Saturday, July 01, 2017

eLife: Parallel Evolution Of Influenza Across Multiple Spatiotemporal Scales

Credit NIAID


We've an absolutely fascinating influenza study that looks back at the viral evolution of seasonal H3N2 in four immunocompromised patients sampled 10 years ago, and finds parallels between the mutations that occurred during their prolonged illnesses, and evolutionary changes to influenza viruses around the globe in the years that followed. 
While I let that sink in, a brief refresher on influenza evolution.
Influenza viruses evolve via two well established routes; Antigenic drift & Antigenic Shift (reassortment).
  • Antigenic drift causes small, incremental changes in the virus over time. Drift is the standard evolutionary process of influenza viruses, and often come about due to replication errors that are common with single-strand RNA viruses (see NIAID Video: Antigenic Drift).
  • Shift occurs when one virus swap out chunks of their genetic code with gene segments from another virus.  This is known as reassortment. While far less common than drift, shift can produce abrupt, dramatic, and sometimes pandemic inducing changes to the virus (see NIAID Video: How Influenza Pandemics Occur).
In either case, most mutations/reassortments are evolutionary failures.

They die out quickly because they are not as biologically `fit’ as the parental virus they must compete with. Only rarely does a mutation convey enough of an evolutionary advantage to allow it to become `fixed' in a host, and potentially transmitted onward.

And while these mutations enable influenza viruses to evade host immunity and avoid extinction, they are random, chance events. It is only through an absolutely astronomical number of rolls of the genetic dice that influenza viruses eventually stumble upon a more advantageous genome sequence.
Today's study adds a new wrinkle to all of this, suggesting that while influenza's mutations are random - there are only a limited number of successful evolutionary pathways available to any given strain - and raises the possibility that future viral mutations may follow a (semi) predictable path.
It is important to note that the original intent of this study was simply to examine how the flu evolves in an immunocompromised individual who can carry a flu infection for weeks or even months.
What they found, quite unexpectedly, were several common mutations across 4 randomly selected cases. Even more surprising, these mutations heralded - by several years - evolutionary changes that would become fixtures in globally circulating seasonal flu viruses. 

First the abstract of the study, followed by some excepts from a press release by the Fred Hutchinson Cancer Research Center, where much of this work was conducted. 
Parallel evolution of influenza across multiple spatiotemporal scales

Katherine S Xue1,2, Terry Stevens-Ayers3, Angela P Campbell3†,
Janet A Englund4,5, Steven A Pergam3,6,7, Michael Boeckh3,6,7, Jesse D Bloom1,2*


Viral variants that arise in the global influenza population begin as de novo mutations in single infected hosts, but the evolutionary dynamics that transform within-host variation to global genetic diversity are poorly understood. Here, we demonstrate that influenza evolution within infected humans recapitulates many evolutionary dynamics observed at the global scale.
We deep-sequence longitudinal samples from four immunocompromised patients with long-term H3N2 influenza infections. We find parallel evolution across three scales: within individual patients, in different patients in our study, and in the global influenza population. In hemagglutinin, a small set of mutations arises independently in multiple patients. These same mutations emerge repeatedly within single patients and compete with one another, providing a vivid clinical example of clonal interference. Many of these recurrent within-host mutations also reach a high global frequency in the decade following the patient infections. Our results demonstrate surprising concordance in evolutionary dynamics across multiple spatiotemporal scales.

DOI: 10.7554/eLife.26875.001

We suggest that parallelism in HA evolution may emerge from the confluence of several evolutionary conditions (Lässig et al., 2017). First, if selection acts concordantly across environments, it will favor a common set of beneficial mutations. Second, in a constrained evolutionary landscape, this set of beneficial mutations will be relatively small. Finally, given sufficiently large population sizes, high mutation rates, and time, these beneficial mutations will emerge and be selected to detectable frequencies. Our observation that similar mutations arise repeatedly within single patients, within multiple different patients, and at the global scale, suggests that at least some of these conditions may hold true.
         (Continue . . . )

The entire (open access) study is well worth reading, as is the press release from the Fred Hutchinson Cancer Research Center, which provides a good lay explanation of the study and its findings.

What we can learn about global flu evolution from one person's infection 
Date:June 27, 2017

Source:Fred Hutchinson Cancer Research Center

Summary: A new study has found that flu evolution within some individuals can hint at the virus's eventual evolutionary course worldwide. The study of 10-year-old flu samples also found the virus's evolution in individual transplant patients partially mirrors later global trends.       
A new study has found that flu evolution within some individuals can hint at the virus's eventual evolutionary course worldwide.

Samples taken more than 10 years ago from people with unusually long flu infections -- and analyzed recently using modern genome sequencing methods -- revealed certain viral changes that matched global flu evolution trends several years later.

The study, published in the journal eLife, tracked how flu evolved over time in four people who were especially vulnerable to unusually severe viral infections: bone marrow transplant patients. For people with healthy immune systems, a typical flu infection lasts about a week, said Fred Hutchinson Cancer Research Center evolutionary biologist and doctoral student Katherine Xue, first author on the study. So she and her colleagues at the Hutch, Seattle Children's Research Institute and the University of Washington studied viruses that originated from patients who received transplants and developed severe flu infections that lasted two or more months.

These four patients were drawn from a group of nearly 500 transplant recipients who participated in a previous study led by Fred Hutch infectious disease researcher Dr. Michael Boeckh, also a co-author on this study. That large study began in 2005 to improve understanding about the sometimes devastating impact of respiratory viruses in this vulnerable population -- in fact, two of the four patients whose samples were analyzed in the current study went on to die of their infections.

(Continue . . . )

All of this work is in its infancy, and we are a long way from being able to predict what changes will occur in seasonal influenza 1, 2, or 5 years out.  But this research suggests that flu's evolution may be less random, and more predictable, than we previously believed.

One can't help but hope that Chinese researchers are taking note, and perhaps doing similar deep sequencing on H7N9 patients - who often shed the virus for weeks - to see if similar `common' mutations are turning up that might give us some early warning as to where that virus is headed.

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