Various species of ticks carry more than 20 pathogens, including Cat A-C and emerging/re-emerging agents, all capable of causing significant disease in humans, making targeting the tick instead of each individual pathogen a sound intervention strategy. Tick salivary molecules modulate host innate and adaptive immune defenses, naturally facilitating both tick feeding and pathogen transmission. In particular, blood feeding by the tick Ixodes scapularis polarizes responses in host T lymphocytes resulting in a strongly Th2 cytokine profile, while acquired tick resistance (ATR), a phenomenon associated with tick rejection and pathogen transmission impairment, is associated with Th1 cytokines. This proposal is based on the hypothesis that a vaccination strategy evoking a robust ATR response in hosts also will provide protection against tick-borne pathogen transmission. Using state-of-the-art informatics and proteomics methods, our primary objective is to identify vaccine candidates from tick transcriptomes predicted to stimulate robust antibody- and cellmediated immunity in humans. New information will be gathered regarding correlates of immunity to tick salivary molecules in humans, and potential correlates of protection against tick-borne pathogen transmission in a Guinea pig (GP) model.
In aim 1, bioinformatics, epitope mapping tools, and microarrays, are used to identify, isolate and characterize critical antigens from the I. scapularis salivome and design epitope-based vaccines that stimulate: 1) Th1 polarization in PBMCs derived from tick-sensitized patients, and 2) ATR in a GP model of pathogen transmission.
In aim 2, we use high throughput proteomic tools to similarly identify and isolate tick molecules reactive with IgE antibodies that elicit basophil degranulation resulting in an immediate-type dermal erythema/itch reaction at the tick bite site.
The third aim i ncludes measuring symptoms and immune correlates of ATR in sensitized humans challenged with pathogen-free ticks. Additionally, it combines findings from the first two aims and evaluates a bi-valent tick-borne disease transmission vaccine strategy in GPs. This project's innovation is in its application of a novel broad spectrum platform for vaccine design expected to significantly enhance translation of a """"""""gene to vaccine"""""""" strategy to humans.
Discovery of a broad-spectrum vaccine against ticks and tick-borne pathogen transmission would represent a major milestone for improving public health worldwide. This project will use core immunoinformatics tools and immunology facilities to accelerate development of safer, more efficient vaccines for biodefense and emerging infectious diseases.
|Liu, Rui; Moise, Leonard; Tassone, Ryan et al. (2015) H7N9 T-cell epitopes that mimic human sequences are less immunogenic and may induce Treg-mediated tolerance. Hum Vaccin Immunother 11:2241-52|
|Becker, Martin; Felsberger, André; Frenzel, André et al. (2015) Application of M13 phage display for identifying immunogenic proteins from tick (Ixodes scapularis) saliva. BMC Biotechnol 15:43|
|Eickhoff, Christopher S; Van Aartsen, Daniel; Terry, Frances E et al. (2015) An immunoinformatic approach for identification of Trypanosoma cruzi HLA-A2-restricted CD8(+) T cell epitopes. Hum Vaccin Immunother 11:2322-8|
|Losikoff, Phyllis T; Mishra, Sasmita; Terry, Frances et al. (2015) HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients. J Hepatol 62:48-55|
|Terry, Frances E; Moise, Leonard; Martin, Rebecca F et al. (2015) Time for T? Immunoinformatics addresses vaccine design for neglected tropical and emerging infectious diseases. Expert Rev Vaccines 14:21-35|
|De Groot, Anne S; Ross, Ted M; Levitz, Lauren et al. (2015) C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells. Immunol Cell Biol 93:189-97|
|Tomimaru, Yoshito; Mishra, Sasmita; Safran, Howard et al. (2015) Aspartate-?-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma. Vaccine 33:1256-66|
|Mishra, Sasmita; Losikoff, Phyllis T; Self, Alyssa A et al. (2014) Peptide-pulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naïve human T cells. Vaccine 32:3285-92|
|Bailey-Kellogg, Chris; Gutiérrez, Andres H; Moise, Leonard et al. (2014) CHOPPI: a web tool for the analysis of immunogenicity risk from host cell proteins in CHO-based protein production. Biotechnol Bioeng 111:2170-82|
|Shattuck, Wendy M C; Dyer, Megan C; Desrosiers, Joe et al. (2014) Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice. Hum Vaccin Immunother 10:3048-59|
Showing the most recent 10 out of 45 publications