Interferon-γ-dependent control of Anaplasma phagocytophilum by murine neutrophil granulocytes
Kathrin Gussmann1, Susanne Kirschnek1, Friederike D von Loewenich2
1Institute of Medical Microbiology and Hygiene, University of Freiburg, Hermann-Herder-Strasse 11, D-79104, Freiburg, Germany.
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 (gp91phox-/-), myeloperoxidase (MPO-/-) and inducible nitric oxide synthase (iNOS-/-). However, bacterial growth in gene-deficient neutrophils was comparable to that in wild-type cells. Whereas gp91phox 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.
Insights
Neutrophils combat Anaplasma phagocytophilum infection via an interferon-gamma-dependent, inducible nitric oxide synthase-independent pathway. This study reveals neutrophils can act as killer cells against this intracellular pathogen.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Anaplasma phagocytophilum is an obligate intracellular bacterium transmitted by ticks, causing febrile illness in hosts.
- This bacterium specifically targets neutrophils, making it a model for studying host-pathogen interactions.
- The roles of neutrophils as host cells versus active killer cells in A. phagocytophilum infections are debated.
Purpose of the Study:
- To investigate the role of neutrophils as killer cells against Anaplasma phagocytophilum.
- To determine the contribution of specific antimicrobial molecules in neutrophils during infection.
Main Methods:
- Utilized in vitro generated murine neutrophils with genetic deficiencies in NADPH-oxidase, myeloperoxidase, and inducible nitric oxide synthase.
- Infected these neutrophils with A. phagocytophilum and assessed bacterial growth.
- Stimulated neutrophils with interferon-gamma (IFN-γ) to evaluate its effect on bacterial control.
Main Results:
- Bacterial growth in neutrophils deficient in NADPH-oxidase, myeloperoxidase, or inducible nitric oxide synthase was similar to wild-type neutrophils.
- IFN-γ stimulation significantly impaired bacterial growth and induced iNOS expression.
- The antibacterial effect of IFN-γ was observed even in neutrophils lacking iNOS.
Conclusions:
- Murine neutrophils stimulated with IFN-γ exhibit antimicrobial activity against A. phagocytophilum.
- This killing mechanism is independent of inducible nitric oxide synthase.
- Neutrophils can function as killer cells in controlling Anaplasma phagocytophilum infections.
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