Persistent infection contributes to heterologous protective immunity against fatal ehrlichiosis.

Human monocytotropic ehrlichiosis (HME), an emerging and often life-threatening tick-transmitted disease, is caused by the obligately intracellular bacterium Ehrlichia chaffeensis. HME is modeled in C57BL/6 mice using Ehrlichia muris, which causes persistent infection, and Ixodes ovatus Ehrlichia (IOE), which is either acutely lethal or sublethal depending on the dose and route of inoculation. A persistent primary E. muris infection, but not a sublethal IOE infection, protects mice against an ordinarily lethal secondary IOE challenge. In the present study, we determined the role of persistent infection in maintenance of protective memory immune responses. E. muris-infected mice were treated with doxycycline or left untreated and then challenged with an ordinarily lethal dose of IOE. Compared to E. muris-primed mice treated with doxycycline, untreated mice persistently infected with E. muris had significantly greater numbers of antigen-specific gamma interferon-producing splenic memory T cells, significant expansion of CD4(+) CD25(+) T regulatory cells, and production of transforming growth factor beta1 in the spleen. Importantly, E. muris-primed mice treated with doxycycline showed significantly greater susceptibility to challenge infection with IOE compared to untreated mice persistently infected with E. muris. The study indicated that persistent ehrlichial infection contributes to heterologous protection by stimulating the maintenance of memory T-cell responses.

Relative importance of T-cell subsets in monocytotropic ehrlichiosis: a novel effector mechanism involved in Ehrlichia-induced immunopathology in murine ehrlichiosis.

Infection with gram-negative monocytotropic Ehrlichia strains results in a fatal toxic shock-like syndrome characterized by a decreased number of Ehrlichia-specific CD4(+) Th1 cells, the expansion of tumor necrosis factor alpha (TNF-alpha)-producing CD8(+) T cells, and the systemic overproduction of interleukin-10 (IL-10) and TNF-alpha. Here, we investigated the role of CD4(+) and CD8(+) T cells in immunity to Ehrlichia and the pathogenesis of fatal ehrlichiosis caused by infection with low- and high-dose (10(3) and 10(5) bacterial genomes/mouse, respectively) ehrlichial inocula. The CD4(+) T-cell-deficient mice showed exacerbated susceptibility to a lethal high- or low-dose infection and harbored higher bacterial numbers than did wild-type (WT) mice. Interestingly, the CD8(+) T-cell-deficient mice were resistant to a low dose but succumbed to a high dose of Ehrlichia. The absence of CD8(+) T cells abrogated TNF-alpha and IL-10 production, reduced tissue injury and bacterial burden, restored splenic CD4(+) T-cell numbers, and increased the frequency of Ehrlichia-specific CD4(+) Th1 cells in comparison to infected WT mice. Although fatal disease is perforin independent, our data suggested that perforin played a critical role in controlling bacterial burden and mediating liver injury. Similar to WT mice, mortality of infected perforin-deficient mice was associated with CD4(+) T-cell apoptosis and a high serum concentration of IL-10. Depletion of IL-10 restored the number of CD4(+) and CD8(+) T cells in infected WT mice. Our data demonstrate a novel mechanism of immunopathology in which CD8(+) T cells mediate Ehrlichia-induced toxic shock, which is associated with IL-10 overproduction and CD4(+) T-cell apoptosis.