CD4 T-Cell Epitopes Associated with Protective Immunity Induced following Vaccination of Mice with an Ehrlichial Variable Outer Membrane Protein

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Abstract
The ehrlichiae express variable outer membrane proteins (OMPs) that play important roles in both pathogenesis and host defense. Previous studies revealed that OMPs are immunodominant B-cell antigens and that passive transfer of anti-OMP antibodies can protect SCID mice from fatal ehrlichial infection. In this study, we used a model of fatal monocytotropic ehrlichiosis caused by Ehrlichia bacteria from Ixodes ovatus (IOE) to determine whether OMP immunization could generate protective immunity in immunocompetent mice. Immunization of C57BL/6 mice with a purified recombinant OMP expressed by IOE omp19 generated protection from fatal IOE infection and elicited robust humoral and CD4 T-cell responses. To identify CD4 T-cell epitopes within OMPs, we performed enzyme-linked immunospot analyses for gamma interferon (IFN-γ) production using a panel of overlapping 16-mer peptides from IOE OMP-19. Five immunoreactive peptides comprising residues 30 to 45, 77 to 92, 107 to 122, 197 to 212, and 247 to 264 were identified; the strongest response was generated against OMP-19 107-122 . Most of the peptides are conserved between E. muris and E. chaffeensis OMP-19, and they elicited IFN-γ production in CD4 T cells from E. muris -infected mice, indicating that T-cell epitope cross-reactivity likely contributes to heterologous immunity. Accordingly, CD4 T-cell responses to both OMP-19 and OMP-19 107-122 were of greater magnitude following high-dose IOE challenge of mice that had been immunized by prior infection with E. muris . Our studies cumulatively identify B- and T-cell epitopes that are associated with protective homologous and heterologous immunity during ehrlichial infection.

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