The overall goal of the proposed research is to determine the importance of antigenic variation in persistent ehrlichial infection and subsequent tick transmission to susceptible individuals. The risk to humans of acquiring ehrlichial infections reflects the presence of infected ixodid tick vectors in the local environment. Because ticks cannot maintain ehrlichial infection between generations due to the lack of transovarial transmission, sustaining a population of infected ticks requires rickettsemic mammalian hosts as a continual source of ehrlichiae. Persistent infection in the mammalian host, a common feature of ehrlichial pathogens, provides this continual source of organism for tick vectors and is therefore a primary determinant in ehrlichial transmission. How ehrlichiae persist in the mammalian host is unknown and is the central question in part 1 of this project. The system under study is Anaplasma marginale, a member of the ehrlichial genogroup II, and its transmission by the ixodid tick Dermacentor andersoni. Persistent A. marginale infection is characterized by sequential cycles of rickettsemia, each composed of a progressive increase in rickettsemia followed by a precipitous decrease. The rise and fall of rickettsemia during persistent infection parallels the rickettsemia during acute infection in which the sharp decline in organism numbers is due to the primary immune response. Each rickettsemic cycle is associated with the emergence of a new major surface protein-2 (MSP-2) variants, each polymorphic within a central hypervariable region. The hypotheses that cyclic rickettsemia reflects emergence and then immune control of escape variants and that MSP-2 antigenic variation is therefore responsible for persistent infection will be tested. In the second part of the project the role of the infected tick in generating and transmitting antigenic variants will be investigated. Development of infectivity in the salivary gland is associated with de novo expression of A. marginale MSP-2 variants. Importantly, these variants are unique as compared to the A. marginale use to infect the tick but are identical to the transmitted variant that replicates in the newly infected host. The hypothesis to be tested is that development within the tick is a source of antigenic variation relative to the reservoir mammalian host, or alternatively, development within the tick represents a bottleneck for antigenic diversity with reversion to a basic MSP-2 expressed prior to transmission.
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