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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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NK cell depletion in E. muris-primed mice decreases expansion of memory T cells.Splenocytes from different groups of mice were stimulated with E. muris antigens and the frequency of memory cells was determined by flow cytometry. Lower percentages (A) and absolute numbers (B) of effector/effector memory (Em) (CD44high CD62Llow), but not central memory (Cm) (CD44high CD62Lhigh), CD4+ T cells in the spleens of NK-/-E. muris compared with those found in NK+/+E. muris or naïve mice infected with IOE on day 28 post-infection. ** indicate P < 0.01. Data are presented as the means ± SD of four mice per group from two independent experiments. ** indicates P <0.01.
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pone.0153223.g004: NK cell depletion in E. muris-primed mice decreases expansion of memory T cells.Splenocytes from different groups of mice were stimulated with E. muris antigens and the frequency of memory cells was determined by flow cytometry. Lower percentages (A) and absolute numbers (B) of effector/effector memory (Em) (CD44high CD62Llow), but not central memory (Cm) (CD44high CD62Lhigh), CD4+ T cells in the spleens of NK-/-E. muris compared with those found in NK+/+E. muris or naïve mice infected with IOE on day 28 post-infection. ** indicate P < 0.01. Data are presented as the means ± SD of four mice per group from two independent experiments. ** indicates P <0.01.

Mentions: To further examine the effect of NK cell depletion on the protective memory response, we measured the frequency and function of memory CD4+ T cells. Splenocytes were harvested from all groups of mice 28 DPI, and stimulated with E. muris antigens (Ags). Our data show that the spleens of NK-/-EM/IOE mice had a significantly lower percentage Fig 4A and absolute number Fig 4B of Ag-specific CD44+CD62L- effector memory (Em) CD4+ T cells 28 DPI after E. muris infection as compared with the number of Em CD4+ T cells in sham (isotype) control E. muris-infected mice.


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

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

NK cell depletion in E. muris-primed mice decreases expansion of memory T cells.Splenocytes from different groups of mice were stimulated with E. muris antigens and the frequency of memory cells was determined by flow cytometry. Lower percentages (A) and absolute numbers (B) of effector/effector memory (Em) (CD44high CD62Llow), but not central memory (Cm) (CD44high CD62Lhigh), CD4+ T cells in the spleens of NK-/-E. muris compared with those found in NK+/+E. muris or naïve mice infected with IOE on day 28 post-infection. ** indicate P < 0.01. Data are presented as the means ± SD of four mice per group from two independent experiments. ** indicates P <0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153223.g004: NK cell depletion in E. muris-primed mice decreases expansion of memory T cells.Splenocytes from different groups of mice were stimulated with E. muris antigens and the frequency of memory cells was determined by flow cytometry. Lower percentages (A) and absolute numbers (B) of effector/effector memory (Em) (CD44high CD62Llow), but not central memory (Cm) (CD44high CD62Lhigh), CD4+ T cells in the spleens of NK-/-E. muris compared with those found in NK+/+E. muris or naïve mice infected with IOE on day 28 post-infection. ** indicate P < 0.01. Data are presented as the means ± SD of four mice per group from two independent experiments. ** indicates P <0.01.
Mentions: To further examine the effect of NK cell depletion on the protective memory response, we measured the frequency and function of memory CD4+ T cells. Splenocytes were harvested from all groups of mice 28 DPI, and stimulated with E. muris antigens (Ags). Our data show that the spleens of NK-/-EM/IOE mice had a significantly lower percentage Fig 4A and absolute number Fig 4B of Ag-specific CD44+CD62L- effector memory (Em) CD4+ T cells 28 DPI after E. muris infection as compared with the number of Em CD4+ T cells in sham (isotype) control E. muris-infected mice.

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