Tick Immune-Developmental and Metabolic Pathways as Anti-Tick Vaccine Targets

PROJECT 3 – Abstract In this renewal Program Project Grant, we hypothesize that tick proteins that promote critical aspects of tick development, metabolism, and immunity (defined in projects 1 and 2) may serve as novel targets for anti-tick measures, as their interference could impair the life cycles of the tick and the pathogens they harbor. Project 3 will extend the mechanistic observations of Projects 1 and 2 towards anti-tick vaccine development and utilize the mRNA-LNP platform to accelerate vaccine target discovery. Recent studies from Fikrig’s group have demonstrated the utility of the mRNA-lipid nanoparticle (LNP) platform towards anti-tick vaccine target discovery and development and provide the thrust for this research effort. Specific Aim 1 of this proposal will first determine the impact of host immunity against key ectodomains or secreted components of the IMD, JAK/STAT, IsC1ql3, or ISARL pathways on the tick life cycle. Towards this, we will use rabbit, mouse (Mus musculus and additionally Peromyscus leucopus as warranted), and guinea pig animal models to determine the impact of vaccines targeting tick immune and metabolic pathways on the tick life cycle. Animals will be immunized with a cocktail of prioritized mRNA-LNPs and the impact on molting, development, fertility, and fecundity will be evaluated. Specific Aim 2 of the proposal will focus on two tick-borne bacterial pathogens, B. burgdorferi and A. phagocytophilum, that demonstrate differential spatial and temporal kinetics of transmission. Using a murine model of A. phagocytophilum and B. burgdorferi infection, we will evaluate whether immunization with a cocktail of prioritized mRNA-LNPs will impact pathogen survival in the tick and pathogen transmission to the murine host. Results of this study will provide the basis for understanding how tick immune-developmental and metabolic pathways may be targeted to impair tick-pathogen life cycle. These principles may be utilized in future efforts by us and other investigators to develop reservoir host or keystone host targeted vaccines to control infection prevalence and tick populations in endemic regions, or as a human vaccine to prevent tick transmission of human pathogens.