When germs attack: A lens into the molecular dance

Jan 07, 2014
When germs attack: A lens into the molecular dance
Using electron microscopy, researchers observed IFI16 pathogen sensors lining up along pieces of DNA. Credit: The Sohn lab

Researchers at Johns Hopkins have zoomed in on what is going on at the molecular level when the body recognizes and defends against an attack of pathogens, and the findings, they say, could influence how drugs are developed to treat autoimmune diseases.

The focus of the research is a pathogen "sensor" known as human IFN inducible protein-16 or IFI16, one of the body's key responders to viruses and bacteria, including herpes, HIV, listeria and salmonella. When IFI16 goes awry, it can prod the immune system to attack its own cells, triggering such as lupus and Sjögren syndrome (in which the glands that produce tears and saliva are destroyed). By figuring out how IFI16 operates, biophysicist Jungsan "Jay" Sohn, Ph.D., and his team say they have set the stage for finding ways to stop or limit the damage.

For the study, described online at the Proceedings of the National Academy of Science Early Edition in December, the Hopkins team used high-powered microscopy to show that these sensor proteins of the human immune system assemble into strands to signal infection. This strand-forming appears in other pathogen sensors, suggesting that this may be a common host defense mechanism.

"By understanding how IFI16 works at this fine molecular level, we may be able to boost this activity to build up immunity or taper down this activity to correct autoimmune disorders," says Sohn, an assistant professor of biophysics and biophysical chemistry.

Sohn and his research team first generated genetically engineered IFI16 from bacteria and exposed it to synthetic DNA sequences of varying lengths to see how the protein might react to "foreign," pathogenic DNA. They then observed the IFI16 and DNA interact via electron microscopy. What they saw was surprising.

The team expected that IFI16, like other pathogen sensors, would react to foreign DNA if it is long enough to accommodate just one IFI16 molecule. But IFI16 didn't react strongly until the synthetic DNA fragments exceeded 60 base pairs in length, which can accommodate about four IFI16 molecules. It was as if a light went on when the "invading" DNA reached 70 to 100 base pairs, Sohn says. "We call that switch-like behavior."

IFI16's preference for long DNA strands explains a longstanding mystery, according to Sohn. Researchers, he explains, have wondered how our bodies' immune systems mostly avoid "friendly fire," or being sent into overdrive and attacking themselves. The new experiments suggest that the length of DNA could be the key: Our DNA is packaged such that there are only short exposed fragments, and IFI16 won't activate in the presence of short DNA, but will in the presence of pathogenic DNA, which typically expose much longer strands.

"What we found suggests that the sensor uses the length of the naked DNA as a molecular ruler to distinguish self from non-self," Sohn says.

Subsequently, Sohn and his team investigated how a sensor like IFI16 was attracted to such long DNA. They found that IFI16 molecules line up along long pathogenic DNA strands to form chains, or filaments. The longer the naked DNA, the longer the chain. What's more, chains of IFI16 then line up and merge to create an even longer chain.

"The filaments emerge and elongate," Sohn says.

But that left the question of how IFI16 molecules were able to find each other and align. In another set of experiments, the team showed that IFI16 contains three protein parts—HinA, HinB and PYD—and when they broke up PYD, the chain failed to form.

What was surprising, he says, is that PYD doesn't bind directly to the pathogen's DNA. Rather, the Hin domains on IFI16 bind to the DNA, which makes the PYD domains gravitate toward one another. As a result, the PYDs glom together to form a powerful scaffold.

Sohn says his work suggests that the PYD-PYD interaction is very specific and a great potential drug target.

"It's really difficult to develop a drug that's targeting something that binds non-specifically. But PYD-PYD interaction is specific, and it only happens when it encounters DNA. It is what drives the stability of the complex. So if you can disintegrate that, it might alleviate autoimmune disorders," Sohn says. Conversely, developing drugs that bolster the scaffold could enhance immunity, he adds.

Explore further: Scientists discover how immune cells die during HIV infection; identify potential drug to block AIDS

Related Stories

Detailed image shows how genomes are copied

Dec 02, 2013

For the first time, researchers at Umeå University have succeeded in showing how the DNA polymerase epsilon enzyme builds new genomes. The detailed image produced by these researchers shows how mutations ...

The gene sequencing that everyone can afford in future

Dec 06, 2013

DNA sequencing is important to science. While Professor Qian Linmao and his group from Tribology Research Institute, Southwest Jiaotong University, were working on the optimization of the third-generation ...

When DNA is out of place

Jun 04, 2013

When DNA that turns up in the wrong place in mammalian cells, the innate immune system reacts by secreting interferons. The structure and mode of action of the enzyme that mediates this response have now been elucidated.

Bacteria recycle broken DNA

Nov 18, 2013

Bacteria recycle broken DNA that bacteria can take up small as well as large pieces of old DNA from this scrapheap and include it in their own genome. This discovery may have major consequences – both in connection with ...

Recommended for you

Researchers successfully clone adult human stem cells

23 hours ago

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Researchers develop new model of cellular movement

Apr 18, 2014

(Phys.org) —Cell movement plays an important role in a host of biological functions from embryonic development to repairing wounded tissue. It also enables cancer cells to break free from their sites of ...

For resetting circadian rhythms, neural cooperation is key

Apr 17, 2014

Fruit flies are pretty predictable when it comes to scheduling their days, with peaks of activity at dawn and dusk and rest times in between. Now, researchers reporting in the Cell Press journal Cell Reports on April 17th h ...

User comments : 0

More news stories

Researchers successfully clone adult human stem cells

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Plants with dormant seeds give rise to more species

Seeds that sprout as soon as they're planted may be good news for a garden. But wild plants need to be more careful. In the wild, a plant whose seeds sprouted at the first warm spell or rainy day would risk disaster. More ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.

Health care site flagged in Heartbleed review

People with accounts on the enrollment website for President Barack Obama's signature health care law are being told to change their passwords following an administration-wide review of the government's vulnerability to the ...