Evolution of host-microbe cell adherence by receptor domain shuffling
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Evaluation Summary:
Baker et al. investigates the molecular evolution in primates of one protein family, the CEACAMs, that are a recurrent target of bacterial surface adhesions at epithelial surfaces. They show that multiple members of this gene family have experienced repeated episodes of positive selection in primates, especially in the N-terminal domains that are associated with protein binding and go on to evaluate the functional consequences of these evolutionary changes.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)
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Abstract
Stable adherence to epithelial surfaces is required for colonization by diverse host-associated microbes. Successful attachment of pathogenic microbes to host cells via adhesin molecules is also the first step in many devastating infections. Despite the primacy of epithelial adherence in establishing host-microbe associations, the evolutionary processes that shape this crucial interface remain enigmatic. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) encompass a multifunctional family of vertebrate cell surface proteins which are recurrent targets of bacterial adhesins at epithelial barriers. Here, we show that multiple members of the primate CEACAM family exhibit evidence of repeated natural selection at protein surfaces targeted by bacteria, consistent with pathogen-driven evolution. Divergence of CEACAM proteins between even closely related great apes is sufficient to control molecular interactions with a range of bacterial adhesins. Phylogenetic analyses further reveal that repeated gene conversion of CEACAM extracellular domains during primate divergence plays a key role in limiting bacterial adhesin host tropism. Moreover, we demonstrate that gene conversion has continued to shape CEACAM diversity within human populations, with abundant human CEACAM1 variants mediating evasion of adhesins from pathogenic Neisseria . Together this work reveals a mechanism by which gene conversion shapes first contact between microbes and animal hosts.
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Evaluation Summary:
Baker et al. investigates the molecular evolution in primates of one protein family, the CEACAMs, that are a recurrent target of bacterial surface adhesions at epithelial surfaces. They show that multiple members of this gene family have experienced repeated episodes of positive selection in primates, especially in the N-terminal domains that are associated with protein binding and go on to evaluate the functional consequences of these evolutionary changes.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
Baker et al. investigated the molecular evolution in primates of one protein family, the CEACAMs, that are a recurrent target of bacterial surface adhesions at epithelial surfaces. They show that multiple members of this gene family have experienced repeated episodes of positive selection in primates, especially in the N-terminal domains that are associated with protein binding. To test for the functional consequences of these evolutionary changes, Baker et al. incubated recombinant CEACAM N-domain proteins with different bacterial strains, and showed that divergence between species (and within humans) in this domain was sufficient to alter binding. Furthermore, by examining multi-gene phylogenies of just the N-terminal domain, the authors demonstrate that gene conversion between members of the CEACAM family …
Reviewer #1 (Public Review):
Baker et al. investigated the molecular evolution in primates of one protein family, the CEACAMs, that are a recurrent target of bacterial surface adhesions at epithelial surfaces. They show that multiple members of this gene family have experienced repeated episodes of positive selection in primates, especially in the N-terminal domains that are associated with protein binding. To test for the functional consequences of these evolutionary changes, Baker et al. incubated recombinant CEACAM N-domain proteins with different bacterial strains, and showed that divergence between species (and within humans) in this domain was sufficient to alter binding. Furthermore, by examining multi-gene phylogenies of just the N-terminal domain, the authors demonstrate that gene conversion between members of the CEACAM family plays an important role in this divergence.
The major strength of this manuscript is the work the authors have done to tie together molecular evolutionary analysis with functional binding assays to demonstrate that sequence divergence in the N-terminal domain of CEACAM1 is sufficient to alter the binding profile and potentially restrict host range of particular pathogens that bind to CEACAMs. While the authors do not test every positively selected site in every species of great ape, they show that substituting single positively selected residues in humans for the bonobo amino acid is sufficient to alter bacterial binding.
A second major strength of this manuscript is the use of population genetic data to suggest that gene conversion is ongoing in human populations, with segregating alleles that increase similarity between CEACAM1, 3, and 5 in human populations. This observation both validates the pattern observed in other primates, and suggests the importance of gene conversion as an ongoing evolutionary mechanism in this gene family.
Overall, the major conclusions of this work concerning the role of sequence divergence in determining binding, and the presence and importance of gene conversion, appear to be well justified by the results.
My only potential concern is that the general model of gene conversion discussed at the end of the work seems perhaps a bit too speculative. Gene conversion is a natural consequence of sequence similarity among paralogous members of a gene family, and it does not seem that special consequences for pathogen evasion need to be invoked. Instead, the presence of frequent gene conversion among members of the CEACAM family seem to indicate that maintaining some degree of sequence similarity among paralogs is beneficial, perhaps due to the role of CEACAM3 as decoy receptor.
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Reviewer #2 (Public Review):
In this manuscript, Baker et al describe the "Evolution of host-microbe cell adherence by receptor domain shuffling," which specifically examines a vertebrate-specific multigene family known as the CEACAMs, cell surface receptors and adhesion molecules that possess immunoglobulin domains. A subset of these receptors are expressed by the epithelium lining mucosal surfaces, and as such many bacteria adhere (via adhesions) to these receptors during host colonization. In this paper, the authors focus on how these receptors have been evolving in primates, and demonstrate that pathogens are engaged in an evolutionary arms race with CEACAMs, driving genetic diversification of the N-terminal domain (the main docking site for bacteria) to influence or regulate how pathogens colonize host epithelial surfaces.
The …
Reviewer #2 (Public Review):
In this manuscript, Baker et al describe the "Evolution of host-microbe cell adherence by receptor domain shuffling," which specifically examines a vertebrate-specific multigene family known as the CEACAMs, cell surface receptors and adhesion molecules that possess immunoglobulin domains. A subset of these receptors are expressed by the epithelium lining mucosal surfaces, and as such many bacteria adhere (via adhesions) to these receptors during host colonization. In this paper, the authors focus on how these receptors have been evolving in primates, and demonstrate that pathogens are engaged in an evolutionary arms race with CEACAMs, driving genetic diversification of the N-terminal domain (the main docking site for bacteria) to influence or regulate how pathogens colonize host epithelial surfaces.
The study demonstrates that repeated adaptive evolution of primate CEACAMs is shaping host-specific cell surface adherence by pathogenic bacteria. The authors show that over half of the CEACAM paralogs of humans reveal signatures of positive selection across diverse primates, primarily within the N-terminal (extracellular) domain, or the main interaction domain. They also show that rapid evolution is occurring via sequence exchanges across a subset of CEACAM paralogs via gene conversion. And finally, the authors also show that gene conversion is impacting pathogen recognition of CEACAMs in modern humans, suggesting that diversification of CEACAM N-terminal domain sequences is significantly impacting interactions between primates and the bacteria that colonize their surfaces.
It has been hypothesized that "exploitation of host proteins by pathogens places a significant burden on host populations, driving selection for beneficial mutations in these proteins that limit microbial invasion or virulence." But by interacting with host factors not necessarily involved in immunity (such as "housekeeping" proteins or receptors), pathogens may benefit from limited adaptive potentials, e.g., epithelial surface receptors likely have multiple roles critical to cellular and physiological functions. The authors set out to "investigate patterns of CEACAM divergence in primates and propose how CEACAM evolution and human populations have shaped interactions with pathogenic bacteria."
The authors first demonstrate that 8 of 12 primate CEACAM genes are undergoing positive selection (likely pathogen-driven) primarily in the exons encoding the N-terminal domains. Importantly, this includes CEACAM 1, 3, 5, and 6, which have been shown to be important interaction receptors for adhesins from various human pathogens.
The authors then demonstrate that evolution of the N-domains influences binding by bacterial adhesins. This was done using recombinant CEACAM domains, where specific mutations were introduced. First, the authors confirmed that representative CEACAM1 N-domains could bind known bacteria, via their adhesins. Specifically, CEACAMs from representative primates only bound specific bacterial strains. For example, the authors generated CEACAM1 N-domains in which a subset of human and bonobo residues were swapped; introduction of bonobo residue 44 into human CEACAM1 prevents binding to H. pylori and Opa-adhesins (e.g., Neisseria sp.), for example. These data confirm that nonsynonymous substitutions (those that change amino acids) in the N-domain are enough to shape interactions with multiple bacterial adhesins. The authors then use bioinformatic approaches to demonstrate that ongoing polymorphic changes in human CEACAM1 is likely impairing bacterial recognition; gene conversion among CEACAMs is also likely still ongoing in human populations, and that exchange of beneficial mutations may also influence binding to decoy receptors on epithelial cells.
And finally, the authors wrap up the paper by raising and trying to address some remaining questions in the field. In particular, an intriguing conundrum exists and remains to be investigated: if many non-pathogens or commensals also depend on CEACAM-binding for colonization of host surfaces, what are the consequences of pathogen-driven polymorphisms that may impair binding of beneficial microbes to CEACAMs?
Overall, this is simply a fantastic paper that is very well put together, very well thought out, and with a very clear writing style. The figures are nicely presented, organized, and informative. All necessary supplemental and source data are supplied. This is an important contribution to the field, and will be of broad interest. I very much enjoyed and learned from this paper; it was a pleasure to review.
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Reviewer #3 (Public Review):
This manuscript from the Barber group presents an interesting analysis of the CEACAM family of cell receptors in primates and convincingly shows that the N-terminal sequences are under strong purifying selection and have undergone both mutation and gene conversion to create diversity. The paper is clearly written, the figures are clear, and the methods used to examine the relationship are presented in a manner that a non-expert can understand their basis. As a study of the CEACAM gene family these data are very strong and the conclusions justified. The manuscript is less satisfactory in respect to the parameters driving the evolution of the CEACAM family. The authors conclude the evolutionary pressure is due to escape from bacterial (and possibly other) pathogens but the bacterial species known to bind …
Reviewer #3 (Public Review):
This manuscript from the Barber group presents an interesting analysis of the CEACAM family of cell receptors in primates and convincingly shows that the N-terminal sequences are under strong purifying selection and have undergone both mutation and gene conversion to create diversity. The paper is clearly written, the figures are clear, and the methods used to examine the relationship are presented in a manner that a non-expert can understand their basis. As a study of the CEACAM gene family these data are very strong and the conclusions justified. The manuscript is less satisfactory in respect to the parameters driving the evolution of the CEACAM family. The authors conclude the evolutionary pressure is due to escape from bacterial (and possibly other) pathogens but the bacterial species known to bind CEACAMs are host-adapted, opportunistic pathogens (so-called pathobionts) that do not cause significant pathology in hosts and have coevolved with their hosts. Moreover, it is uncertain whether the specific bacterium used in this study, Neisseria gonorrhoeae, has been associated with primates at all and how long it's been associated with humans is under debate and suggests this organism is a major driver of CEACAM evolution can be discussed but is not solid. It is more likely that one or more primordial commensal Neisseria species have been present in primates and humanoids. They also have ignored the phase variable nature of the Neisseria Opas and the different specificity for CEACAM orthologues. While the microbe/host evolutionary arms race model is simple and easy to swallow, I believe they need to back off from concluding any microbe are the evolutionary pressure and provide a more thoughtful discussion of the possible pressures similar but expanded from that they propose for CEACAM7/8. Lastly, if you are going to rest the model on a Neisseria species, showing a spirochete form in the model figures is not accurate. In summary, I see no issues with the data and it shows that the CEACAM family of receptors has been under strong purifying selection. There are major issues with the context provided for the data and the conclusions about the pressures for the selection of CEACAM family members.
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