the face of a significant bacterial infection, for example, indoleomine 2,3-dioxegenase, or IDO, also appears capable of helping key immune cells called macrophages produce inflammation to destroy the invader.

Dr. Tracy L. McGaha is an immunologist at Medical College of Georgia at Georgia Regents University and GRU Cancer Center.
Credit: Phil Jones

A well-documented suppressor of immunity that's used by fetuses and tumors alike just may be able to change its spots, researchers report.

In the face of a significant bacterial infection, for example, indoleomine 2,3-dioxegenase, or IDO, also appears capable of helping key immune cells called macrophages produce inflammation to destroy the invader, said Dr. Tracy L. McGaha, immunologist at the Medical College of Georgia at Georgia Regents University and GRU Cancer Center.

The surprising finding points toward new therapeutic targets when inflammation goes overboard, known as a cytokine storm, as with the overwhelming and highly lethal infection septicemia.

"It's always described as a one-way street, but it appears IDO has a dual role," said McGaha, corresponding author of the study in the journal Molecular and Cellular Biology. "It promotes inflammation when it needs to and, where there is no need for classic inflammation, it can immediately switch to a suppressant mechanism," McGaha said.

IDO's upregulation in macrophages helps these immune cells make important decisions about whether to ignore or attack. "It just depends on the environment the cell finds itself in," McGaha said. He and others also are showing that macrophages, well-documented garbage consumers in the body, have this larger role as well as a driver of the immune response.

While studying more about IDO's role in modulating macrophages response to cell debris, McGaha and his colleagues found that when they added a piece of a bacterial cell wall to prompt an inflammatory reaction, they found an increased number of IDO-expressing macrophages in the mix, which seemed counterintutitive considering IDO's role as a suppressor, McGaha said.

That's how they learned IDO actually does both. IDO basically works by degrading the essential amino acid tryptophan, producing a stress response in the now-starving cell that prompts an increase in the stress response kinase GCN2, which essentially shuts down protein production and cell activity. Unless there is another stressor, which is what happened when the researchers added the bacterial cell wall.

In this infection model, high levels of GCN2 appear instead to nudge macrophages to make more pro-inflammatory mediators, resulting in rampant inflammation in the mice. In this environment, gene activity goes up to the point that the previously sluggish protein production is revived. "The overall affect is you get more inflammation," McGaha said.

And that's where potential new therapies for selectively blocking inflammation surfaced. When they knocked out GCN2, severe inflammation decreased and survival increased in animal models of septicemia. McGaha hopes the laboratory findings will eventually translate to hospital intensive care units.

"Macrophages can do a lot of things and only one of them is make inflammatory products, like cytokines, in response to infection," McGaha said. "They also are involved in wound healing and tissue reconstitution maitenance. So if a macrophage comes into an area that has a lot of mechanical damage, say from trauma, you don't want to make proinflammatory things because that will hurt the ability of the tissue to heal itself."

The good news is that drugs that block GCN2 already are under development to fight cancer and agonists exist that could bolster a positive immune response, such as increasing the potency of a vaccine, McGaha said. "If we can manipulate GCN2's activity in various contexts, we can help finetune the immune response in the direction we want."

Next steps including looking at how GCN2 manipulates immunity, particularly its impact on protein production.

MCG's Drs. Andrew Mellor and David Munn were the first to report that the fetus expresses IDO to help avoid rejection by the mother's immune system. Subsequent studies have shown tumors also use IDO for protection and clinical trials are studying the tumor-fighting potential of an IDO inhibitor. On the flip side, there is evidence that increasing IDO expression can protect transplanted organs and counter autoimmune disease. Mellor and Munn are co-authors on the new study, which was supported in part by the National Institutes of Health and Wellcome Trust.


Story Source:

The above story is based on materials provided by Medical College of Georgia at Georgia Regents University. Note: Materials may be edited for content and length.


Journal Reference:

  1. H. Liu, L. Huang, J. Bradley, K. Liu, K. Bardhan, D. Ron, A. L. Mellor, D. H. Munn, T. L. McGaha. GCN2 dependent metabolic stress is essential for cytokine induction and pathology in murine sepsis. Molecular and Cellular Biology, 2013; DOI: 10.1128/MCB.00946-13

Cite This Page:

Medical College of Georgia at Georgia Regents University. "New therapies for bad infections based on finding on classic suppressor of immunity." ScienceDaily. ScienceDaily, 7 January 2014. <www.sciencedaily.com/releases/2014/01/140107170913.htm>.
Medical College of Georgia at Georgia Regents University. (2014, January 7). New therapies for bad infections based on finding on classic suppressor of immunity. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2014/01/140107170913.htm
Medical College of Georgia at Georgia Regents University. "New therapies for bad infections based on finding on classic suppressor of immunity." ScienceDaily. www.sciencedaily.com/releases/2014/01/140107170913.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com
Tooth Plaque Provides Insight Into Diets Of Ancient People

Tooth Plaque Provides Insight Into Diets Of Ancient People

Newsy (July 19, 2014) Research on plaque from ancient teeth shows that our prehistoric ancestor's had a detailed understanding of plants long before developing agriculture. Video provided by Newsy
Powered by NewsLook.com
Contaminated Water Kills 3 Babies in South African Town

Contaminated Water Kills 3 Babies in South African Town

AFP (July 18, 2014) Contaminated water in South Africa's northwestern town of Bloemhof kills three babies and hospitalises over 500 people. The incident highlights growing fears over water safety in South Africa. Duration: 02:22 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.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

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