Whole-Chain Tick Saliva Proteins Presented on Hepatitis B Virus Capsid-Like Particles Induce High-Titered Antibodies with Neutralizing Potential.
Ticks are vectors for various, including pathogenic, microbes. Tick saliva contains multiple anti-host defense factors that enable ticks their bloodmeals yet also facilitate microbe transmission. Lyme disease-causing borreliae profit specifically from the broadly conserved tick histamine release factor (tHRF), and from cysteine-rich glycoproteins represented by Salp15 from Ixodes scapularis and Iric-1 from Ixodes ricinus ticks which they recruit to their outer surface protein C (OspC). Hence these tick proteins are attractive targets for anti-tick vaccines that simultaneously impair borrelia transmission. Main obstacles are the tick proteins´ immunosuppressive activities, and for Salp15 orthologs, the lack of efficient recombinant expression systems. Here, we exploited the immune-enhancing properties of hepatitis B virus core protein (HBc) derived capsid-like particles (CLPs) to generate, in E. coli, nanoparticulate vaccines presenting tHRF and, as surrogates for the barely soluble wild-type proteins, cysteine-free Salp15 and Iric-1 variants. The latter CLPs were exclusively accessible in the less sterically constrained SplitCore system. Mice immunized with tHRF CLPs mounted a strong anti-tHRF antibody response. CLPs presenting cysteine-free Salp15 and Iric-1 induced antibodies to wild-type, including glycosylated, Salp15 and Iric-1. The broadly distributed epitopes included the OspC interaction sites. In vitro, the anti-Salp15 antibodies interfered with OspC binding and enhanced human complement-mediated killing of Salp15 decorated borreliae. A mixture of all three CLPs induced high titered antibodies against all three targets, suggesting the feasibility of combination vaccines. These data warrant in vivo validation of the new candidate vaccines´ protective potential against tick infestation and Borrelia transmission.
University Hospital Freiburg, Internal Medicine 2 / Molecular Biology, Hugstetter Str. 55, D-79106, Freiburg, Germany; University of Freiburg, Biological Faculty, Schänzlestr. 1, D-79104, Freiburg, Germany.
Philipp
P
Kolb
University Hospital Heidelberg, Institute of Immunology, Im Neuenheimer Feld 305, D-69120, Heidelberg, Germany.
Reinhard
R
Wallich
University Hospital Freiburg, Internal Medicine 2 / Molecular Biology, Hugstetter Str. 55, D-79106, Freiburg, Germany.
Michael
M
Nassal
D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis* / Q000276:immunology; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000378:metabolism; D001096:Arachnid Vectors / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D025065:Borrelia burgdorferi / Q000276:immunology*; D002213:Capsid / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D006512:Hepatitis B Core Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D018884:Ixodes / Q000276:immunology*; D008193:Lyme Disease / Q000517:prevention & control / Q000635:transmission; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012471:Salivary Proteins and Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination; D014614:Vaccines, Synthetic
D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D000939:Epitopes; D006512:Hepatitis B Core Antigens; C000607909:Iric-1 protein, Ixodes scapularis; C079616:OspC protein; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012471:Salivary Proteins and Peptides; C464566:Salp15 protein, Ixodes scapularis; D014614:Vaccines, Synthetic