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Typhus
Group Rickettsial Antigens Recognized by CD8+ T Lymphocytes Collaborating Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX
Principal Investigator: Gustavo Valbuena, M.D., Ph.D.
Expected Product: Vaccine against epidemic and endemic typhus.
Description: The long-term goal of this research is to develop an effective prophylactic vaccine against the two typhus group rickettsiae, Rickettsia 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 the known 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 Rickettsia among the category B biothreat select agents. The development of a vaccine is feasible because natural rickettsial infection provides strong protective immunity; however, no safe and effective vaccines have been developed thus far. Based on the knowledge that CD8+ T cells are fundamental effectors of immunity against rickettsiae, that the genomes of the two typhus group rickettsiae are almost identical, and that I have demonstrated that T cell-mediated cross-protection between distantly related rickettsiae occurs, I hypothesize that cross-reactive typhus group rickettsial antigens recognized by CD8+ T cells will protect mice immunized with a DNA-prime and recombinant vaccinia-boost protocol from a lethal rickettsial challenge. Thus, the objective of this application is to identify typhus group rickettsial cross-reactive protective antigens. I will approach this objective through the following specific aims: 1) identify cross-reactive typhus group rickettsial antigens recognized by CD8+ T cells of mice and humans; and 2) determine the protection conferred by rickettsial DNA-priming and rickettsial recombinant vaccinia virus boosting with the selected 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 a novel system that uses a representative rickettsial DNA library in vaccinia and takes advantage of the survival of vaccinia in recombinant-vaccinia infected cells killed by cytotoxic lymphocytes (lethality-based selection); and 2) testing the immunogenicity and efficacy of the selected antigens in appropriate rickettsial mouse models. The health impact of this research is that it will establish the most important knowledge necessary for the rational design of effective vaccines against rickettsial diseases, particularly typhus.
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