New study explains what happens when the immune system ages
An anti-aging protein called SIRT1, commonly known for being activated by red wine, has been shown to protect against age-related diseases, such as cancer, neurodegeneration, and cardiovascular disease. A study now reveals that it could also be targeted to rejuvenate cells in the immune system.
Anti-aging proteins have long been shown to protect against age-related diseases, such as cancer, neurodegeneration, and cardiovascular disease. A study by researchers at the Gladstone Institutes now reveals that one such protein could also be targeted to rejuvenate cells in the immune system.
The protein in question is called SIRT1, more commonly known for being activated by red wine. In the new study, published in the Journal of Experimental Medicine, the scientists found that it is also involved in how cells in the immune system develop with age.
They wanted to find out how this anti-aging protein affects a specific category of immune cells known as cytotoxic T cells. These cells are highly specialized guardians of the immune system and their role is to kill cells infected by a virus, damaged cells, or cancer cells.
“Over the course of a person’s life, with repeated exposure to bacteria and viruses, these T cells mature and eventually lose a protein called CD28,” said Gladstone Senior Investigator Melanie Ott, senior author of the new study. “And as these cells get older, they become more toxic to their environment.”
This aging process is accelerated by persistent viral infections, such as HIV and CMV (human cytomegalovirus). In fact, HIV-infected patients accumulate mature cytotoxic T cells at a much younger age than an uninfected person.
“A higher number of mature cytotoxic T cells in the body has been associated with age-related, autoimmune, and inflammatory diseases,” added Ott, who is also a professor in the Department of Medicine at the UC San Francisco. “We wanted to come up with a way to counteract this phenomenon.”
What Happens in Aging Cells
When a young (or naive) T cell is in a resting state, it uses oxygen to “breathe.” Once it is activated to defend the body against a bacteria or virus, it shifts into enhanced glycolysis and uses sugar to get an immediate boost in energy. This is useful to jump into action, but it isn’t sustainable for long-term performance.
“You can think of it like a 60-meter sprint runner who needs a quick boost of energy to finish the race, in comparison to a marathon runner who needs different energy sources to keep going for a long period of time,” said Ott.
As the cells age and lose CD28, they can shift into glycolysis much more quickly if breathing is inhibited. They also lose the anti-aging protein SIRT1. This becomes a problem, as it makes them more toxic to the cells around them.
In the new study, Ott and her team finally explain how this all happens.
“We studied human T cells, isolated from blood donors of all ages, to compare mature cytotoxic T cells with naive ones,” said Philip Ansumana Hull, graduate student in Ott’s lab and one of the first authors of the study.
They found that naive T cells have a high concentration of SIRT1. This stabilizes an entire mechanism that prevents the cells from entering glycolysis to use sugar as an energy source, and limits their toxic effects.
As the cells age, they lose SIRT1, which changes their basic metabolism. They can then rapidly shift into glycolysis and start producing more toxic proteins called cytokines, which could lead to inflammatory diseases.
One Mechanism to Fight Both Aging and Aggressive Tumors
Based on a better understanding of the crucial role played by SIRT1 in the aging of T cells, the researchers identified two potential new drug targets.
First, new drugs could be developed to strengthen SIRT1 to rejuvenate mature cytotoxic T cells or keep them from progressing too quickly into a highly toxic state.
“This could postpone the development of age-related diseases,” said Mark Y. Jeng, the study’s other first author and former graduate student in Ott’s lab. “It could also help people with a weaker immune system fight infections or better respond to immune vaccination, such as seniors or chronically-infected patients.”
Alternatively, drugs could be used to obtain the opposite effect and encourage the T cells to be more toxic. By temporarily making young T cells more aggressive and behave like mature cells, they could, for example, support an aggressive anti-tumor response or other immune therapeutic approaches.
- Mark Y. Jeng, Philip A. Hull, Mingjian Fei, Hye-Sook Kwon, Chia-Lin Tsou, Herb Kasler, Che-Ping Ng, David E. Gordon, Jeffrey Johnson, Nevan Krogan, Eric Verdin, Melanie Ott. Metabolic reprogramming of human CD8 memory T cells through loss of SIRT1. The Journal of Experimental Medicine, 2017; jem.20161066 DOI: 10.1084/jem.20161066
New Lyme disease tests could offer quicker, more accurate detection
New tests to detect early Lyme disease — which is increasing beyond the summer months -could replace existing tests that often do not clearly identify the infection before health problems occur.
In an analysis published on December 7 in Clinical Infectious Diseases, scientists from Rutgers University, Harvard University, Yale University, National Institute of Allergy and Infectious Diseases of the NIH and other academic centers, industry and public health agencies say new diagnostic methods offer a better chance for more accurate detection of the infection from the Lyme bacteria.
“New tests are at hand that offer more accurate, less ambiguous test results that can yield actionable results in a timely fashion,” said Steven Schutzer, a physician-scientist at Rutgers New Jersey Medical School and senior author. “Improved tests will allow for earlier diagnosis which should improve patient outcomes.”
Lyme disease is the most common tick-borne infection in North America and Europe. There are currently over 300,000 cases of Lyme disease annually in the United States alone and the disease is increasing and spreading into new regions. Lyme disease frequently, but not always, presents with a bull’s-eye rash. When the rash is absent, a laboratory test is needed.
The only FDA approved Lyme disease tests, based on technology developed more than two decades ago, rely on detecting antibodies that the body’s immune system makes in response to the disease. These antibody-based tests are the most commonly used tests for Lyme disease and are the current standard.
One problem, however, is that many people produce similar — called “cross-reactive” — antibodies in response to other bacteria not associated with Lyme disease, which causes confusing results and makes test accuracy more difficult.
“New tests are more exact and are not as susceptible to the same false-positive or false-negative results associated with current tests,” said Schutzer.
Schutzer and his colleagues say more accurate testing would help doctors decide when to prescribe the antibiotics used to clear the infection and help avoid severe long-term health problems. Antibody tests, can take three weeks or more for the antibody levels to reach a point where the tests can pick up a positive result.
Those involved in the paper joined forces after meeting at Cold Spring Harbor Laboratory’s Banbury Center, a nonprofit research institution in New York. The meeting organized and chaired by Schutzer and John A. Branda, assistant professor of pathology at Harvard Medical School, focused on current Lyme disease tests and new scientific advances made in increasing the accuracy of the diagnosis.
“This meeting and paper resulting from it are particularly significant,” said Jan Witkowski, professor in the Watson School of Biological Sciences at Cold Spring Harbor Laboratory who along with Nobel Laureate James Watson asked Schutzer to lead several symposia. “The participants noted that there are greatly improved diagnostic tests for Lyme disease that can be implemented now, and that the way is open to the development of further tests.”
- John A Branda, Barbara A Body, Jeff Boyle, Bernard M Branson, Raymond J Dattwyler, Erol Fikrig, Noel J Gerald, Maria Gomes-Solecki, Martin Kintrup, Michel Ledizet, Andrew E Levin, Michael Lewinski, Lance A Liotta, Adriana Marques, Paul S Mead, Emmanuel F Mongodin, Segaran Pillai, Prasad Rao, William H Robinson, Kristian M Roth, Martin E Schriefer, Thomas Slezak, Jessica Snyder, Allen C Steere, Jan Witkowski, Susan J Wong, Steven E Schutzer. Advances in Serodiagnostic Testing for Lyme Disease Are at Hand. Clinical Infectious Diseases, 2017; DOI: 10.1093/cid/cix943
Possible new way to treat parasitic infections discovered
A chemical that suppresses the lethal form of a parasitic infection caused by roundworms that affects up to 100 million people and usually causes only mild symptoms has now been identified by researchers.
UT Southwestern Medical Center researchers have identified a chemical that suppresses the lethal form of a parasitic infection caused by roundworms that affects up to 100 million people and usually causes only mild symptoms.
“The approach we used could be applied generally to any nematode parasite, not just this one type,” said Dr. David Mangelsdorf, Chair of Pharmacology, an Investigator in the Howard Hughes Medical Institute (HHMI), and one of three corresponding authors of the study published in the Proceedings of the National Academy of Sciences. The study’s other corresponding authors are at two universities in Philadelphia.
“The plan is to develop better compounds that mimic the Δ7-dafachronic acid used in this study and eventually to treat the host to stop parasitic infection,” he added.
The Centers for Disease Control and Prevention (CDC) reports that the soil-dwelling Strongyloides stercoralis nematode, or roundworm, is the primary strongyloides species that infects humans. Experts estimate that between 30 million and 100 million people are infected worldwide, and most of them are unaware of it because their symptoms are so mild. The parasite can persist for decades in the body because of the nematode’s unique ability to reinfect the host, repeatedly going through the early stages of its life cycle. The nematode that causes the original infection exists in dirt on all continents except Antarctica, and it is most common in warmer regions, particularly remote rural areas in the tropics and subtropics where walking barefoot combined with poor sanitation leads to infection.
However, in people with compromised immune systems — such as those using long-term steroids for asthma, joint pain, or after an organ transplant — the mild form of the illness can progress to the potentially lethal form, a situation called hyperinfection. Studies indicate that mortality from untreated hyperinfection can be as high as 87 percent.
The World Health Organization reports that although the parasitic illness has almost disappeared in countries where sanitation has improved, children remain especially vulnerable in endemic regions due to their elevated contact with dirt. Further, the drug of choice, ivermectin, is unavailable in some affected countries.
“Ivermectin is used to treat the disease but is less effective in the lethal form of the infection,” said Dr. Mangelsdorf, a Professor of Pharmacology and Biochemistry. “We do not know exactly how the glucocorticoid [steroid] causes hyperinfection, but once it does, ivermectin is much less effective, prompting the search for new drugs. The new drug we used in our mouse model appears to be very effective,” he said.
To study the still unknown pathogenesis of the disease, the researchers developed a mouse model susceptible to the full range of infection by the human parasite. Because mice with intact immune systems are resistant to S. stercoralis infection, the researchers began with an immunocompromised strain of mice, and then exposed some to a synthetic steroid called methylprednisolone (MPA) that is commonly used to treat asthma in humans.
The mice were then exposed to the parasitic worms. Compared with untreated mice, those that received the steroid showed a tenfold increase in the number of parasitic female worms and a 50 percent increase in mortality, said Dr. Mangelsdorf, who holds both the Alfred G. Gilman Distinguished Chair in Pharmacology and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.
In addition, third-stage larvae — the life cycle stage in which the worms can initiate hyperinfection — were found in higher numbers in the steroid-treated versus untreated mice, he added.
“Strikingly, treatment with a steroid hormone called Δ7-dafachronic acid, a chemical that binds to a parasite nuclear receptor called Ss-DAF-12, significantly reduced the worm burden in MPA-treated mice,” Dr. Mangelsdorf said. The Ss-DAF-12 receptor corresponds to a similar receptor in the long-studied C. elegans worm.
Dr. Mangelsdorf and colleagues previously showed (PNAS, 2009) that the DAF-12 receptor pathway is found in many parasitic species. They also showed that activating the receptor with Δ7-dafachronic acid could override the parasite’s development and prevent S. stercoralis from becoming infectious.
“Overall, this latest study provides a useful mouse model for S. stercoralis autoinfection and opens the possibility of new chemotherapy for hyperinfection by targeting the parasite’s own steroid hormone mechanism,” Dr. Mangelsdorf said.
- John B. Patton, Sandra Bonne-Année, Jessica Deckman, Jessica A. Hess, April Torigian, Thomas J. Nolan, Zhu Wang, Steven A. Kliewer, Amy C. Durham, James J. Lee, Mark L. Eberhard, David J. Mangelsdorf, James B. Lok, David Abraham. Methylprednisolone acetate induces, and Δ7-dafachronic acid suppresses,Strongyloides stercoralishyperinfection in NSG mice. Proceedings of the National Academy of Sciences, 2018; 201712235 DOI: 10.1073/pnas.1712235114
Dibenzoazepine defender: Drug found to be effective against resistant hepatitis C
Researchers have identified a class of chemicals that can combat resistant strains of the hepatitis C virus, as well as parasites that cause malaria and toxoplasmosis.
Hepatitis C is caused by a highly infectious virus affecting millions across the globe and can lead to a variety of liver ailments. While the hepatitis C virus (HCV) can sometimes be fought off and cleared by the immune system during the first few months of acute infection, up to 80% of those with HCV develop a chronic infection. This can lead to serious liver illnesses, including inflammation, cirrhosis, and hepatocellular carcinoma — the third leading cause of cancer death worldwide.
While highly effective treatments for HCV have become available in recent years, drug-resistant viral strains can still lead to treatment failure for a sizable proportion of patients. Now, in a recent study published in PNAS Plus, a compound has been reported that may eventually prove effective against drug-resistant HCV.
A team of researchers centered at Osaka University infected human liver cells with HCV, then treated the infected cells with different drugs to see which might prevent the virus from spreading. One compound, innocuously named YO-01027, stood out above the rest.
“For HCV to propagate in a host cell, the proteins that make up the virus particle need to be cleaved into their mature form,” lead author Junki Hirano explains. “We tested several compounds we thought may inhibit this cleavage process, and found that YO-01027 prevents a key HCV protein from undergoing cleavage and maturation. We correspondingly found the drug is very effective at suppressing HCV infection.”
Importantly, resistant strains of HCV did not emerge over time when the infected cells were treated with YO-01027. This may owe to the unique way the compound prevents the virus from maturing.
Patients with HCV are currently given direct-acting antivirals, which (as their name suggests) directly target and disrupt HCV proteins themselves. The drug tested in this study, however, inhibits one of the host cell’s proteins — signal peptide peptidase (SPP) — that HCV hijacks during an infection.
“Direct-acting antivirals have made tremendous progress in treating HCV,” corresponding author Yoshiharu Matsuura explains. “The difficulty is that HCV shows quite high genetic diversity, even within a single patient. Antivirals produce a strong selective pressure that can cause HCV strains with resistant forms of the target protein to spread. By inhibiting the host’s own SPP protein, we can largely bypass this selection problem.”
Through a combination of computer simulations and in vitro tests, the researchers identified the chemical signature of YO-01027 responsible for its effectiveness, a structure called dibenzoazepine. With this and other molecular details in hand, the researchers may now be able to modify YO-01027 and other dibenzoazepine-containing drugs to develop novel therapies for drug-resistant HCV — and, serendipitously, to potentially develop therapies against a variety of other diseases.
“Now that we know some of the key structural features that make YO-01027 effective at inhibiting SPP, we can start the chemical fine tuning,” Matsuura adds. “Ultimately, the goal is to make highly selective drugs to combat pathogens that need SPP to survive and spread. This includes not only viruses like HCV, but also parasites such as Plasmodium falciparum and Toxoplasma gondii that are responsible for malaria and toxoplasmosis. The possible applications are very exciting.”
- Junki Hirano, Toru Okamoto, Yukari Sugiyama, Tatsuya Suzuki, Shinji Kusakabe, Makoto Tokunaga, Takasuke Fukuhara, Miwa Sasai, Takahiro Tougan, Yasue Matsunaga, Kazuo Yamashita, Yusuke Sakai, Masahiro Yamamoto, Toshihiro Horii, Daron M. Standley, Kohji Moriishi, Kyoji Moriya, Kazuhiko Koike, and Yoshiharu Matsuura. Characterization of SPP inhibitors suppressing propagation of HCV and protozoa. PNAS, 2017; DOI: 10.1073/pnas.1712484114
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