Interferon-γ-dependent Control of Anaplasma Phagocytophilum by Murine Neutrophil Granulocytes

Overview

Journal Parasit Vectors

Publisher Biomed Central

Specialties Parasitology
Tropical Medicine

Date 2017 Jul 13

PMID 28697801

Citations 5

Authors

Kathrin Gussmann

Susanne Kirschnek

Friederike D von Loewenich

Affiliations

Soon will be listed here.

Abstract

Background: Anaplasma phagocytophilum is a Gram-negative obligate intracellular bacterium that is transmitted by ticks of the Ixodes ricinus complex. It replicates in neutrophils and elicits febrile disease in humans and animals. Because of its striking tropism for neutrophils, A. phagocytophilum has been used as a model organism to study the immune response against obligate intracellular pathogens. In mice, the control of A. phagocytophilum in the early phase of infection is dependent on natural killer cell-derived interferon-γ (IFN-γ). In contrast, the final elimination strictly requires CD4 T-cells. It is a matter of debate, whether neutrophils serve only as host cells or as killer cells as well.

Results: To study this, we used in vitro generated murine neutrophils with defects in major antimicrobial molecules such as NADPH-oxidase (gp91), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS). However, bacterial growth in gene-deficient neutrophils was comparable to that in wild-type cells. Whereas gp91 and MPO expression remained unchanged, the infection led to an induction of iNOS. In neutrophils stimulated with IFN-γ, bacterial growth was significantly impaired, and iNOS was induced. However, the antibacterial effect of IFN-γ was still seen in iNOS neutrophils.

Conclusion: Thus, murine in vitro generated neutrophils stimulated with IFN-γ seem to act as killer cells by an iNOS-independent mechanism.

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References

Rennoll-Bankert K, Sinclair S, Lichay M, Dumler J . Comparison and characterization of granulocyte cell models for Anaplasma phagocytophilum infection. Pathog Dis. 2013; 71(1):55-64. PMC: 4037391. DOI: 10.1111/2049-632X.12111. View

Kim H, Rikihisa Y . Expression of interleukin-1beta, tumor necrosis factor alpha, and interleukin-6 in human peripheral blood leukocytes exposed to human granulocytic ehrlichiosis agent or recombinant major surface protein P44. Infect Immun. 2000; 68(6):3394-402. PMC: 97610. DOI: 10.1128/IAI.68.6.3394-3402.2000. View

Rikihisa Y . Mechanisms of obligatory intracellular infection with Anaplasma phagocytophilum. Clin Microbiol Rev. 2011; 24(3):469-89. PMC: 3131063. DOI: 10.1128/CMR.00064-10. View

de la Fuente J, Ayoubi P, Blouin E, Almazan C, Naranjo V, Kocan K . Gene expression profiling of human promyelocytic cells in response to infection with Anaplasma phagocytophilum. Cell Microbiol. 2005; 7(4):549-59. DOI: 10.1111/j.1462-5822.2004.00485.x. View

Pedra J, Sutterwala F, Sukumaran B, Ogura Y, Qian F, Montgomery R . ASC/PYCARD and caspase-1 regulate the IL-18/IFN-gamma axis during Anaplasma phagocytophilum infection. J Immunol. 2007; 179(7):4783-91. DOI: 10.4049/jimmunol.179.7.4783. View

Thomas V, Samanta S, Wu C, Berliner N, Fikrig E . Anaplasma phagocytophilum modulates gp91phox gene expression through altered interferon regulatory factor 1 and PU.1 levels and binding of CCAAT displacement protein. Infect Immun. 2004; 73(1):208-18. PMC: 538944. DOI: 10.1128/IAI.73.1.208-218.2005. View

Guzik T, Korbut R, Adamek-Guzik T . Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol. 2004; 54(4):469-87. View

Costantini C, Cassatella M . The defensive alliance between neutrophils and NK cells as a novel arm of innate immunity. J Leukoc Biol. 2010; 89(2):221-33. DOI: 10.1189/jlb.0510250. View

Dumler J . The biological basis of severe outcomes in Anaplasma phagocytophilum infection. FEMS Immunol Med Microbiol. 2011; 64(1):13-20. PMC: 3256277. DOI: 10.1111/j.1574-695X.2011.00909.x. View

10.

Panday A, Sahoo M, Osorio D, Batra S . NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol. 2014; 12(1):5-23. PMC: 4654378. DOI: 10.1038/cmi.2014.89. View

11.

Martens S, Howard J . The interferon-inducible GTPases. Annu Rev Cell Dev Biol. 2006; 22:559-89. DOI: 10.1146/annurev.cellbio.22.010305.104619. View

12.

Akkoyunlu M, Malawista S, Anguita J, Fikrig E . Exploitation of interleukin-8-induced neutrophil chemotaxis by the agent of human granulocytic ehrlichiosis. Infect Immun. 2001; 69(9):5577-88. PMC: 98672. DOI: 10.1128/IAI.69.9.5577-5588.2001. View

13.

Borjesson D, Kobayashi S, Whitney A, Voyich J, Argue C, DeLeo F . Insights into pathogen immune evasion mechanisms: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils. J Immunol. 2005; 174(10):6364-72. DOI: 10.4049/jimmunol.174.10.6364. View

14.

Bogdan C . Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol. 2015; 36(3):161-78. DOI: 10.1016/j.it.2015.01.003. View

15.

McDonald J, Cortini A, Rosas M, Fossati-Jimack L, Ling G, Lewis K . In vivo functional analysis and genetic modification of in vitro-derived mouse neutrophils. FASEB J. 2011; 25(6):1972-82. DOI: 10.1096/fj.10-178517. View

16.

Little S . Ehrlichiosis and anaplasmosis in dogs and cats. Vet Clin North Am Small Anim Pract. 2010; 40(6):1121-40. DOI: 10.1016/j.cvsm.2010.07.004. View

17.

Bussmeyer U, Sarkar A, Broszat K, Ludemann T, Moller S, van Zandbergen G . Impairment of gamma interferon signaling in human neutrophils infected with Anaplasma phagocytophilum. Infect Immun. 2009; 78(1):358-63. PMC: 2798180. DOI: 10.1128/IAI.01005-09. View

18.

Wang G, Calvo K, Pasillas M, Sykes D, Hacker H, Kamps M . Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8. Nat Methods. 2006; 3(4):287-93. DOI: 10.1038/nmeth865. View

19.

Mott J, Rikihisa Y . Human granulocytic ehrlichiosis agent inhibits superoxide anion generation by human neutrophils. Infect Immun. 2000; 68(12):6697-703. PMC: 97769. DOI: 10.1128/IAI.68.12.6697-6703.2000. View

20.

Wang T, Malawista S, Pal U, Grey M, Meek J, Akkoyunlu M . Superoxide anion production during Anaplasma phagocytophila infection. J Infect Dis. 2002; 186(2):274-80. DOI: 10.1086/341451. View