Trillions of bacteria live in and on the human body. Most of them are harmless but some can cause serious infections. To grow in or on the body, bacteria often attach to proteins on the surface of cells that make up the lining of tissues like the gut or the throat. In some cases, bacteria use these proteins to invade the cells causing an infection. Genetic mutations in the genes encoding these proteins that protect against infection are more likely to be passed on to future generations. This may lead to rapid spread of these beneficial genes in a population.

A family of proteins called CEACAMs are frequent targets of infection-causing bacteria. These proteins have been shown to play a role in cancer progression. But they also play many helpful roles in the body, including helping transmit messages between cells, aiding cell growth, and helping the immune system recognize pathogens. Scientists are not sure if these multi-tasking CEACAM proteins can evolve to evade bacteria without affecting their other roles.

Baker et al. show that CEACAM proteins targeted by bacteria have undergone rapid evolution in primates. In the experiments, human genes encoding CEACAMs were compared with equivalent genes from 19 different primates. Baker et al. found the changes in human and primate CEACAMs often occur through a process called gene conversion. Gene conversion occurs when DNA sections are copied and pasted from one gene to another. Using laboratory experiments, they showed that some of these changes enabled CEACAM proteins to prevent certain harmful bacteria from binding.

The experiments suggest that some versions of CEACAM genes may protect humans or other primates against bacterial infections. Studies in natural populations are needed to test if this is the case. Learning more about how CEACAM proteins evolve and what they do may help scientists better understand the role they play in cancer and help improve cancer care. Studying CEACAM evolution may also help scientists understand how bacteria and other pathogens drive protein evolution in the body.

Epithelial surfaces are typically the initial point of contact between metazoans and microbes (Brown and Clarke, 2017). As such, host factors at this barrier play an important role in facilitating or deterring microbial colonization. Bacterial attachment to epithelial surfaces is often mediated by a broad class of surface proteins termed adhesins (Kline et al., 2009). In addition to permitting the growth and colonization of commensal microbes, adhesins are also key virulence factors for many pathogenic bacteria. Adhesin-mediated adherence to host cells is often required for other downstream processes including biofilm formation, epithelial invasion, and the delivery of toxic effectors into host cells (Kline et al., 2009; Sadarangani et al., 2011; Figure 1). Microbial adherence can also trigger epithelial cell signaling cascades, further shaping host responses to resident and invasive microbes. Despite the fundamental importance of epithelial adherence for bacterial colonization and infectious disease pathogenesis, the dynamics of these interactions between host surface proteins and bacterial adhesions over evolutionary timescales remain a mystery. Theory predicts that exploitation of host proteins by pathogens places a significant burden on host populations, driving selection for beneficial mutations that limit microbial invasion or virulence. From a microbial perspective, host defenses can also pose an existential threat resulting in reciprocal adaptation to enhance colonization, growth, and transmission (Aleru and Barber, 2020; Brockhurst et al., 2014; Hamilton et al., 1990; Van Valen, 1973). However, pathogens hijack many host factors not directly involved in immunity, possibly limiting their adaptive potential in response to pathogen interaction. For example, epithelial surface proteins are not only essential for interacting with the environment but also serve crucial cellular and physiological functions including barrier maintenance, cell-cell communication, as well as coordinating host physiological and developmental pathways (Kuespert et al., 2006). It therefore remains unclear the extent to which such proteins are able to adapt in the face of pathogen antagonism.

Figure 1

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Bacterial adhesins interact with a wide range of molecules present on host epithelial surfaces (Chatterjee et al., 2021). One important target of bacterial adhesins on vertebrate epithelia are the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family of proteins (Gray-Owen and Blumberg, 2006). There have been multiple independent expansions of this gene family across mammals (Kammerer and Zimmermann, 2010; Pavlopoulou and Scorilas, 2014) and the human genome encodes 12 functional CEACAM genes as well as several pseudogenes (Gray-Owen and Blumberg, 2006; Kammerer and Zimmermann, 2010). Collectively, CEACAMs are expressed on nearly all vertebrate epithelial surfaces including the microbe-rich surfaces of the urogenital, respiratory, and gastrointestinal tracts (Tchoupa et al., 2014). Epithelial CEACAMs play a variety of roles in cell adhesion as well as intra- and intercellular signaling (Gray-Owen and Blumberg, 2006; Kuespert et al., 2006; Tchoupa et al., 2014). A subset of CEACAMs are also expressed on other cell types, including T-cells and neutrophils where they play important roles in immune signaling and pathogen recognition. CEACAMs typically consist of an extracellular N-terminal IgV-like domain (also termed the N-domain), a variable number of IgC-like domains, and either a GPI anchor or a transmembrane and cytoplasmic domains. The characteristics of this cytoplasmic domain in turn influences the functional properties of CEACAM proteins. Extracellular protein-protein interactions involving CEACAMs have been shown to primarily occur through the extracellular N-domain (Kuespert et al., 2007; Markel et al., 2004).

While the functions of many CEACAM proteins remain obscure, mammalian CEACAM1, CEACAM5 (also known as CEA), and CEACAM6 have been shown to contribute to immunoregulation, cell-cycle progression, and development (Gray-Owen and Blumberg, 2006; Kuespert et al., 2006; Tchoupa et al., 2014). These CEACAMs, along with CEACAM3, are also notable as recurrent targets of bacterial adhesins (Gray-Owen and Blumberg, 2006; Tchoupa et al., 2014). A growing number of bacterial genera have been found to target these CEACAM proteins to promote epithelial adherence and host colonization, including Neisseria, Haemophilus, Escherichia, Fusobacterium, Streptococcus, and Helicobacter (Brewer et al., 2019; Gray-Owen and Blumberg, 2006; Javaheri et al., 2016; Königer et al., 2016; van Sorge et al., 2021). Additionally, several viruses have been reported to bind CEACAMs, including human cytomegalovirus, influenza A, murine coronavirus, and Middle East respiratory syndrome coronavirus (Chan et al., 2016; Hemmila et al., 2004; Macmaniman et al., 2014; Rahman et al., 2021). While many of the bacteria reported to target CEACAMs are able to colonize the host as benign commensals, they are also capable of causing serious infection especially in young children. Such infections may prove severely detrimental to host fitness even when not fatal.

Among bacteria, a number of structurally unrelated CEACAM-binding adhesin proteins have been described. This diversity of structures suggests that CEACAM recognition has arisen independently multiple times during bacterial evolution. These structurally diverse proteins include the integral outer membrane Opa proteins in Neisseria (Fox et al., 2014), the immunoglobulin-type β protein from group B Streptococcus (van Sorge et al., 2021), as well as other trimeric and globular protein domains (Bonsor et al., 2018; Conners et al., 2008).

Bacterial CEACAM recognition can lead to several distinct outcomes (Figure 1). First, adherence to epithelial CEACAMs can provide a stable habitat to support bacterial growth and proliferation. In mice, for example, expression of human CEACAM1 is sufficient to establish stable colonization by otherwise human-restricted strains of Neisseria meningitidis (Johswich et al., 2013). Second, CEACAM binding may facilitate bacterial dissemination through the host epithelium (Wang et al., 1998). Third, in the case of the bacterium Helicobacter pylori, CEACAM-adhesin interactions promote the translocation of virulence factors into host cells via the type 4 secretion system leading to severe gastritis and stomach ulcers in humans (Javaheri et al., 2016; Königer et al., 2016). Finally, bacterial adhesins can potentiate CEACAM-mediated signaling cascades to manipulate cellular functions, including preventing immune cell activation (Gur et al., 2019a; Gur et al., 2019b; Sadarangani et al., 2011), increasing cellular adhesion to prevent shedding of infected cells (Muenzner et al., 2016; Muenzner et al., 2010), and activation of apoptosis (N’Guessan et al., 2007). Interactions between adhesins and CEACAMs, particularly bacterial immunoglobulins that appear to mimic CEACAMs, are predicted to further disrupt endogenous CEACAM adhesion and signaling functions (Macmaniman et al., 2014; Moonens, 2018; van Sorge et al., 2021).

Previous work has reported multiple instances of gene gain and loss as well as high levels of sequence divergence among a subset of CEACAM genes (Adrian et al., 2019; Rhesus Macaque Genome Sequencing and Analysis Consortium et al., 2007; Kammerer and Zimmermann, 2010; Pavlopoulou and Scorilas, 2014). These findings, coupled with the observation that many CEACAM-binding bacteria possess a narrow host range, suggest that host genetic variation may be a major determinant of bacterial colonization. In the case of CEACAM3, which is expressed exclusively in neutrophils and aids in destruction of CEACAM-binding bacteria, there is compelling evidence that residues at the interface of adhesin binding are evolving rapidly in a manner consistent with positive selection (Adrian et al., 2019). Unlike many other characterized mammalian CEACAMs, CEACAM3 appears to be a dedicated immune protein acting as a decoy receptor for CEACAM targeting bacteria (Bonsignore et al., 2019). The evolution of epithelial CEACAMs not dedicated to immune defense and the consequences of their evolution for microbial interactions remains unclear.

Our investigation of species-specific bacterial adherence to CEACAM1 revealed an unforeseen example of extreme genetic divergence within the great apes. The bonobo CEACAM1 gene could represent a rapid succession of single residue changes combined with multiple recombination events arising in bonobos under strong selection and/or a population bottleneck. Alternatively, this allele may be ancient and have been subject to balancing selection or incomplete lineage sorting in ancestral hominid populations. We also considered that the source of the bonobo CEACAM1 sequence may not be from functional CEACAM genes, but a pseudogenized CEACAM sequence or a pregnancy-specific glycoprotein, a family of proteins closely related to CEACAMs. However, a BLAST search of relevant NCBI databases (see Materials and methods) fails to identify any new genomic regions in bonobos or other primates with greater sequence identity than what had already been found. While there are multiple possible explanations for the highly divergent nature of bonobo CEACAM1, absent further evidence the origin of this particular allele remains obscure. What is clear from the example of bonobo CEACAM1, however, is the extent to which gene conversion can rapidly generate diversity between closely related species and the impact of such variation on interactions with microbes.

During the course of investigating the origin of the bonobo CEACAM1 sequence, we discovered evidence that gene conversion has shaped the evolution of many CEACAMs across primates, primarily impacting homologous proteins targeted by bacteria. While we identify several instances of likely gene conversion, results from phylogenetic analyses probably represent an underestimate of the true number of recombination events that have occurred among rapidly evolving CEACAMs in primates. Repeated episodes of gene conversion can obscure past instances of recombination and hinder their identification by gene-species tree discordance. GARD analyses and recombination detection programs in general also tend to miss many recombination events (Bay and Bielawski, 2011; Kosakovsky Pond et al., 2006). One particularly interesting example in orangutans implicates multiple conversion events impacting CEACAM1, CEACAM5, and CEACAM8 (Figure 5—figure supplement 1). Phylogenetic analyses indicate a species-specific conversion event between CEACAM1 and CEACAM5 in orangutans. Prior to the CEACAM1-CEACAM5 conversion, however, residues 29–64 in either CEACAM1 or CEACAM5 were likely replaced by the homologous sequence from CEACAM8. Evidence for this event includes not only multiple nonsynonymous substitutions shared with orangutan CEACAM8, but a shared synonymous substitution in both orangutan CEACAM1 and CEACAM5 only observed in hominid CEACAM8 homologs. Despite this evidence, neither our phylogenetic analyses nor GARD analyses suggest CEACAM8 has been involved in gene conversion. Like CEACAM7, the involvement of CEACAM8 in intra-paralog gene conversion is consistent with CEACAMs with rapid N-domain evolution participating in gene conversion events. Overall, the rapid shuffling of genetic variation among CEACAM genes that we observe could greatly augment the potential for host adaptation in the face of microbial antagonism.

It has been suggested that gene conversion between CEACAM paralogs preserves the ability of CEACAM3 to effectively mimic bacterially antagonized CEACAMs and thereby maintain its function as a decoy receptor (Zid and Drouin, 2013; Zimmermann, 2019). Indeed, our results and those of Adrian et al., 2019, support the importance of maintaining the similarity of CEACAM3 to other adhesin-binding CEACAMs in apes and Old World monkeys. However, our findings suggest that gene conversion does not only serve to maintain CEACAM3’s mimicry function. There is no evidence that New World monkeys encode a CEACAM3 homolog, yet within this group gene conversion appears to be rampant between CEACAM1, CEACAM5, and CEACAM6 (Figure 4C). Additionally, we observe multiple conversion events in hominids that do not involve CEACAM3 (Figure 4C, Figure 5—figure supplement 1, and Figure 6—figure supplement 4). Though we cannot rule out the possibility that New World monkey CEACAM1, CEACAM5, or CEACAM6 may have evolved a mimicry function similar to CEACAM3, our observations in hominids suggest additional drivers for pervasive gene conversion within the CCM₁₃₅₆ group.

High sequence similarity and close chromosomal proximity, such as that seen for the N-domains of the CCM₁₃₅₆ group (Figure 2—figure supplement 1B, Figure 4—figure supplement 3), could result in periodic interconversion of paralogous sequences, which in many cases may be functionally neutral (Bittihn and Tsimring, 2017; Zid and Drouin, 2013). However, we show that the common CEACAM1 variant, Q89H, which matches CEACAM5 at this position, abolishes binding to at least two Opa proteins (Figure 6C). Human CEACAM1 variant A49V, which reduces binding to Opa74, also matches the equivalent residue in CEACAM5 as well as CEACAM3. These examples illustrate the potential benefit of gene conversion between epithelial CEACAM paralogs beyond CEACAM3 mimicry. Given that gene conversion within this family appears to be enriched specifically among CEACAMs recognized by bacteria, we propose that gene conversion among epithelial CEACAMs reflects a general mechanism of pathogen evasion (Figure 7). Such a mechanism allows beneficial sets of mutations to spread, whether between decoys and targets or among antagonized epithelial CEACAMs, more rapidly than conversion of residues through independent mutational events (Bittihn and Tsimring, 2017). In addition, recombination provides decoys the ability to gain binding to CEACAM antagonists through exchanges from epithelial CEACAMs as observed for CEACAM3 (Adrian et al., 2019). Finally, the interchangeability of CEACAM domains could further accelerate the exchange and spread of beneficial mutations in host genomes (Bittihn and Tsimring, 2017). In these ways gene conversion provides an important mechanism by which the host can keep pace with rapidly evolving pathogenic microbes.

Figure 7

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Our study examined the influence of CEACAM1 diversity on bacterial binding using adhesins from H. pylori and N. gonorrhoeae as models. However, a diverse range of pathogenic and commensal microbes are known to bind host CEACAMs, and it is unlikely that natural selection across primates has been driven by any single pathogen. What is clear from these results is the major influence that CEACAM divergence and polymorphisms can have on recognition by structurally unrelated bacterial adhesins, and moreover the impact that such diversity could have on shaping future disease outbreaks. It is also notable that recombination between paralogs contributes to the immense diversity of Opa genes Neisseria (Sadarangani et al., 2011). In this regard CEACAM-Opa interactions could reflect a general mechanism by which gene conversion between paralogs contributes to reciprocal adaptation in both hosts and microbes.

In addition to exploring the role of CEACAM gene conversion among primates, we provide evidence that this process continues to shape CEACAM diversity within human populations. The three human CEACAM1 variants we test in our adhesin-binding assay are part of a group of related CEACAM1 haplotypes that increase sequence similarity to CEACAM3 and/or CEACAM5 (Figure 6—figure supplement 1). Extended haplotypes that increase similarly to CEACAM1 at both synonymous and nonsynonymous positions in the N-domain are also found for CEACAM3 and CEACAM5 in humans (Figure 6—figure supplement 3 and Figure 6—figure supplement 4). Indeed, haplotypes consisting of variants of putative recombination events are the most common non-reference alleles for CEACAM1, CEACAM3, and CEACAM5 (Figure 6, Figure 6—figure supplements 1–4). Variant sites in these proteins tend to lie along the protein-binding interface of the N-domain and often impact residues known to influence adhesin recognition. The relationships between these different CEACAM haplotypes appears to be complex, as many different combinations of partial variant haplotypes exist for each CEACAM paralog. The haplotype structures we observe suggest these CEACAM variants are the result of one or more conversion events between paralogous sequences, likely followed by further recombination with the major CEACAM allele.

Important questions remain regarding the rapid evolution of a subset of primate CEACAM proteins. Among these questions is why CEACAM7 and CEACAM8 show similar patterns of evolution to bacterially antagonized CEACAMs despite no known instances of bacterial antagonism. The simplest explanation is that CEACAM7 and CEACAM8 are themselves the targets of as yet unidentified pathogen antagonists (Sintsova et al., 2015). Alternatively, their rapid evolution may reflect pressure to maintain binding with rapidly evolving bacterially antagonized CEACAMs (Gray-Owen and Blumberg, 2006; Skubitz and Skubitz, 2008) could merely be a result of their genomic proximity to rapidly evolving CEACAMs prone to gene conversion (Zid and Drouin, 2013) or could be the result of some as yet unknown evolutionary pressures. Another intriguing aspect of rapid CEACAM evolution is the impact rapid divergence might have beyond interactions with pathogenic microbes. Given the extensive overlap of CEACAM-binding sites among unrelated bacterial adhesins, the ramifications of rapid CEACAM evolution likely extend beyond the adhesins of pathogens to those of commensal and beneficial microbes as well. For commensal microbes that rely on these interaction surfaces, CEACAM evolution could significantly alter their ability to colonize the host. The impact of CEACAM divergence on composition of the host microbiome and/or the evolution of commensal strains warrants further investigation.

Studies of other ‘housekeeping’ proteins targeted by pathogens have found that sites under positive selection typically do not overlap with sites involved in essential host functions (Barber and Elde, 2014; Demogines et al., 2013). This is clearly not the case for CEACAMs, where we observed extensive overlap between sites involved in host protein interactions, sites targeted by bacterial adhesins, and sites undergoing rapid evolution (Figure 2B). How CEACAMs are able to rapidly evolve while maintaining their other essential host protein interactions remains a mystery. Future studies on CEACAM protein functions, interaction networks, and pathogen antagonism will likely clarify these outstanding questions regarding rapidly evolving CEACAMs.

Collectively our study provides evidence that repeated adaptation among primate CEACAMs has shaped host-specific cell adherence by diverse pathogenic bacteria. We find that over half of the CEACAM paralogs found in humans display signatures of positive selection across the primate lineage, localized primarily to the extracellular N-domain. We further discovered that rapid evolution of CEACAM N-domains has been facilitated by extensive ‘shuffling’ of sequences between a subset of CEACAM paralogs likely through repeated gene conversion. The diversification of primate CEACAM N-domain sequences has likely had significant consequences for interactions between primates and bacteria. Consistent with observations across other primate species, we also provide evidence that gene conversion events may impact bacterial pathogen recognition of CEACAMs in contemporary human populations. Together this work reveals how dynamic evolutionary processes have shaped bacterial-host cell associations with consequences for infectious disease susceptibility.

The following files contain the images, data and/or code used to perform analyses and generate figures for this work, Figure 3 - Source data 1, Figure 3 - SuppFig 1 - source data 1, Figure 5 - Source data 1, Figure 6 - Source data 1, Figure 6 - Source data 2, Figure 6 - SuppFig 3 - source data 1, Figure 6 - SuppFig 4 - source data 1.

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Author details

1. EmilyClare P Baker

   Institute of Ecology and Evolution, University of Oregon, Eugene, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Validation, Visualization, Writing – original draft, Writing – review and editing, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7875-2144

2. Ryan Sayegh

   Institute of Ecology and Evolution, University of Oregon, Eugene, United States

   Contribution

   Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Kristin M Kohler

   Institute of Ecology and Evolution, University of Oregon, Eugene, United States

   Contribution

   Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Wyatt Borman

   Institute of Ecology and Evolution, University of Oregon, Eugene, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

5. Claire K Goodfellow

   1. Institute of Ecology and Evolution, University of Oregon, Eugene, United States
   2. Department of Biology, University of Oregon, Eugene, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

6. Eden R Brush

   Institute of Ecology and Evolution, University of Oregon, Eugene, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Matthew F Barber

   1. Institute of Ecology and Evolution, University of Oregon, Eugene, United States
   2. Department of Biology, University of Oregon, Eugene, United States

   Contribution

   Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – review and editing, Writing – original draft

   For correspondence

   mfbarber@uoregon.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2008-2165

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