NK Cell-Mediated Regulation of Protective Memory Responses against Intracellular Ehrlichial Pathogens.
Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis. We previously showed that natural killer (NK) cells play a critical role in host defense against Ehrlichia during primary infection. However, the contribution of NK cells to the memory response against Ehrlichia remains elusive. Primary infection of C57BL/6 mice with Ehrlichia muris provides long-term protection against a second challenge with the highly virulent Ixodes ovatus Ehrlichia (IOE), which ordinarily causes fatal disease in naïve mice. Here, we show that the depletion of NK cells in E. muris-primed mice abrogates the protective memory response against IOE. Approximately, 80% of NK cell-depleted E. muris-primed mice succumbed to lethal IOE infection on days 8-10 after IOE infection, similar to naïve mice infected with the same dose of IOE. The lack of a recall response in NK cell-depleted mice correlated with an increased bacterial burden, extensive liver injury, decreased frequency of Ehrlichia-specific IFN-γ-producing memory CD4+ and CD8+ T-cells, and a low titer of Ehrlichia-specific antibodies. Intraperitoneal infection of mice with E. muris resulted in the production of IL-15, IL-12, and IFN-γ as well as an expansion of activated NKG2D+ NK cells. The adoptive transfer of purified E. muris-primed hepatic and splenic NK cells into Rag2-/-Il2rg-/- recipient mice provided protective immunity against challenge with E. muris. Together, these data suggest that E. muris-induced memory-like NK cells, which contribute to the protective, recall response against Ehrlichia.
Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.
Samar
S
Habib
Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.
Abdeljabar
A
El Andaloussi
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Ahmed
A
Hisham
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Nahed
N
Ismail
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004536:Ehrlichia / Q000276:immunology*; D016873:Ehrlichiosis / Q000276:immunology* / Q000382:microbiology; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D018884:Ixodes / Q000276:immunology / Q000382:microbiology; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL
D000907:Antibodies, Bacterial; D019409:Interleukin-15; D018664:Interleukin-12; D007371:Interferon-gamma