title: Variable Major Proteins as Targets for Specific Antibodies against Borrelia miyamotoi.
abstract: Borrelia miyamotoi is a relapsing fever spirochete in Ixodes ticks that has been recently identified as a human pathogen causing hard tick-borne relapsing fever (HTBRF) across the Northern Hemisphere. No validated serologic test exists, and current serologic assays have low sensitivity in early HTBRF. To examine the humoral immune response against B. miyamotoi, we infected C3H/HeN mice with B. miyamotoi strain LB-2001 expressing variable small protein 1 (Vsp1) and demonstrated that spirochetemia was cleared after 3 d, coinciding with anti-Vsp1 IgM production. Clearance was also observed after passive transfer of immune sera to infected SCID mice. Next, we showed that anti-Vsp1 IgG eliminates Vsp1-expressing B. miyamotoi, selecting for spirochetes expressing a variable large protein (VlpC2) resistant to anti-Vsp1. The viability of Asian isolate B. miyamotoi HT31, expressing Vlp15/16 and Vlp18, was also unaffected by anti-Vsp1. Finally, in nine HTBRF patients, we demonstrated IgM reactivity to Vsp1 in two and against Vlp15/16 in four ∼1 wk after these patients tested positive for B. miyamotoi by PCR. Our data show that B. miyamotoi is able to express various variable major proteins (VMPs) to evade humoral immunity and that VMPs are antigenic in humans. We propose that serologic tests based on VMPs are of additional value in diagnosing HTBRF.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Alex
authors.initials: A
authors.lastname: Wagemakers
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Joris
authors.identifier: 0000-0002-4604-5111
authors.initials: J
authors.lastname: Koetsveld
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Sukanya
authors.identifier: 0000-0003-0396-8757
authors.initials: S
authors.lastname: Narasimhan
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Melvin
authors.initials: M
authors.lastname: Wickel
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Deponte
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Boris
authors.identifier: 0000-0001-9797-2161
authors.initials: B
authors.lastname: Bleijlevens
authors.affiliation: Center for Infectious Disease Control, National Institute for Public Health and the Environment, 3720 BA Bilthoven, the Netherlands;
authors.forename: Seta
authors.initials: S
authors.lastname: Jahfari
authors.affiliation: Center for Infectious Disease Control, National Institute for Public Health and the Environment, 3720 BA Bilthoven, the Netherlands;
authors.forename: Hein
authors.identifier: 0000-0002-0218-4320
authors.initials: H
authors.lastname: Sprong
authors.affiliation: Central Research Institute of Epidemiology, Moscow 111123, Russia;
authors.forename: Lyudmila S
authors.initials: LS
authors.lastname: Karan
authors.affiliation: Izhevsk State Medical Academy, Izhevsk 426034, Russia; and.
authors.forename: Denis S
authors.initials: DS
authors.lastname: Sarksyan
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Linda K
authors.identifier: 0000-0001-9349-8757
authors.initials: LK
authors.lastname: Bockenstedt
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
authors.forename: Adriaan D
authors.identifier: 0000-0002-9794-6526
authors.initials: AD
authors.lastname: Bins
authors.affiliation: Central Research Institute of Epidemiology, Moscow 111123, Russia;
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Platonov
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; lyme@amc.uva.nl.
authors.forename: Joppe W
authors.initials: JW
authors.lastname: Hovius
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology*; D000917:Antibody Formation; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D001483:Base Sequence; D001898:Borrelia / Q000276:immunology; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D017434:Protein Structure, Tertiary; D012061:Relapsing Fever / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001425:Bacterial Outer Membrane Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008074:Lipoproteins; C120881:vmp protein, Borrelia