Limits...
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.

Show MeSH

Related in: MedlinePlus

NK cells confer protection against IOE-mediated immunopathology during recall response.Compared with naïve mice (A), and IOE-infected/unprimed mice (B), the livers of NK+/+EM/IOE mice (C) have minimal apoptotic and necrotic cells but contain lymphohistiocytic cellular infiltration (arrowhead and inset) and minimal apoptosis. In contrast, the livers of NK-/-EM/IOE-infected mice (D) has a greater number of apoptotic cells and foci of liver necrosis (arrows), as detected by H&E staining after challenge with IOE. (Original magnification, X40). Data are representative of sections from one mouse in each group with similar results obtained in three independent experiments with three mice per group.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4836677&req=5

pone.0153223.g012: NK cells confer protection against IOE-mediated immunopathology during recall response.Compared with naïve mice (A), and IOE-infected/unprimed mice (B), the livers of NK+/+EM/IOE mice (C) have minimal apoptotic and necrotic cells but contain lymphohistiocytic cellular infiltration (arrowhead and inset) and minimal apoptosis. In contrast, the livers of NK-/-EM/IOE-infected mice (D) has a greater number of apoptotic cells and foci of liver necrosis (arrows), as detected by H&E staining after challenge with IOE. (Original magnification, X40). Data are representative of sections from one mouse in each group with similar results obtained in three independent experiments with three mice per group.

Mentions: We previously showed that primary and secondary fatal ehrlichiosis is due to excessive inflammation, which is mediated in part by TNF-α and leads to extensive liver injury [6,10,25,28]. Thus, we examined the liver pathology of undepleted and NK cell-depleted EM/IOE mice 7 DPI by H&E staining. Compared to uninfected controls Fig 12A and unprimed/IOE-infected mice Fig 12B, NK+/+EM/IOE-infected mice developed prominent lymphohistiocytic infiltrates in the liver, which were associated with minimal necrosis and apoptosis Fig 12C. However, NK-/-EM/IOE-infected mice exhibited focal areas of confluent necrosis, extensive apoptosis of Kupffer cells and hepatocytes, and microvesicular steatosis and congestion 7–10 days post IOE infection Fig 12D, which was similar to that detected in unprimed, IOE-infected mice Fig 12B. These data suggest that NK cells prevent the development of pathology and liver injury during the recall response to Ehrlichia infection.


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 cells confer protection against IOE-mediated immunopathology during recall response.Compared with naïve mice (A), and IOE-infected/unprimed mice (B), the livers of NK+/+EM/IOE mice (C) have minimal apoptotic and necrotic cells but contain lymphohistiocytic cellular infiltration (arrowhead and inset) and minimal apoptosis. In contrast, the livers of NK-/-EM/IOE-infected mice (D) has a greater number of apoptotic cells and foci of liver necrosis (arrows), as detected by H&E staining after challenge with IOE. (Original magnification, X40). Data are representative of sections from one mouse in each group with similar results obtained in three independent experiments with three mice per group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153223.g012: NK cells confer protection against IOE-mediated immunopathology during recall response.Compared with naïve mice (A), and IOE-infected/unprimed mice (B), the livers of NK+/+EM/IOE mice (C) have minimal apoptotic and necrotic cells but contain lymphohistiocytic cellular infiltration (arrowhead and inset) and minimal apoptosis. In contrast, the livers of NK-/-EM/IOE-infected mice (D) has a greater number of apoptotic cells and foci of liver necrosis (arrows), as detected by H&E staining after challenge with IOE. (Original magnification, X40). Data are representative of sections from one mouse in each group with similar results obtained in three independent experiments with three mice per group.
Mentions: We previously showed that primary and secondary fatal ehrlichiosis is due to excessive inflammation, which is mediated in part by TNF-α and leads to extensive liver injury [6,10,25,28]. Thus, we examined the liver pathology of undepleted and NK cell-depleted EM/IOE mice 7 DPI by H&E staining. Compared to uninfected controls Fig 12A and unprimed/IOE-infected mice Fig 12B, NK+/+EM/IOE-infected mice developed prominent lymphohistiocytic infiltrates in the liver, which were associated with minimal necrosis and apoptosis Fig 12C. However, NK-/-EM/IOE-infected mice exhibited focal areas of confluent necrosis, extensive apoptosis of Kupffer cells and hepatocytes, and microvesicular steatosis and congestion 7–10 days post IOE infection Fig 12D, which was similar to that detected in unprimed, IOE-infected mice Fig 12B. These data suggest that NK cells prevent the development of pathology and liver injury during the recall response to Ehrlichia infection.

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