Rare immune cell is asset and liability in fighting infection

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The same trait that makes a rare immune cell invaluable in fighting some infections also can be exploited by other diseases to cause harm, two new studies show. In papers published online in Immunity, scientists at Washington University School of Medicine in St. Louis reveal that the cells, known as CD8 alpha+ dendritic cells (CD8a+ DCs), can help the body beat back infection by a common parasite, but the same cells can be hijacked by a bacterium to decimate the body's defenses.

The trait that makes the cells both an asset and a liability is the way they alert other immune cells, causing them to attack invaders. CD8a+ DCs can sound the alarm in a manner that is particularly helpful for stripping away invaders' disguises. But this process takes time, and Listeria bacteria can take advantage of that delay to wreak havoc inside the spleen.

"As we've discovered how useful these cells can be in fighting different kinds of infections, researchers have wondered why they're so rare," says Kenneth Murphy, MD, PhD, the Eugene L. Opie First Centennial Professor of Pathology and Immunology. "This may be why -- overcommitting to any one defensive strategy opens up opportunities for counterstrategies that exploit it."

CD8a+ DCs make up about 10 percent of all dendritic cells in the body. By studying the basic functions of these cells, scientists are laying the groundwork to use them to fight infections. The cells also appear to be essential for some cancer vaccines, which enlist the power of the immune system to help fight tumors.

Murphy, who is a Howard Hughes Medical Institute Investigator, previously created genetically altered mice where CD8a+ DCs could be selectively eliminated. By comparing these mice with normal mice, Murphy and his collaborators have shown that CD8a+ DCs are essential to priming the body's defenses against viral infections.

Viruses often try to disguise themselves to evade defenders, but CD8a+ DCs can extract characteristic parts of a virus and display them on their surface. Other cells also can make these displays, but CD8a+ DCs do it in a way that helps peel back disguises, causing other immune cells to seek out additional copies of the virus and kill them.

In one of the new studies, doctoral student Mona Mashayekhi showed that CD8a+ DCs are early responders to infection with the Toxoplasma gondiiparasite, which causes serious disease in patients with weakened or suppressed immune systems. She found only CD8a+ DCs produce a signal that causes other immune cells to fight the parasite.

In the second paper, Brian Edelson, MD, PhD, assistant professor of pathology and immunology, tested the cells against the bacteria Listeria, which can cause food poisoning. He discovered that CD8a+ DCs could make Listeria infection worse.

"Listeria likes to get into immune cells using a pathway that typically leads to the bacteria's death in garbage disposals inside the cell," Murphy explains. "But that pathway is slowed down in CD8a+ DCs to ensure that they can retain part of the invader to display to other immune cells."

Researchers watched Listeria use this delay to ride inside CD8a+ DCs as they entered the spleen, where immune cells not yet activated for attacking invaders are kept. These cells are easy targets for the bacteria, and infection worsens.

According to Murphy, CD8a+ DCs' specialized ability to initiate immune attacks makes them essential for efforts to create cancer vaccines based on DNA from tumors. He and collaborator William Gillanders, MD, professor of surgery, are working to use these vaccines to make immune cells attack cancers.

"What we're learning from basic studies, for example, has already enabled us to increase the number of CD8a+ DCs in mice until they're about 30 to 40 percent of dendritic cells," Murphy says. "Learning more about how this cell interacts with other immune cells will allow us to create effective cancer vaccines."

New Drug Cures Multiple Viruses in Human Cells

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There's no cure for the common cold—yet. 

A new drug can scout out and kill numerous types of viruses infecting human and animal cells, researchers have announced. It's the first time a single drug has been shown to work against a range of viruses, from those that cause seasonal sniffles to more fatal diseases.

"Several decades ago the discovery and production of antibiotics revolutionized the way bacterial infections were treated," said study co-author Todd Rider, a senior staff scientist at the Massachusetts Institute of Technology's Lincoln Laboratory and Division of Comparative Medicine.

"We hope that this will similarly revolutionize the way viral infections are treated. That covers everything from cold and flu viruses to more serious clinical pathogens like HIV and hepatitis viruses and ultimately even more deadly viruses like Ebola and smallpox."

(Watch video: "How Flu Viruses Attack.")

Alien-Like Viruses Tough to Beat

Though there are plenty of drugs to treat bacterial infections, there are few that can battle viruses. The antiviral drugs that have been developed are highly specific, with each drug targeting just one strain of a virus, which can easily mutate and become resistant to the medication.

So Rider and colleagues took a different approach—tailoring their new drug to work with the body's built-in defense mechanism.

Viruses operate "sort of like the aliens in the Alien movies," Rider said. "They'll enter a cell, replicate inside the cell, and ultimately burst out of the cell," killing it.

(Take a quiz on infectious diseases.)

While taking over cells, viruses produce what's called long double-stranded RNA, a complex acid that controls the virus's chemical activities and is not produced in healthy human cells, according to the study, published July 27 in the journal PLoS ONE.

Human bodies do have natural defenses against viruses: They produce proteins that latch onto double-stranded RNA and prevent the virus from replicating itself. But many viruses have evolved ways to shut down these proteins.

New Drug Packs Double Whammy

Rider and his team developed a drug that combines the natural-defense protein with another protein that triggers a cell's suicide switch. All human cells have these suicide switches, which are usually activated when cells start to become cancerous, Rider said.

The result is like the mythological centaur, said Marie Pizzorno, a molecular virologist at Pennsylvania's Bucknell University.

"The horse is one piece of a protein that normally we make and that can recognize the [long double-stranded RNA] made by the virus, and the man is something that triggers the cell-death pathway," she said.

The new drug, called DRACO, works by searching for cells in the body that contain long double-stranded RNA—a surefire sign of a virus. If the drug finds a viral infection, it tells the cell to self-destruct.

Since our body doesn't use these proteins together naturally, combining them in drug form may outsmart even the most adaptable of viruses, added Pizzorno, who was not involved in the new study.

"Viruses have figured out how to handle our normal defenses, [but] by activating these two pathways with one protein, they've hopefully prevented the viruses from getting around it."

If the drug does not find double-stranded RNA in the body, it eventually flushes out with no side effects, study leader Rider added. (See a human-body interactive.)

Common-Cold Drug Still a Decade Away

So far, the drug has proven to be effective and nontoxic in killing 15 types of virus—including the ones that cause dengue hemorrhagic fever and H1N1 influenza, or swine flu—in 11 types of mammalian cells, including human.

The drug also cured 100 percent of mice injected with a lethal dose of H1N1, and there are ongoing trials in mice with other viruses.

The next step will be to see if the drug can kill viruses in bigger animals, such as rabbits, guinea pigs, and ultimately monkeys, Rider said.

Then, if the drug is still safe and effective, the U.S. Food and Drug Administration may approve human clinical trials, Rider said. Still, it will be "at least a decade before you can buy this at the drugstore."

Even with all these steps yet to go, the new drug has promise, Bucknell's Pizzorno added.

"It's a really innovative way to consider doing an antiviral," she said. "I don't think anyone has ever thought of this before."