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NK Cell-Mediated Regulation of Protective Memory Responses against Intracellular Ehrlichial Pathogens.

Habib S, El Andaloussi A, Hisham A, Ismail N - PLoS ONE (2016)

Bottom Line: Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis.However, the contribution of NK cells to the memory response against Ehrlichia remains elusive.Together, these data suggest that E. muris-induced memory-like NK cells, which contribute to the protective, recall response against Ehrlichia.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.

ABSTRACT
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.

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Secondary high-dose challenge with IOE is fatal in NK-depleted EM/IOE-infected mice.C57BL/6 mice were infected with a high dose of E. muris, and were either depleted of NK cells at 22, 23, 24, and 26 DPI (NK-/- EM/IOE) or treated with isotype control antibody (NK+/+EM/IOE). Both groups of mice (n = 12 mice/group) were re-challenged with a high dose of IOE on day 28 after infection. The other control group includes naïve mice infected only with IOE. Depletion of E. muris-primed mice with anti-asialo GM1 antibodies resulted in: A) ~95% depletion of NK cells on day 3 after IOE infection; B) decreased survival of NK-/-EM/IOE mice group; and C) higher bacterial burden in the liver of NK-/-EM/IOE mice on day 7 after IOE infection as compared with NK+/+EM/IOE-infected mice. The data represent the means ± SD from four mice per group and are representative of three independent experiments.
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pone.0153223.g003: Secondary high-dose challenge with IOE is fatal in NK-depleted EM/IOE-infected mice.C57BL/6 mice were infected with a high dose of E. muris, and were either depleted of NK cells at 22, 23, 24, and 26 DPI (NK-/- EM/IOE) or treated with isotype control antibody (NK+/+EM/IOE). Both groups of mice (n = 12 mice/group) were re-challenged with a high dose of IOE on day 28 after infection. The other control group includes naïve mice infected only with IOE. Depletion of E. muris-primed mice with anti-asialo GM1 antibodies resulted in: A) ~95% depletion of NK cells on day 3 after IOE infection; B) decreased survival of NK-/-EM/IOE mice group; and C) higher bacterial burden in the liver of NK-/-EM/IOE mice on day 7 after IOE infection as compared with NK+/+EM/IOE-infected mice. The data represent the means ± SD from four mice per group and are representative of three independent experiments.

Mentions: To further examine the contribution of NK cells to the memory response against Ehrlichia, we depleted NK cells from E. muris-primed mice before we challenged these mice with IOE. The treatment of E. muris-primed mice with anti-asialo GM1 antibodies did not influence the number of T cells and NKT cells on day 3 S1 Fig or day 5 S2 Fig post-infection, respectively. The treatment of E. muris-primed mice with anti-asialo GM1 antibodies did not also influence the number of CD11b+ macrophages (data not shown). However, anti-asialo GM1 antibodies resulted in a ~95% depletion of NK cells on day 3 after IOE infection Fig 3A.


NK Cell-Mediated Regulation of Protective Memory Responses against Intracellular Ehrlichial Pathogens.

Habib S, El Andaloussi A, Hisham A, Ismail N - PLoS ONE (2016)

Secondary high-dose challenge with IOE is fatal in NK-depleted EM/IOE-infected mice.C57BL/6 mice were infected with a high dose of E. muris, and were either depleted of NK cells at 22, 23, 24, and 26 DPI (NK-/- EM/IOE) or treated with isotype control antibody (NK+/+EM/IOE). Both groups of mice (n = 12 mice/group) were re-challenged with a high dose of IOE on day 28 after infection. The other control group includes naïve mice infected only with IOE. Depletion of E. muris-primed mice with anti-asialo GM1 antibodies resulted in: A) ~95% depletion of NK cells on day 3 after IOE infection; B) decreased survival of NK-/-EM/IOE mice group; and C) higher bacterial burden in the liver of NK-/-EM/IOE mice on day 7 after IOE infection as compared with NK+/+EM/IOE-infected mice. The data represent the means ± SD from four mice per group and are representative of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836677&req=5

pone.0153223.g003: Secondary high-dose challenge with IOE is fatal in NK-depleted EM/IOE-infected mice.C57BL/6 mice were infected with a high dose of E. muris, and were either depleted of NK cells at 22, 23, 24, and 26 DPI (NK-/- EM/IOE) or treated with isotype control antibody (NK+/+EM/IOE). Both groups of mice (n = 12 mice/group) were re-challenged with a high dose of IOE on day 28 after infection. The other control group includes naïve mice infected only with IOE. Depletion of E. muris-primed mice with anti-asialo GM1 antibodies resulted in: A) ~95% depletion of NK cells on day 3 after IOE infection; B) decreased survival of NK-/-EM/IOE mice group; and C) higher bacterial burden in the liver of NK-/-EM/IOE mice on day 7 after IOE infection as compared with NK+/+EM/IOE-infected mice. The data represent the means ± SD from four mice per group and are representative of three independent experiments.
Mentions: To further examine the contribution of NK cells to the memory response against Ehrlichia, we depleted NK cells from E. muris-primed mice before we challenged these mice with IOE. The treatment of E. muris-primed mice with anti-asialo GM1 antibodies did not influence the number of T cells and NKT cells on day 3 S1 Fig or day 5 S2 Fig post-infection, respectively. The treatment of E. muris-primed mice with anti-asialo GM1 antibodies did not also influence the number of CD11b+ macrophages (data not shown). However, anti-asialo GM1 antibodies resulted in a ~95% depletion of NK cells on day 3 after IOE infection Fig 3A.

Bottom Line: Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis.However, the contribution of NK cells to the memory response against Ehrlichia remains elusive.Together, these data suggest that E. muris-induced memory-like NK cells, which contribute to the protective, recall response against Ehrlichia.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus