Horizontal gene transfer and endogenous retroviruses as mechanisms for molecular mimicry

Advances in genomics and proteomics have facilitated research into genetic elements of microbial origin that have been integrated into the mammalian genome, including products of horizontal gene transfer (HGT) and endogenous retroviruses. We postulate that these genetic elements could have both positive and negative effects, enabling crucial functions but predisposing genetically susceptible hosts to autoimmunity through molecular mimicry (appendix pp 1,2). In prokaryotes, HGT is an evolutionary mechanism prevalent enough to complicate phylogenetic analysis and propagate antibiotic resistance. Interdomain HGT from prokaryotes into eukaryotes, which requires germline transfers for heritability, is controversial, but research has identified several candidates that might have arisen due to HGT.1Kibby EM Conte AN Burroughs AM et al.Bacterial NLR-related proteins protect against phage.Cell. 2023; 186: 2410-2424Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2Kalluraya CA Weitzel AJ Tsu BV Daugherty MD Bacterial origin of a key innovation in the evolution of the vertebrate eye.Proc Natl Acad Sci USA. 2023; 120e2214815120Crossref Scopus (3) Google Scholar Key components of mammalian immunity, such as the NACHT module of nucleotide oligomerisation domain (NOD)-like receptors and stimulator of interferon genes (STING) receptors, are homologous to microbial proteins.1Kibby EM Conte AN Burroughs AM et al.Bacterial NLR-related proteins protect against phage.Cell. 2023; 186: 2410-2424Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar These components probably originated in metazoans through ancestral HGT from bacteria, such as extracellular bacteria for the STING protein and endosymbiotic bacteria for NOD-like receptors.1Kibby EM Conte AN Burroughs AM et al.Bacterial NLR-related proteins protect against phage.Cell. 2023; 186: 2410-2424Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar By contrast, endogenous retroviruses are products of past retroviral integration into host DNA that make up 8% of the human genome.3Morandi E Tanasescu R Tarlinton RE et al.The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis.PLoS One. 2017; 12e0172415Crossref PubMed Scopus (71) Google Scholar Endogenous retroviruses are predominantly non-functional, but there are some exceptions, including syncitin-1, a retroviral envelope protein that facilitates cell fusion to form placental synctiotrophoblasts.3Morandi E Tanasescu R Tarlinton RE et al.The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis.PLoS One. 2017; 12e0172415Crossref PubMed Scopus (71) Google Scholar Molecular mimicry denotes homology between host proteins and foreign antigens, which might allow microbes to avoid immune-mediated destruction. Alternatively, molecular mimicry can cause activation of autoreactive T lymphocytes, B lymphocytes, or both, and is an established driver of autoimmune diseases.4Mohammed JP Mattner J Autoimmune disease triggered by infection with alphaproteobacteria.Expert Rev Clin Immunol. 2009; 5: 369-379Crossref PubMed Scopus (0) Google Scholar Recently, the interphotoreceptor retinoid-binding protein (IRBP), a shuttling protein that transports retinoids between layers of vertebrate retinas, was identified as a product of interdomain HGT, derived from a bacterial S41 family serine peptidase more than 500 million years ago.2Kalluraya CA Weitzel AJ Tsu BV Daugherty MD Bacterial origin of a key innovation in the evolution of the vertebrate eye.Proc Natl Acad Sci USA. 2023; 120e2214815120Crossref Scopus (3) Google Scholar IRBP is an autoantigen that can induce inflammatory eye disease in mouse models of uveitis through immunisation or activating autoreactive T cells, which express transgenic T-cell receptors specific for IRBP residues.5Horai R Zarate-Blades CR Dillenburg-Pilla P et al.Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site.Immunity. 2015; 43: 343-353Summary Full Text Full Text PDF PubMed Scopus (294) Google Scholar Horai and colleagues identified a role for gut microbiota in ocular inflammation, using mice expressing IRBP-transgenic T-cell receptors; they showed that proteinaceous products from gut bacteria activated autoreactive T cells, and that the germfree state and antibiotic combinations attenuated disease.5Horai R Zarate-Blades CR Dillenburg-Pilla P et al.Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site.Immunity. 2015; 43: 343-353Summary Full Text Full Text PDF PubMed Scopus (294) Google Scholar The study was unable to identify a culprit bacterium or protein, and reported that treatment with single antibiotics resulted in minimal benefit.5Horai R Zarate-Blades CR Dillenburg-Pilla P et al.Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site.Immunity. 2015; 43: 343-353Summary Full Text Full Text PDF PubMed Scopus (294) Google Scholar We propose that the activation of IRBP-specific autoreactive T cells might be triggered by molecular mimicry with the widely expressed bacterial S41 family peptidases. In support of our hypothesis, primary biliary cholangitis, an autoimmune liver disease, involves anti-mitochondrial antibodies directed at the pyruvate dehydrogenase complex E2 (PDC-E2).4Mohammed JP Mattner J Autoimmune disease triggered by infection with alphaproteobacteria.Expert Rev Clin Immunol. 2009; 5: 369-379Crossref PubMed Scopus (0) Google Scholar Since mitochondria are believed to originate from Alphaproteobacteria endosymbionts, this raises the possibility of molecular mimicry in primary biliary cholangitis. Indeed, the sera of patients with primary biliary cholangitis strongly cross-reacts with the PDC-E2 of Alphaproteobacterium Novosphingobium aromaticivorans.4Mohammed JP Mattner J Autoimmune disease triggered by infection with alphaproteobacteria.Expert Rev Clin Immunol. 2009; 5: 369-379Crossref PubMed Scopus (0) Google Scholar Antibodies to N aromaticivorans are highly specific for patients with primary biliary cholangitis, even those seronegative for anti-PDC-E2, and infection of mice with N aromaticivorans induces anti-PDC-E2 antibodies and autoimmune cholangitis.4Mohammed JP Mattner J Autoimmune disease triggered by infection with alphaproteobacteria.Expert Rev Clin Immunol. 2009; 5: 369-379Crossref PubMed Scopus (0) Google Scholar Furthermore, vertebrate glycosyltransferase-6, which determines ABO blood type, is an HGT candidate.6Brew K Tumbale P Acharya KR Family 6 glycosyltransferases in vertebrates and bacteria: inactivation and horizontal gene transfer may enhance mutualism between vertebrates and bacteria.J Biol Chem. 2010; 285: 37 121-37 127Summary Full Text Full Text PDF Scopus (15) Google Scholar Production of ABO antibodies requires exposure to microbes like Escherichia coli O86, which expresses a vertebrate B-group-like glycosyltransferase and induces anti-B antibodies in humans with blood types A and O.7Cooling L Blood groups in infection and host susceptibility.Clin Microbiol Rev. 2015; 28: 801-870Crossref PubMed Scopus (329) Google Scholar This HGT-mediated immune tolerance could underpin the heightened susceptibility of patients with B and AB blood types to sepsis caused by Enterobacteriaceae.7Cooling L Blood groups in infection and host susceptibility.Clin Microbiol Rev. 2015; 28: 801-870Crossref PubMed Scopus (329) Google Scholar Considerable epidemiological evidence also implicates endogenous retroviruses in multiple sclerosis, most notably the human endogenous retrovirus-W family, which includes syncitin-1. Epstein-Barr virus can activate superantigenic human ERVK-18,8Sutkowski N Conrad B Thorley-Lawson DA Huber BT Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen.Immunity. 2001; 15: 579-589Summary Full Text Full Text PDF PubMed Scopus (233) Google Scholar and uses HLA-DRB1*15:01 as a co-receptor for B-cell infection.9Menegatti J Schub D Schäfer M Grässer FA Ruprecht K HLA-DRB1*15:01 is a co-receptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis.Eur J Immunol. 2021; 51: 2348-2350Crossref PubMed Scopus (11) Google Scholar The link between multiple sclerosis and viral factors, such as Epstein-Barr virus and human ERVK-18, is especially robust among patients with HLA-DRB1*15:01.3Morandi E Tanasescu R Tarlinton RE et al.The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis.PLoS One. 2017; 12e0172415Crossref PubMed Scopus (71) Google Scholar Homology between endogenous retroviruses and exogenous viruses might allow unchecked pathogenicity due to immunological anergy. HGT-derived or endogenous retrovirus-derived host proteins could also be more susceptible to post-translational modification by microbes, since they mimic microbial products. These post-translational modifications might generate neoantigens that trigger autoimmunity, as suggested in rheumatoid arthritis, for which antibodies to α-enolase were found to be cross-reactive between humans and Porphyromonas gingivalis.10Lundberg K Kinloch A Fisher BA et al.Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase.Arthritis Rheum. 2008; 58: 3009-3019Crossref PubMed Scopus (324) Google Scholar We suggest that some autoantigens might be derived from ancestral HGT or endogenous retroviruses, whereby products present in pathobionts that have high homology to eukaryotic products can trigger a human immune response, catalysing the conversion of previously inert peptide sequences into immunogenic epitopes. We propose that this process could convert inert low-affinity autoreactive lymphocytes into high-affinity pathogenic autoreactive cells that drive autoimmunity. Thus, investigation of interdomain HGT candidates and endogenous retroviruses could identify novel autoimmune triggers. Molecules that act on shared metabolic pathways across diverse domains of life and genes that are dissimilar in sequence characteristics to other products from the same organism could be potential candidates. However, large-scale genomic analyses of HGT have been prone to error, thus, dedicated analysis of individual candidates is a prerequisite for reliability. We declare no competing interests. RP is supported by a scholarship from The Royal College of Pathologists of Australasia. The figure in the appendix was created with BioRender.com. Download .pdf (1.95 MB) Help with pdf files Supplementary appendix