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The bacterium is associated with bronchitis and exacerbations in patients suffering from chronic obstructive pulmonary disease and frequently causes acute otitis media in preschool children. We have previously demonstrated that the binding of C4b binding protein (C4BP) is important for NTHi complement evasion. In this study, we identified outer membrane protein 5 (P5) of NTHi as a novel ligand of C4BP. Importantly, we observed significantly lower C4BP binding and decreased serum resistance in P5-deficient NTHi mutants. Surface expression of recombinant P5 on Escherichia coli conferred C4BP binding and consequently increased serum resistance. Moreover, P5 expression was positively correlated with C4BP binding in a series of clinical isolates. We revealed higher levels of P5 surface expression and consequently more C4BP binding in isolates from the lower respiratory tract of chronic obstructive pulmonary disease patients and tonsil specimens compared with isolates from the upper respiratory tract and the bloodstream (invasive strains). Our results highlight P5 as an important protein for protecting NTHi against complement-mediated killing.<\/jats:p>","DOI":"10.4049\/jimmunol.2100105","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T16:20:11Z","timestamp":1629908411000},"page":"1566-1577","source":"Crossref","is-referenced-by-count":10,"title":["Nontypeable <i>Haemophilus influenzae<\/i> P5 Binds Human C4b-Binding Protein, Promoting Serum Resistance"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4284-1006","authenticated-orcid":false,"given":"Oskar","family":"Thofte","sequence":"first","affiliation":[{"name":"Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Bettoni","sequence":"additional","affiliation":[{"name":"Protein Chemistry, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3398-6294","authenticated-orcid":false,"given":"Yu-Ching","family":"Su","sequence":"additional","affiliation":[{"name":"Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Thegerstr\u00f6m","sequence":"additional","affiliation":[{"name":"Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-3951","authenticated-orcid":false,"given":"Sandra","family":"Jonsson","sequence":"additional","affiliation":[{"name":"Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Mattsson","sequence":"additional","affiliation":[{"name":"Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3492-3287","authenticated-orcid":false,"given":"Linda","family":"Sandblad","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University , Umea ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0405-2305","authenticated-orcid":false,"given":"Sara","family":"Mart\u00ed","sequence":"additional","affiliation":[{"name":"Microbiology Department, Research Network for Respiratory Diseases, Bellvitge Institute for Biomedical Research, Bellvitge University Hospital , Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkal","family":"Garmendia","sequence":"additional","affiliation":[{"name":"Instituto de Agrobiotecnolog\u00eda, Consejo Superior de Investigaciones Cient\u00edficas\u2013Gobierno de Navarra , Mutilva ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1348-1734","authenticated-orcid":false,"given":"Anna M","family":"Blom","sequence":"additional","affiliation":[{"name":"Protein Chemistry, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6274-6965","authenticated-orcid":false,"given":"Kristian","family":"Riesbeck","sequence":"additional","affiliation":[{"name":"Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University , Malm\u00f6 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"2025022610321162800_r1","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/14760584.2018.1484286","article-title":"Update on nontypeable Haemophilus influenzae-mediated disease and vaccine development","volume":"17","author":"Jalalvand","year":"2018","journal-title":"Expert Rev. 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