Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
- Harvard University, United States
- Massachusetts Institute of Technology, United States
- Stanford University, United States
- École Normale Supérieure, France
Abstract
Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens. However, our understanding of the evolutionary pathways leading to bnAbs, and thus how best to elicit them, remains limited. Here, we measure equilibrium dissociation constants of combinatorially complete mutational libraries for two naturally isolated influenza bnAbs (CR9114, 16 heavy-chain mutations; CR6261, 11 heavy-chain mutations), reconstructing all possible evolutionary intermediates back to the unmutated germline sequences. We find that these two libraries exhibit strikingly different patterns of breadth: while many variants of CR6261 display moderate affinity to diverse antigens, those of CR9114 display appreciable affinity only in specific, nested combinations. By examining the extensive pairwise and higher-order epistasis between mutations, we find key sites with strong synergistic interactions that are highly similar across antigens for CR6261 and different for CR9114. Together, these features of the binding affinity landscapes strongly favor sequential acquisition of affinity to diverse antigens for CR9114, while the acquisition of breadth to more similar antigens for CR6261 is less constrained. These results, if generalizable to other bnAbs, may explain the molecular basis for the widespread observation that sequential exposure favors greater breadth, and such mechanistic insight will be essential for predicting and eliciting broadly protective immune responses.
Data availability
Data and code used for this study are available at https://github.com/klawrence26/bnab-landscapes. CR9114 data are also available in an interactive data browser at https://yodabrowser.netlify.app/yoda_browser/.FASTQ files from high-throughput sequencing have been deposited in the NCBI BioProject database with accession number PRJNA741613, and will be publicly released upon acceptance.
Article and author information
Author details
Aleksandra M Walczak
Funding
Howard Hughes Medical Institute (Hanna H. Gray Postdoctoral Fellowship)
- Angela M Phillips
International Human Frontier Science Program Organization
- Thomas Dupic
The NSF-Simons Center for Mathematical and Statistical Analysis of Biology at Harvard (1764269)
- Katherine R Lawrence
Hertz Foundation (Graduate Fellowship Award)
- Katherine R Lawrence
National Science Foundation (Graduate Research Fellowship Program)
- Katherine R Lawrence
National Science Foundation (Graduate Research Fellowship Program)
- Milo S Johnson
National Science Foundation (Graduate Research Fellowship Program)
- Jeffrey Chang
European Research Council (COG 724208)
- Thierry Mora
- Aleksandra M Walczak
National Institutes of Health (GM104239)
- Michael M Desai
National Science Foundation (PHY-1914916)
- Michael M Desai
Stanford University (Stanford Science Fellowship)
- Ivana Cvijovic
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Phillips et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,429
- views
-
- 515
- downloads
-
- 48
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies
eLife 10:e71393.
https://doi.org/10.7554/eLife.71393
Further reading
-
- Cancer Biology
- Evolutionary Biology
In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.
-
- Evolutionary Biology
Lineages of rod-shaped bacteria such as Escherichia coli exhibit a temporal decline in elongation rate in a manner comparable to cellular or biological aging. The effect results from the production of asymmetrical daughters, one with a lower elongation rate, by the division of a mother cell. The slower daughter compared to the faster daughter, denoted respectively as the old and new daughters, has more aggregates of damaged proteins and fewer expressed gene products. We have examined further the degree of asymmetry by measuring the density of ribosomes between old and new daughters and between their poles. We found that ribosomes were denser in the new daughter and also in the new pole of the daughters. These ribosome patterns match the ones we previously found for expressed gene products. This outcome suggests that the asymmetry is not likely to result from properties unique to the gene expressed in our previous study, but rather from a more fundamental upstream process affecting the distribution of ribosomal abundance. Because damage aggregates and ribosomes are both more abundant at the poles of E. coli cells, we suggest that competition for space between the two could explain the reduced ribosomal density in old daughters. Using published values for aggregate sizes and the relationship between ribosomal number and elongation rates, we show that the aggregate volumes could in principle displace quantitatively the amount of ribosomes needed to reduce the elongation rate of the old daughters.
