The long-term goal of this research is to develop an effective prophylactic vaccine against the two typhusgroup rickettsiae, Ricketisia typhi and R. prowazekii. These obligately intracellular bacteria are, respectively,the agents of murine typhus and louse-borne epidemic typhus. The latter is among the most severe of theknown human infections. This characteristic together with the facts that R. prowazekii is stably infectious,transmissible by aerosol, and has been previously weaponized, justifies the placement of this Ricketisiaamong the category B biothreat select agents. The development of a vaccine is feasible because naturalrickettsial infection provides strong protective immunity; however, no safe and effective vaccines have beendeveloped thus far. Based on the knowledge that CD8+ T cells are fundamental effectors of immunityagainst rickettsiae, that the genomes of the two typhus group rickettsiae are almost identical, and that I havedemonstrated that T cell-mediated cross-protection between distantly related rickettsiae occurs, Ihypothesize that cross-reactive typhus group rickettsial antigens recognized by CD8+ T cells will protectmice immunized with a DMA-prime and recombinant vaccinia-boost protocol from a lethal rickettsialchallenge. Thus, the objective of this application is to identify typhus group rickettsial cross-reactiveprotective antigens. I will approach this objective through the following specific aims: 1) identify crossreactivetyphus group rickettsial antigens recognized by CD8+ T cells of mice and humans; and 2) determinethe protection conferred by rickettsial DNA-priming and rickettsial recombinant viral boosting with theselected antigens against a lethal challenge with rickettsiae in a mouse model. I will carry out these aims by:1) identifying typhus group rickettsial antigens through the activation of anti-rickettsia CD8+ Tcell effectorfunctions by exposure to antigen presenting cells (APCs) transfected with a vector that drives the expressionof rickettsial genes; and 2) testing the immunogenicity and efficacy of the selected antigens in appropriaterickettsial mouse models. The health impact of this research is that it will establish the most importantknowledge necessary for the rational design of effective vaccines against rickettsial diseases, particularlytyphus.
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