{"doi":"10.1073/pnas.2301549120","title":"Structural evolution of an immune evasion determinant shapes pathogen host tropism","abstract":"Modern infectious disease outbreaks often involve changes in host tropism, the preferential adaptation of pathogens to specific hosts. The Lyme disease-causing bacterium Borrelia burgdorferi ( Bb ) is an ideal model to investigate the molecular mechanisms of host tropism, because different variants of these tick-transmitted bacteria are distinctly maintained in rodents or bird reservoir hosts. To survive in hosts and escape complement-mediated immune clearance, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to facilitate bacterial dissemination in vertebrates. Despite high sequence conservation, CspZ variants differ in human FH-binding ability. Together with the FH polymorphisms between vertebrate hosts, these findings suggest that minor sequence variation in this bacterial outer surface protein may confer dramatic differences in host-specific, FH-binding-mediated infectivity. We tested this hypothesis by determining the crystal structure of the CspZ–human FH complex, and identifying minor variation localized in the FH-binding interface yielding bird and rodent FH-specific binding activity that impacts infectivity. Swapping the divergent region in the FH-binding interface between rodent- and bird-associated CspZ variants alters the ability to promote rodent- and bird-specific early-onset dissemination. We further linked these loops and respective host-specific, complement-dependent phenotypes with distinct CspZ phylogenetic lineages, elucidating evolutionary mechanisms driving host tropism emergence. Our multidisciplinary work provides a novel molecular basis for how a single, short protein motif could greatly modulate pathogen host tropism.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":328659,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1050575,"name":"Kalvis Brangulis","orcid":"0000-0003-0757-7462","position":1,"is_corresponding":false},{"id":240976,"name":"Alan P. Dupuis","orcid":"0000-0003-0703-9250","position":2,"is_corresponding":false},{"id":703565,"name":"Thomas Hart","orcid":"0000-0001-5949-9932","position":3,"is_corresponding":false},{"id":1051198,"name":"Maxime Zamba‐Campero","orcid":null,"position":4,"is_corresponding":false},{"id":244719,"name":"Tristan A. Nowak","orcid":"0000-0002-4113-0309","position":5,"is_corresponding":false},{"id":1051199,"name":"Jessica L. Stout","orcid":null,"position":6,"is_corresponding":false},{"id":1051200,"name":"Ināra Akopjana","orcid":null,"position":7,"is_corresponding":false},{"id":1050576,"name":"Andris Kazāks","orcid":"0000-0003-4964-0984","position":8,"is_corresponding":false},{"id":1051201,"name":"Jānis Bogans","orcid":null,"position":9,"is_corresponding":false},{"id":335264,"name":"Alexander T. Ciota","orcid":"0000-0001-6589-4728","position":10,"is_corresponding":false},{"id":248141,"name":"Peter Kraiczy","orcid":null,"position":11,"is_corresponding":false},{"id":343886,"name":"Sergios‐Orestis Kolokotronis","orcid":"0000-0003-3309-8465","position":12,"is_corresponding":false},{"id":244717,"name":"Yi‐Pin Lin","orcid":"0000-0002-5240-2031","position":13,"is_corresponding":false},{"id":1003628,"name":"Ashley L. Marcinkiewicz","orcid":"0000-0003-1417-5699","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:08:56.940647Z","pmid":"37364114","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}