An enzyme that stimulates the breakdown of fats in immune cells helps trigger inflammation, or an immune response to pathogens, a new study by Weill Cornell Medicine researchers suggests. The findings enhance scientists' understanding of the connection between metabolism and inflammation, and may offer a new approach to treat dangerous infections such as pneumonia.

In their study, published July 25 in Nature Medicine, the team showed that the mitochondrial enzyme NOX4 regulates the activation of an inflammation-triggering protein complex called an inflammasome. It does this by increasing the levels of a key enzyme in fat breakdown, a process called free fatty acid oxidation.

"Inflammation is an important immune response to pathogens, but when it becomes chronic or if the response is too strong, it can hurt the patient," said senior author Dr. Augustine M.K. Choi, interim dean of Weill Cornell Medicine and Weill Chairman of the Weill Department of Medicine. "We knew that people with obesity-induced metabolic diseases, like diabetes, have an abnormal response to infectious agents, and in this paper we were able to make a connection between the two."

The connection is found in mitochondria, which in addition to being the cell's powerhouse plays an important role in the cellular stress response. The mitochondrial enzyme NADPH oxidase-4 (NOX4) produces reactive oxygen species (ROS), chemically reactive molecules that kill pathogens and signal that the cell is under stress, among other cellular responses. "Since NOX4 was linked to both diabetes and immunity, we wanted to understand what it was doing at the interface between the two," said lead author Dr. Jong-Seok Moon, a postdoctoral fellow in Dr. Choi's laboratory.

In mice infected with pneumonia, the researchers found a reduced inflammatory response and reduced mortality in mice lacking NOX4. Human immune cells lacking NOX4 also showed a reduced inflammasome response when presented with chemicals that normally provoke the cells. The group showed that these responses were lacking because there was a corresponding failure to increase levels of a key enzyme for mitochondria fatty acid oxidation, called CPT1a. Without this NOX-4-dependent boost in fat breakdown, the inflammatory response was blunted.

Currently, a drug that inhibits NOX4 is in phase 2 clinical trials to treat diabetic nephropathy, a condition where blood vessels in the kidney are destroyed. The team showed that the drug, GKT137831, was also effective in reducing inflammasome activation in mice, including in the pneumonia model. "Since this drug is already in phase 2 clinical trials, we think it is a good candidate for additional research as a treatment for patients with metabolic inflammation and infectious disease as well," said Dr. Choi, who is also physician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center. "With the number of people affected by type 2 diabetes and obesity growing each year, we need to understand the link to inflammation and infection so we can treat these patients more effectively."

A chemical reaction that affects the behavior of a gene crucial to the body's defense against pathogens mobilizes immune cells to effectively fight the invaders, a team led by scientists at Weill Cornell Medical College discovered in a new study. Their findings are the first to demonstrate an epigenetic role for the gene, activation-induced cytidine deaminase (AID), and may reveal a potential cause of blood cancers.

Scientists have long understood AID's crucial role in the adaptive immune system, which is responsible for managing the body's responses against pathogens. The gene ensures that B cells — the cells responsible for antibody production — can mutate their genome, generating antibodies that can mount more effective immune responses.

Now, the Weill Cornell researchers have discovered a new role for the gene. In their study, published online Sept. 10 and in the Sept. 29 issue of Cell Reports, the researchers discovered that the enzyme encoded by the AID gene is also involved in removing chemical tags from DNA. These tags, known as methyl groups, regulate gene expression. Removing these methyl groups, a process called hypomethylation, allows B cells to rapidly change their genome in preparation for antibody production.

"AID is a gene traditionally not known to be linked to DNA methylation, but we found that it is a player in removing methyl groups — the first time anyone has found molecules that perform this powerful form of gene regulation," said co-senior author Dr. Olivier Elemento, an associate professor of computational genomics in the Department of Physiology and Biophysics who heads the Laboratory of Cancer Systems Biology in the Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell and co-chairs the Meyer Cancer Center Program in Genetics, Epigenetics and Systems Biology. "What is interesting is that many tumor types, and that includes B-cell lymphomas, tend to be linked to global — genome-wide — hypomethylation, compared to normal cells. How hypomethylation occurs is not well understood. AID is so far the only enzyme that has been directly linked to this active process. So AID or related enzymes could be involved in other cancers as well."

The researchers also found that the enzyme may increase epigenetic diversity — the extent to which each cell has a distinct pattern of chemical tags attached to DNA. Epigenetic diversification may promote the production of more diversified antibodies but may also contribute to the development of cancers such as non-Hodgkin lymphoma, chronic lymphocytic leukemia and diffuse large B-cell lymphoma, among others. This may happen because once a methyl group is removed from a gene, it is not put back on, "raising the risk that epigenetic alterations can turn on other pathways that cause the cells to grow out of control," Dr. Elemento said. "A lot of potentially dangerous processes occur during this sensitive stage, and while much of it is tightly controlled, some may get out of control."

Understanding AID's epigenetic role could lead to new strategies to treat these cancers, which affect some 100,000 Americans a year, the researchers said.

"Our animal models lead us to believe that expression of AID and epigenetic changes do contribute to cancer, making disease more aggressive. This is something we are investigating now," says co-senior author Dr. Rita Shaknovich, a former Weill Cornell Medical College researcher now working with Cancer Genetics Inc., a global cancer diagnostic biotech company. "No drugs that we know of now could target AID, but we are becoming more and more sophisticated in creating targeted therapies, and so it is feasible that we could base a future treatment that disables AID in a specific way."

Scientists have long worked to understand why antibiotics that shut down most infections offer only limited success with tuberculosis (TB), the leading bacterial cause of death around the world.

A new study by Weill Cornell Medical College scientists has found a possible explanation: an enzyme that allows TB to bypass free radicals that are thought to arise from the stress of antibiotic treatment. Free radicals, which are toxic, have the ability to kill bacteria — but appear to be suppressed by the type of bacteria that causes TB.

"We found a new function for a well-known enzyme linked to the virulence of the TB bacterium, helping to answer the question of what makes this bacteria naturally resistant to antibiotic treatment," says the study’s senior investigator, Dr. Kyu Y. Rhee, associate professor of medicine and associate professor of microbiology and immunology at Weill Cornell.

The findings , published June 30 in Nature Communications, offer some potentially good news, Dr. Rhee says. "Our findings suggest a strategy that could make the antibiotics we have on hand more powerful," he says. "By knowing exactly what these drugs do, scientists will be able to improve existing antibiotics and design new, smarter ones." 

The problem centers on isocitrate lyase (ICL), which scientists previously pinpointed as a major culprit behind the bacterium’s ability to cause infection. During an infection, ICL allows the TB bacteria to continue to feed on fatty acids as a source of energy.

In their study, Dr. Rhee and his team describe a secondary function for ICL in TB. They employed technology to watch, at a basic biochemical level, what happens to both the antibiotic agent and the infecting bacteria over time after mainstays of TB treatment &mdash rifampicin, streptomycin, and isoniazid — are administered. The researchers saw that all three drugs activated ICLs.

 They also discovered that ICL-deficient TB bacteria were 100 times more sensitive to the beneficial treatment provided by all three antibiotics — seemingly because of an increase in the levels of free radicals resulting from treatment with those drugs.

Antibiotics to treat TB were developed 50 years ago through trial, error and serendipity, Dr. Rhee says. "But the drugs never worked well," he says. "Current TB treatments are long and complex, lasting a minimum of six months, often resulting in treatment failures and multi-drug resistance."

His team’s findings suggest that antibiotics that inhibit the ability of ICL to protect against cell stress may, finally, provide a potent treatment for TB. "Previous efforts to identify drugs against ICL failed to identify compounds that were good enough to inhibit its nutritional function," Dr. Rhee says. "However, it is possible that some of these compounds, or others yet to be discovered, may work by inhibiting the adaptive stress response — providing, at last, more rapidly effective drugs against this deadly pathogen."