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Genotypic and phenotypic variation among <jats:styled-content style=\"fixed-case\"><jats:italic>Borrelia burgdorferi<\/jats:italic><\/jats:styled-content> strains correlates with variable manifestations of Lyme disease in humans; this diversity is attributed in part to variation in surface\u2010exposed lipoproteins, which are targets of the human antibody response and contribute to tissue adhesion, immune evasion, and other host interactions. Many <jats:styled-content style=\"fixed-case\"><jats:italic>B. burgdorferi<\/jats:italic><\/jats:styled-content> lipoproteins are encoded as multi\u2010copy gene families, such as the OspE\/F\u2010like leader peptide (Elp) protein family, which inhibits classical complement activation by binding complement C1s. To characterize Elp allelic variants, we adapted the <jats:styled-content style=\"fixed-case\"><jats:italic>Pseudomonas syringae<\/jats:italic><\/jats:styled-content> ice nucleation protein (INP) system to present <jats:styled-content style=\"fixed-case\"><jats:italic>B. burgdorferi<\/jats:italic><\/jats:styled-content> lipoproteins on the surface of <jats:styled-content style=\"fixed-case\"><jats:italic>Escherichia coli<\/jats:italic><\/jats:styled-content>. Using this system, we identified interactions with classical complement proteins and mapped binding regions, then validated interactions using recombinant proteins and <jats:styled-content style=\"fixed-case\"><jats:italic>B. burgdorferi<\/jats:italic><\/jats:styled-content> surface display. We also discovered a novel potential interaction between Elp proteins and the mammalian basement membrane protein perlecan, thus revealing a bifunctional nature of Elps. Our findings indicate that Elps have undergone functional diversification while maintaining classical complement inhibition mediated by potent and conserved C1s binding and demonstrate that <jats:styled-content style=\"fixed-case\"><jats:italic>E. coli<\/jats:italic><\/jats:styled-content> surface display offers an efficient, cost\u2010effective, and relatively high\u2010throughput approach to characterize <jats:styled-content style=\"fixed-case\"><jats:italic>B. burgdorferi<\/jats:italic><\/jats:styled-content> lipoproteins.<\/jats:p>","DOI":"10.1111\/mmi.15369","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:35:38Z","timestamp":1747373738000},"page":"77-90","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Heterologous Surface Display Reveals Conserved Complement Inhibition and Functional Diversification of <i>Borrelia burgdorferi<\/i> Elp Proteins"],"prefix":"10.1111","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9762-4538","authenticated-orcid":false,"given":"Nathan","family":"Hill","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School Harvard University  Boston Massachusetts USA"},{"name":"Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara M.","family":"Matulina","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine East Carolina University  Greenville North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cameron","family":"MacIntyre","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School Harvard University  Boston Massachusetts USA"},{"name":"Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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