The dream: just one shot

We are engaged in an arms race with the flu virus, but we have a secret weapon hidden in our DNA.  We can make antibodies that neutralize a bunch of different flu variants.

Viruses are little packets of DNA cloaked in proteins.  We make antibodies that target the outer protein shell, flagging the virus as an invader to be destroyed.  In the arms race, viruses evade detection by making constant changes to that outer coating.  But not the whole coating, just a piece of it that is referred to as the “head.”  We might gain a foothold in this race because the flu keeps the same “stem” region across many of its flavors, including H1N1 and the much-talked about H5N1 (avian flu).  In response to the pandemic 2009 H1N1 infection, some people made broadly neutralizing antibodies directed against that stem region. We all have the gene to do it; the trick seems to be finding the right immunogen to show to the immune system.  The seasonal vaccines we get at the doctor’s office haven’t been able to elicit such a response, yet, though people who have been exposed to many flu vaccines are more likely to have broadly neutralizing antibodies.  So all those shots you got weren’t for nothing.

Research is bringing us closer to that dream of a universal flu vaccine.  It’s been making headlines in the big journals this month. A paper published in Nature this week shows what makes for a good universal antibody and how the immune system needs to display it.  A paper in Science Express earlier this month found that people can make broadly universal antibodies that target both influenzas A and B.  If all the pieces come together, it could be the end of annual flu vaccines for future generations.

RNA fire alarm

“Inflammation” finds its roots in the Latin verb flammo, “to set on fire,” and it’s an apt descriptor of sunburn. As uncomfortable as it is, sunburn is actually a defense mechanism.  The inflammatory pathway that turns sunburned skin hot and red recruits immune cells to the damaged area.  The thinking goes that immune cells pick off skin cells with DNA damage before anything goes seriously awry (skin cancer).

How do skin cells sound the alarm that they’ve been damaged, as is the case in sunburn?  New research

by Jamie Bernard, a post-doc in Richard Gallo’s lab at University of California, San Diego, and their colleagues shows that damage to small noncoding RNAs can initiate the inflammatory response that’s better known as sunburn.  This is interesting on two fronts: one, we’ve long thought about DNA damage in the context of sunburn, but there’s much less research on UV-induced RNA damage.  Two, it’s another important function now ascribed to non-coding RNAs, once thought of as “junk” since they don’t get translated into proteins.

Bernard and his team found that UVB radiation damaged U1 RNA, a short strand of non-coding RNA in cultured skin cells.  RNA is single-stranded, but U1 RNA has an almost clover-like pattern, with complimentary regions looping around on themselves to create sections of double-stranded RNA.  As it turns out, UVB damage causes duplications of the loops, and these double-stranded fragments activate a protein (TLR3) that turns on inflammatory cytokines IL6 and TNF-alpha.  It also suppresses the immune system, which increases the risk of skin cancer, but can have therapeutic benefits in psoriasis or graft-vs-host transplantation.  In mouse models, the group was able to activate TLR3 simply by injecting UVB-damaged synthetic U1 RNA into the skin.

A few therapeutic treatments could fall out of this research. UVB phototherapy is currently used to treat psoriasis, a disorder in which immune cells stimulate skin cells to proliferate. Phototherapy is effective against psoriasis on several fronts, including toning down immune cell activity.   Maybe we can activate this UV-induced immunosuppression without the UV-aspect. This would reduce risk of skin cancer and eye damage.  Or, as the authors point out, by blocking the body’s ability to recognize bits of damaged RNA, these findings may help people that are especially sensitive to light, such as those with lupus.

In these sunny summer months, I find it a good reminder to use my sunscreen.

Stay, bacteria…stay

We are teeming with bacteria, fungi, and viruses.  This is a deliberate arrangement that every one of us unwittingly enters into.  From the moment we are born, we begin to accumulate and cultivate certain desired microbes.  They live without and within, on our skin and in our guts.  We co-evolved with the microbes and it’s a mutually beneficial relationship.

In our intestines, microbes help us with digestion and nutrition.  They give us access to the energy stored in some complex carbohydrates that would otherwise just pass through.  They make the vitamin K that we need. For that, we give them room and board.  It’s a happy relationship.

But these are bacteria, viruses, and fungi.  Those are the same words ascribed to infections and disease.  How do we make this work?

In order to safely contain these microbes, we have constructed barriers and safeguards that separate what’s going on in the gut from the rest of the body.  The gut is lined by epithelial tissue with tight junctions between cells to prevent microbes from slipping through.  The thick layers of mucous secreted into the intestines are hard for microbes to cross.  In that mucous are gut-specific immune cells.  They deal with surveying the massive numbers of bacteria within the gut, and reporting back to gut’s immune tissue.  Any hardy invaders that bypass these defenses should be picked up by the gut’s lymphatic tissue. Ideally, problems are dealt with before the body’s general immune system has to get involved, which would lead to system-wide infection and inflammation.

The tissue and mucous barriers that restrict microbes to the guts are physical barriers, like walls. In a paper published by David Artis’s group at the University of Pennsylvania in Science on June 8th, 2012, scientists describe the first non-physical barrier known to keep microbes in their place.  They found that cells of the immune system secrete a signal that prevents a bacteria called Alcaligenes from being spread throughout the body.

Alcaligenes are relegated to the gut’s immune tissues: Peyer’s Patches and mesenteric lymph nodes, which sit on the other side of that epithelial wall.  They sample what sneaks through, keeping a watchful eye out for foreign invaders.  So, the same tissues that constantly patrol for invading bacteria have selected one to let in, and they work to keep it there.

In the lab, Alcaligenes are known to secrete antimicrobials that can kill some E. coli, Strep, and Staph.  Maybe that’s why the gut has invited these bacteria to call our bodies home.  It may be of extra benefit to have them in the Peyer’s Patches, where immune cells sit in wait for foreign invaders.  Like a team, the immune cells can detect an invasion, and the Alcaligenes might help eliminate it.

These lymph nodes sit next to the intestines, straddling that physical barrier that our body erected to keep the microbes that help us with digestion from crossing into the rest of the body.  So how do we confine the Alcaligenes to those places, if they’re on the other side of the wall?

Innate lymphoid cells, that’s how.  Researchers found that innate lymphoid cells secrete a signal, the cytokine IL22, which keeps Alcaligenes in the lymphatic tissue of the gut.  When innate lymphoid cells are taken out of the picture, the Alcaligenes disperse throughout the body.  Treating mice that are missing innate lymphoid cells with IL22 keeps the Alcaligenes in their place, so it appears to be the secretion of IL22 that contains the Alcaligenes.

If the Alcaligenes escape the gut, the adaptive immune system mounts a response to eliminate them.  In the lab, two weeks after Alcaligenes escaped their gut confinement, the only thing remaining were antibodies specific to the bacteria, patrolling for more. But the mice weren’t necessarily good as new.  The mice had residual systemic inflammation following the infection.

This research could have bearing on people with chronic or inflammatory diseases.  Patients with Crohn’s disease, cancer, HIV, and Hepatitis C infection are more likely to have experienced a system-wide Alcaligenes infection.  If we can prevent Alcaligenes from leaving the gut, we may be able to limit inflammation in chronic human diseases, which would improve patient outcome.  It’s also another surprising role for innate lymphoid cells, which were only discovered about ten years ago.  Scientists are still teasing apart their varied functions.  It’s a mixed bag so far.  The cells have been implicated as helpful in recovering from the flu and initiating immune responses, to harmful in colitis and asthma.  We can add this discovery to the growing list of potential therapeutic targets to treat inflammatory disease.


More reading:

There’s a collection of articles on the Science website about the microbiome.  And it’s free to anyone in the month of June…a step in the right direction towards open access.

Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria, Science, vol. 336, 8 June 2012.

Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis, PNAS, vol. 107:16, April 20, 2010.

Crossover immune cells blur the boundaries, Science 8 June 2012: Vol. 336 no. 6086


Photo credit: Thanks to Euthman for the great histology pic on Flickr, kindly available under the Creative Commons license.