Emergence of Anaplasma marginale antigenic variants during persistent rickettsemia

Anaplasma marginale is an ehrlichial pathogen of cattle, in the order Ricke ttsiales, that establishes persistent cyclic rickettsemia in the infected h ost. Within each rickettsemic cycle, A. marginale expressing antigenically variant major surface protein 2 (MSP2) emerge. By cloning 17 full-length ms p2 transcripts expressed during cyclic rickettsemia, we determined that eme rgent variants have a single, central hypervariable region encoding variant B-cell epitopes, The N- and C-terminal regions are highly conserved among the expressed A. marginale variants, and similar sequences define the MSP2 homologues in the agent of human granulocytic ehrlichiosis (FIGE). This is in contrast to the MSP2 homologues in ehrlichial genogroup I pathogens, Ehr lichia chaffeensis, Ehrlichia canis, and Cowdria ruminantium, that have mul tiple hypervariable regions. By defining the variable and conserved regions , we were able to show that the single hypervariable region of A. marginale MSP2 encodes epitopes that are immunogenic and induce variant-specific ant ibody responses during persistent infection. These findings demonstrate tha t the MSP2 structural variants that emerge during each cycle of persistent rickettsemia are true antigenic variants, consistent with MSP2 antigenic va riation as a mechanism of A. marginale persistence.