When the Burroughs Wellcome Fund created the Investigators in the Pathogenesis of Infectious Disease (PATH) award nearly two decades ago, one of its defining principles was to move past the metaphor of “war” against infectious diseases. No longer did it make sense to limit thinking around the relationship between host and microbe as a battle between us and them. Microbes could be our allies as well as our adversaries, and wiping them out could do more harm than good.
But with a pair of recent publications from PATH awardees, the war is back on. The two publications provide startingly detail of an evolutionary arms race taking place between the flu virus and the human immune system.
“These results were both surprising and satisfying in that they show that evolution isn’t something that just happens in the drawers of the history museum or a classroom textbook,” said Victoria McGovern, the senior program officer overseeing the PATH program. “It’s something that’s rapidly affecting the natural history of our interactions with flu and probably all kinds of other microbes.”
The findings were the culmination of a years-long collaboration between the University of Washington’s Jesse Bloom and the University of Pennsylvania’s Scott Hensley. They suggest that only by joining forces can scientists hope to outsmart one of the smartest viruses on the planet.
Crossing paths
The two met early in their careers, when Bloom was still a postdoc under David Baltimore and Hensley was starting his own lab. At first, they connected over shared interests: Hensley studied how the human immune system recognizes flu, while Bloom was interested in how the virus evolves to escape that immunity. After they were granted PATH awards — Bloom in 2015 and Hensley in 2016 — their paths began to cross even more. At one point, they began discussing ways to get members of their labs to interact with each other.
“One thing that Seattle has that Philadelphia doesn’t is lots of outdoor things to do,” joked Bloom. After some searching, a graduate student in his lab found a ski lodge perched on the crest of Snoqualmie Pass, right outside Seattle, that was affordable during the off-season.
As PATH investigators, Bloom and Hensley each had access to $1000 a year to invite other awardees to give a seminar at their home institution. Rather than use the money for a single speaker’s travel, they decided to pool their resources and fly Hensley’s entire lab to Seattle.
“This has been a creative and unexpected use of this funding mechanism,” said McGovern. “Since the whole purpose of these funds is to get scientists out there and talking to each other, we think there is probably nothing better than including grad students and postdocs. They’re the ones who are the closest to the cutting edge on any given day.”
S’mores and science
For two days, about thirty undergrads, technicians, graduate students, and postdocs bunked in the looming and light-filled lodge. Before their labs even arrived, Bloom and Hensley were already conspiring on ways to get them to collaborate. They created teams with members from each of their labs to handle meal prep in the lodge’s commercial scale kitchens. The teams began emailing each other weeks before the retreat to plan the meals and buy ingredients.
“It was a cool idea because it basically made the labs get together and solve a problem, how to cook the meal for 30 people,” said Hensley.
The retreat was structured to provide plenty of time for science and plenty of time for socialization. Each day started with a series of informal 15-minute science talks given by the members of each lab. Those talks were followed by various indoor and outdoor activities, including games in the basement and hiking in the nearby wilderness. One afternoon the entire group hiked a section of the Pacific Crest Trail, posing for pictures near rocky outcroppings and pools of blue-green water.
“Just like with conferences, some of the best stuff came from informal talks over beer or hiking,” said Hensley.
After much bonding and brainstorming, the scientists jotted down bits of their shared ideas on a giant sheet of butcher paper. Many of those ideas turned into experiments, and now papers.
“One of the lessons that I took away from that butcher paper is that you can write things down and make plans, but the key thing is that there’s people who are on the ground doing this work that talk to each other and believe they are worthwhile ideas to actually pursue,” said Bloom.
A ground war
After the retreat, graduate students Juhye Lee from Bloom’s lab and Seth Zost from Hensley’s lab pursued several of those worthwhile ideas. The first question they tackled was a longstanding one in the field of viral immunology. The flu virus has an amazing ability to mutate, making tiny tweaks to its structure to evade the immune system’s defenses. However, the human immune system is amazing too. It can make a slew of antibodies that target many different parts of the flu virus, and it seems unlikely that a single mutation could escape them all. Why, then, do millions of people succumb to the flu every flu season?
Lee used a new technique, called deep mutational scanning, to map how mutations to the virus affected its recognition by antibodies circulating in the serum of 16 different study volunteers. They were surprised to find that though the human immune system can potentially make an astronomical number of antibodies, for many people, the actual immune response is very narrowly focused on a specific part of the virus.
“I think that’s incredible,” said Bloom. “We found that different people’s immunity is focused in different ways, meaning that they may be more protected or more susceptible to whatever strain is circulating. It also means that as the virus is evolving, there may be new mutations that are strongly favored while the virus is replicating in one person, but that are no longer favored when the virus jumps to another person. It presents a lot of interesting evolutionary implications.”
The year of the rabbit
The findings jibed with Hensley’s previous research, which suggested that each of us harbor different types of antibodies because we have encountered different types of flu viruses in our lives. “I was born in the late seventies, and my immune system was probably primed or educated with viruses from the late seventies and early eighties,” said Hensley. “I have a different sort of immune repertoire compared to someone who was born in the 90s, because their immune system was exposed to different viruses.”
Hensley said the impact of immune history is so strong that it might be possible to one day predict people’s susceptibility to the flu simply by asking their birthday, like a Chinese horoscope for infectious diseases. With more research, such knowledge could be used for more than just a parlor trick. It could be parlayed into population models that predict how the flu virus will evolve and circulate throughout the population, making it possible to more accurately pick which flu vaccine strains to produce for the next flu season.
Because the flu virus changes so rapidly, new batches of the flu vaccine have to be formulated and administered every year. Having a universal flu vaccine, like we have for the measles or the mumps, could save a lot of headaches and a lot of lives. But to create a universal vaccine, researchers would need to target a region of the virus that doesn’t change from season to season. Not surprisingly, that idea was discussed during the joint lab retreat.
Again, Zost and Lee joined forces, this time combining Zost’s curation of human sera with Lee’s computational techniques to map exactly where antibodies latch onto flu viruses. They identified one antibody, from one individual, that targeted a conserved region of the virus. As a result, the antibody was effective against several strains of the flu.
“The real trick is figuring out why that person developed that type of immunity,” said Hensley. “If we could figure that out, then we could start thinking about developing new vaccines that are harder for the flu virus to defeat.”
The next retreat
Lee and Zost, who are first authors of their respective papers, have now graduated. But other collaborations continue between the Bloom and Hensley labs, with more exciting results in the offing. “Successful collaborations like this one make it easier to get new ones going, because people see it’s a productive route to work together,” said Bloom. They hope to do another joint retreat next year, perhaps hosting one every two to three years.
McGovern said that as more people have grown to appreciate the value of collaboration, other PATH awardees have begun holding their own joint retreats.
“I think collaboration has always been important, because of its ability to play one axis against another, like biochemistry and genetics, or in this case, computational biology and immunology,” said McGovern. “That’s always been true, but it is especially true now because the problems we are bigger than any one scientist or discipline.”
New work from our lab led by @juhyemlee maps how flu can escape polyclonal human immunity: https://t.co/knKQA7K5Pn
Watch the video abstract below for key findings (or read on in this Tweet chain): pic.twitter.com/LhAJRTP8fr
— Bloom Lab (@jbloom_lab) June 13, 2019
Citations:
Lee JM, Eguia R, Zost SJ, Choudhary S, Wilson PC, Bedford T, Stevens-Ayers T, Boeckh M, Hurt A, Seema Lakdawala SS, Hensley SE, and Bloom JD. Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin. doi: https://doi.org/10.1101/670497
Zost SJ, Lee J, Gumina ME, Parkhouse K, Henry C, Wilson PC, Bloom JD, and Hensley SE. Identification of antibodies targeting the H3N2 hemagglutinin receptor binding site following vaccination of humans. doi: https://doi.org/10.1101/675272
By: Marla Broadfoot, PhD
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