Antibacterial Role for Natural Killer Cells in Host Defense to Bacillus anthracis

Gonzales, Christine M; Williams, Courtney B.; Calderon, Veronica E.; Huante, Matthew B.; Moen, Scott T.; Popov, Vsevolod L.; Baze, Wallace B.; Peterson, Johnny W.; Endsley, Janice J.

doi:10.1128/iai.05439-11

Cited by 29 publications

(27 citation statements)

References 30 publications

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“…Although IL-10 usually acts as an anti-inflammatory cytokine, it has also been shown to be a potent stimulator of NK cells (38,39) that can increase their killing capacity and release of perforin and granzyme B (37). NK cells have recently been shown to contribute to suppressing bacteremia during B. anthracis infection in mice (40,41). IL-6 can support survival of the naive T cell pool (42) and can drive differentiation of Th17 cells (43).…”

Section: Discussionmentioning

confidence: 99%

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

et al. 2014

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The antiphagocytic capsule of Bacillus anthracis is a major virulence factor. We hypothesized that it may also mediate virulence through inhibition of the host's immune responses. During an infection, the capsule exists attached to the bacterial surface but also free in the host tissues. We sought to examine the impact of free capsule by assessing its effects on human monocytes and immature dendritic cells (iDCs). Human monocytes were differentiated into iDCs by interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) over 7 days in the presence of capsule derived from wild-type encapsulated B. anthracis Ames (WT) or a control preparation from an isogenic B. anthracis Ames strain that produces only 2% of the capsule of the WT (capA mutant). WT capsule consistently induced release of IL-8 and IL-6 while the capA mutant control preparation elicited either no response or only a minimal release of IL-8. iDCs that were differentiated in the presence of WT capsule had increased side scatter (SSC), a measure of cellular complexity, when assessed by flow cytometry. iDCs differentiated in the presence of WT capsule also matured less well in response to subsequent B. anthracis peptidoglycan (Ba PGN) exposure, with reduced upregulation of the chemokine receptor CCR7, reduced CCR7-dependent chemotaxis, and reduced release of certain cytokines. Exposure of naive differentiated control iDCs to WT capsule did not alter cell surface marker expression but did elicit IL-8. These results indicate that free capsule may contribute to the pathogenesis of anthrax by suppressing the responses of immune cells and interfering with the maturation of iDCs. Bacillus anthracis is the causative agent of anthrax and an important biothreat agent. The virulence of B. anthracis derives primarily from the products of two plasmids, pX01, which carries the genes for lethal toxin and edema toxin (1), and pX02, which carries the genes required for synthesizing capsule (2, 3). B. anthracis capsule covers the outer surface of the bacilli and protects them from phagocytosis by immune cells (4-6). While most bacterial capsules are polysaccharides, B. anthracis capsule is a homopolymer composed entirely of D-glutamic acid residues connected by ␥ linkages (7). These unusual attributes make B. anthracis capsule both relatively resistant to degradation by mammalian proteases and a poorly immunogenic thymus-independent type 2 antigen (8, 9).In in vitro broth culture and during infection, B. anthracis bacilli release capsule fragments. These free capsule fragments can accumulate to significant concentrations in the blood of moribund animals (7). Serum concentrations of B. anthracis capsule greater than 500 g/ml have been reported in mice (10), and concentrations greater than 1 mg/ml have been reported in rhesus macaques (11). Concentrations in local lesions could potentially be as high or even higher. Capsule free from the bacillus has been demonstrated to accumulate in animal tissues (12, 13). Early experiments with capsule recovered ...

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Section: Discussionmentioning

confidence: 99%

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

et al. 2014

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“…SEM observations indicate that the bacterial cell wall is damaged by both cytolytic proteins, suggesting that disruption of cell-wall integrity may be the main mechanism leading to bacterial death. Previously, Gonzales et al [30] reported that human and murine NK cells show antibacterial activity against the bacterial pathogen, Bacillus anthracis. Our results indicate that NK cells use relatively high concentrations of perforin and granulysin to kill mycobacteria and that the killing activity of these cytolytic proteins requires direct contact with the pathogen.…”

Section: Discussionmentioning

confidence: 99%

NK cells kill mycobacteria directly by releasing perforin and granulysin

Hsu³

et al. 2014

Journal of Leukocyte Biology

100

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Although the mechanisms underlying the cytotoxic effect of NK cells on tumor cells and intracellular bacteria have been studied extensively, it remains unclear how these cells kill extracellular bacterial pathogens. In this study, we examine how human NK cells kill Mycobacterium kansasii and M.tb. The underlying mechanism is contact dependent and requires two cytolytic proteins: perforin and granulysin. Mycobacteria induce enhanced expression of the cytolytic proteins via activation of the NKG2D/NCR cell-surface receptors and intracellular signaling pathways involving ERK, JNK, and p38 MAPKs. These results suggest that NK cells use similar cellular mechanisms to kill both bacterial pathogens and target host cells. This report reveals a novel role for NK cells, perforin, and granulysin in killing mycobacteria and highlights a potential alternative defense mechanism that the immune system can use against mycobacterial infection.

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“…This T cell response was identified by quantitation of IFN-γ-producing cells rather than a marker of a Th2-type T cell response, such as Interleukin-4. Killing of B. anthracis by murine macrophages [20] and human NK cells [21] involve IFN-γ; although IFN-γ production by NK cells may be down-regulated somewhat by anthrax lethal toxin [21]. In mice, IFN-γ-inducible chemokines CXCL9, -10 and -11, contributed directly to in vitro anti-microbial effects against B. anthracis Sterne strain spores [22], and IFN-γ was produced by NK cells in response to B. anthracis spores [23].…”

Section: Discussionmentioning

confidence: 99%

Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

Minang

Inglefield

Harris

et al. 2014

Vaccine

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NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a Phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24 to 48 hours after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALC), correlated with transiently increased IP-10. Cellular recall responses to anthrax Protective Antigen (PA) or PA peptides were assessed by IFN-gamma ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25 mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 hours (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.

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Antibacterial Role for Natural Killer Cells in Host Defense to Bacillus anthracis

Cited by 29 publications

References 30 publications

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

NK cells kill mycobacteria directly by releasing perforin and granulysin

Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

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