Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

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Abstract
The roles of antibodies and memory T cells in protection against virulentEhrlichiahave not been completely investigated. In this study, we addressed these issues by using murine models of mild and fatal ehrlichiosis caused by related monocytotropicEhrlichiastrains. Mice were primed with eitherEhrlichia murisor closely related virulent ehrlichiae transmitted byIxodes ovatus(IOE) ticks given intraperitoneally or intradermally. All groups were reinfected intraperitoneally, 30 days later, with a lethal high dose of IOE. Priming withE. muris, but not IOE, induced strong CD4+and CD8+memory type 1 T-cell responses,Ehrlichia-specific immunoglobulin G (IgG) antibodies, and persistent infection. Compared to IOE-primed mice, subsequent lethal IOE challenge ofE. muris-primed mice, resulted in (i) 100% protection against lethal infection, (ii) strongEhrlichia-specific secondary gamma interferon (IFN-γ)-producing effector/effector memory CD4+and CD8+T-cell responses, (iii) enhanced secondary anti-ehrlichial antibody response, (iv) accelerated bacterial clearance, and (v) the formation of granulomas in the liver and lung.E. muris-primed mice challenged with IOE had lower levels of serum interleukin-1α (IL-1α), IL-6, and IL-10 compared to unprimed mice challenged with IOE. Interestingly, the fatal secondary response in IOE-primed mice correlated with (i) decline in theEhrlichia-specific CD4+and CD8+type 1 responses, (ii) marked hepatic apoptosis and necrosis, and (iii) substantial bacterial clearance, suggesting that fatal secondary response is due to immune-mediated tissue damage. In conclusion, protection against fatal ehrlichial infection correlates with strong expansion of IFN-γ-producing CD4+and CD8+effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.