T-Cell-Independent Humoral Immunity Is Sufficient for Protection against Fatal Intracellular Ehrlichia Infection

Abstract

Although humoral immunity has been shown to contribute to host defense during intracellular bacterial infections, its role has generally been ancillary. Instead, CD4 T cells are often considered to play the dominant role in protective immunity via their production of type I cytokines. Our studies of highly pathogenic Ehrlichia bacteria isolated from Ixodes ovatus (IOE) reveal, however, that this paradigm is not always correct. Immunity to IOE infection can be induced by infection with a closely related weakly pathogenic ehrlichia, Ehrlichia muris. Type I cytokines (i.e., gamma interferon, tumor necrosis factor alpha, and interleukin-12) were not necessary for E. muris-induced immunity. In contrast, humoral immunity was essential, as shown by the fact that E. muris-infected B-cell-deficient mice were not protected from IOE challenge and because E. muris immunization was effective in CD4-, CD8-, and major histocompatibility complex (MHC) class II-deficient mice. Immunity was unlikely due to nonspecific inflammation, as prior infection with Listeria monocytogenes did not induce immunity to IOE. Antisera from both wild-type and MHC-II-deficient mice provided at least partial resistance to challenge infection, and protection could also be achieved following transfer of total, but not B-cell-depleted, splenocytes obtained from E. muris-immunized mice. The titers of class-switched antibodies in immunized CD4 T-cell-and MHC class II-deficient mice, although lower than those observed in immunized wild-type mice, were significant, indicating that E. muris can induce class switch recombination in the absence of classical T-cellmediated help. These studies highlight a major protective role for classical T-cell-independent humoral immunity during an intracellular bacterial infection.

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

“…Alternatively, as we concluded above, local, but not systemic, production of proinflammatory and type 1 cytokines such as TNF-␣ and IFN-␥ contributes to the protection against fatal secondary ehrlichiosis, most likely by activation of intracellular bactericidal effector mechanisms of phagocytic cells. The findings of the present study are different from a previous study by Bitsaktsis et al that suggested that B cells and antibodies, but not T cells and type 1 cytokines, are essential for the crossprotection induced by E. muris against IOE based on studies with gene-targeted mice (2). However, generation of strong memory T-cell responses in cross-protected EM/IOE mice, but not unprotected IOE/IOE mice, observed in the present study suggest that memory T cells contribute to protection.…”

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

“…Abmediated aggravation of infections with intracellular pathogens might be due to FcR-mediated facilitation of entry of the pathogen into the host cell or to macrophage deactivation conveyed by inhibitory FcRs (68)(69)(70). Conversely, Ab-dependent control of intracellular microbes may result from Ab binding to the pathogen during intermittent extracellular phases, leading to opsonization and classical complement activation or to opsonophagocytosis (71).…”

Detection of “ Candidatus Neoehrlichia mikurensis” in Two Patients with Severe Febrile Illnesses: Evidence for a European Sequence Variant

“…Interestingly, B-cell-dependent, as well as T-cell-dependent, mechanisms of protection have been described for infections with members of the family Anaplasmataceae (2,3,19). The B-cell deficiency of patient 1 offers an explanation for his very high bacterial burden of at least 100,000 bacterial cells/ml peripheral blood (data not shown), which was calculated based on the sensitivity of our broad-range 16S rRNA gene-based PCR assay and the assumption that the genome of "Candidatus N. mikurensis" harbors only one copy of the 16S rRNA gene, as has been shown for the genera Anaplasma and Ehrlichia.…”