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Immunol."],"abstract":"<jats:p>Pathogens that traffic in the blood of their hosts must employ mechanisms to evade the host innate immune system, including the complement cascade. The Lyme disease spirochete,<jats:italic>Borreliella burgdorferi<\/jats:italic>, has evolved numerous outer membrane lipoproteins that interact directly with host proteins. Compared to Lyme disease-associated spirochetes, relatively little is known about how an emerging tick-borne spirochetal pathogen,<jats:italic>Borrelia miyamotoi<\/jats:italic>, utilizes surface lipoproteins to interact with a human host.<jats:italic>B. burgdorferi<\/jats:italic>expresses the multifunctional lipoprotein, BBK32, that inhibits the classical pathway of complement through interaction with the initiating protease C1r, and also interacts with fibronectin using a separate intrinsically disordered domain.<jats:italic>B. miyamotoi<\/jats:italic>encodes two separate<jats:italic>bbk32<\/jats:italic>orthologs denoted<jats:italic>fbpA<\/jats:italic>and<jats:italic>fbpB<\/jats:italic>; however, the activities of these proteins are unknown. Here, we show that<jats:italic>B. miyamotoi<\/jats:italic>FbpA binds human fibronectin in a manner similar to<jats:italic>B. burgdorferi<\/jats:italic>BBK32, whereas FbpB does not. FbpA and FbpB both bind human complement C1r and protect a serum-sensitive<jats:italic>B. burgdorferi<\/jats:italic>strain from complement-mediated killing, but surprisingly, differ in their ability to recognize activated C1r versus zymogen states of C1r. To better understand the observed differences in C1r recognition and inhibition properties, high-resolution X-ray crystallography structures were solved of the C1r-binding regions of<jats:italic>B. miyamotoi<\/jats:italic>FbpA and FbpB at 1.9\u00c5 and 2.1\u00c5, respectively. Collectively, these data suggest that FbpA and FbpB have partially overlapping functions but are functionally and structurally distinct. The data presented herein enhances our overall understanding of how bloodborne pathogens interact with fibronectin and modulate the complement system.<\/jats:p>","DOI":"10.3389\/fimmu.2022.886733","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T13:09:05Z","timestamp":1653656945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Borrelia miyamotoi FbpA and FbpB Are Immunomodulatory Outer Surface Lipoproteins With Distinct Structures and Functions"],"prefix":"10.3389","volume":"13","author":[{"suffix":"Jr","given":"Charles E.","family":"Booth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra D.","family":"Powell-Pierce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon T.","family":"Skare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon L.","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.21775\/9781913652616.14","article-title":"Pathogenesis of Relapsing Fever","volume-title":"Curr Issues Mol Biol","author":"Lopez","year":"2021"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/vetsci3030016","article-title":"Tick-Borne Relapsing Fever Spirochetes in the Americas","volume":"3","author":"Lopez","year":"2016","journal-title":"Vet Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2015.03.008","article-title":"Borrelia miyamotoi: A Widespread Tick-Borne Relapsing Fever Spirochete","volume":"31","author":"Wagemakers","year":"2015","journal-title":"Trends Parasitol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2807\/1560-7917.ES.2019.24.18.1800170","article-title":"A New Borrelia on the Block: Borrelia miyamotoi - a Human Health Risk","volume":"24","author":"Cutler","year":"2019","journal-title":"Euro Surveill"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cll.2015.08.002","article-title":"Borrelia miyamotoi Disease: Neither Lyme Disease Nor Relapsing Fever","volume":"35","author":"Telford","year":"2015","journal-title":"Clin Lab Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00098","article-title":"Relapsing Fevers: Neglected Tick-Borne Diseases","volume":"8","author":"Talagrand-Reboul","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/cid\/ciac107","article-title":"Frequency and Geographic Distribution of Borrelia miyamotoi, Borrelia burgdorferi, and Babesia microti Infections in New England Residents","author":"Johnston","year":"2022","journal-title":"Clin Infect Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/nejmc1215469","article-title":"Human Borrelia miyamotoi Infection in the United States","volume":"368","author":"Krause","year":"2013","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/AAC.00535-17","article-title":"In Vitro Susceptibility of the Relapsing-Fever Spirochete Borrelia miyamotoi to Antimicrobial Agents","volume":"61","author":"Koetsveld","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ttbdis.2018.11.017","article-title":"An Immunocompromised Mouse Model to Infect Ixodes scapularis Ticks With the Relapsing Fever Spirochete, Borrelia miyamotoi","volume":"10","author":"Lynn","year":"2019","journal-title":"Ticks Tick Borne Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2009.09-0208","article-title":"Niche Partitioning of Borrelia burgdorferi and Borrelia miyamotoi in the Same Tick Vector and Mammalian Reservoir Species","volume":"81","author":"Barbour","year":"2009","journal-title":"Am J Trop Med Hyg"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/bmj.m1041","article-title":"Lyme Borreliosis: Diagnosis and Management","volume":"369","author":"Kullberg","year":"2020","journal-title":"BMJ"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2016.90","article-title":"Lyme Borreliosis","volume":"2","author":"Steere","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.21775\/cimb.042.333","article-title":"Lyme Disease in Humans","volume":"42","author":"Radolf","year":"2021","journal-title":"Curr. 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