Rafeld, Heike Linda: Role of IFN‑γ induced genes in cell autonomous defence against Legionellae. - Bonn, 2022. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-66575
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-66575,
author = {{Heike Linda Rafeld}},
title = {Role of IFN‑γ induced genes in cell autonomous defence against Legionellae},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = may,

note = {L. pneumophila and L. longbeachae are ubiquitous environmental bacteria that can cause a severe pneumonia, known as Legionnaires’ Disease, when contaminated aerosols are inhaled by susceptible humans. During infection, Legionella establishes an intracellular niche, known as the Legionella containing vacuole (LCV). The biogenesis of the LCV is dependent on the defective organelle trafficking/intracellular multiplication (Dot/Icm) type IV secretion system, which translocates a large arsenal of bacterial effector proteins into the host cell. It is known that during Legionella lung infection, the mammalian host mounts a robust inflammatory response. It was previously shown that IFN‑γ is crucial for host defence against Legionella in mice, since disruption of IFN‑γ signalling or IFN‑γ deficiency results in a high replication of Legionella in the lung as well as a failure to clear the infection from the host, despite the activity of other inflammatory cytokines. However, which interferon-induced genes and through what mechanism this strikingly potent restriction is mediated remains elusive for Legionella.
In this study, we shed some light on the mode of action of the IFN‑γ induced host defence against Legionella. We identified a new mechanism of host defence mediated by interferon stimulated genes (ISGs), that results in the disruption of effector translocation into host cells by the Dot/Icm secretion system. We demonstrated that this mechanism is uniquely triggered by interferon signalling and is independent of well-known host defence mechanisms such as host cell death, direct bactericidal activities, inflammasome activation as well as proteasome and autophagy-mediated degradation.
Currently, more than 65 Legionella species are known and roughly half of them have been clinically associated with infection. After L. pneumophila, L. longbeachae is the second most common causative agent of Legionnaire’s Disease worldwide. Despite this, knowledge about the pathogenesis of L. longbeachae is minimal. Therefore, during this study, we also aimed to provide new insights into the pathogenesis of L. longbeachae infection and characterise the impact of IFN‑γ on immune control. We observed unique features of L. longbeachae infection in comparison to L. pneumophila, such as the ability to survive within a wider range of lung phagocytes, dampening of the cytokine response of the host and translocation of effectors into all lung phagocytes tested. Furthermore, we were able to show that IFN‑γ is crucial for host defence against L. longbeachae in vivo, with neutrophils and monocyte derived cells dependent on IFN‑γ signalling to mediate their bactericidal properties.
Overall, this study substantiates the importance of IFN‑γ in host defence against Legionella and supports the need to broaden research efforts to non‑L. pneumophila species. Investigation and deeper understanding of critical host defence mechanisms can be used as a starting point to develop anti-infective agents against pathogens targeting the process of effector translocation or effector mediated manipulation of host function and cell-autonomous defence.},

url = {https://hdl.handle.net/20.500.11811/9825}

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