101. MyD88-dependent IFN-gamma production by NK cells is key for control of Legionella pneumophila infection.
- Author
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Spörri R, Joller N, Albers U, Hilbi H, and Oxenius A
- Subjects
- Adaptor Proteins, Signal Transducing deficiency, Adaptor Proteins, Signal Transducing genetics, Animals, Cells, Cultured, Cytokines biosynthesis, Inflammation Mediators metabolism, Interferon-gamma metabolism, Killer Cells, Natural metabolism, Legionella pneumophila pathogenicity, Legionnaires' Disease pathology, Mice, Mice, Inbred A, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Receptors, Interferon deficiency, Receptors, Interferon genetics, Toll-Like Receptors physiology, Virulence, Interferon gamma Receptor, Adaptor Proteins, Signal Transducing physiology, Interferon-gamma biosynthesis, Killer Cells, Natural immunology, Legionella pneumophila immunology, Legionnaires' Disease immunology, Legionnaires' Disease metabolism
- Abstract
Legionella pneumophila (Lpn) is a ubiquitous Gram-negative bacterium in aquatic systems and an opportunistic intracellular pathogen in immunocompromised humans causing a severe pneumonia known as Legionnaires' disease. Using a mouse model, we investigated molecular and cellular players in the innate immune response to infection with Lpn. We observed robust levels of inflammatory cytokines in the serum upon intranasal or i.v. infection with live, virulent Lpn, but not with inactivated or avirulent bacteria lacking the Icm/Dot type IV secretion system. Interestingly, Lpn-induced serum cytokines were readily detectable regardless of the capacity of Icm/Dot-proficient Lpn to replicate in host cells and the Lpn permissiveness of the host mice. We found NK cell-derived IFN-gamma to be the key cytokine in the resolution of Lpn infection, whereas type I IFNs did not appear to play a major role in our model. Accordingly, NK cell-depleted or IFN-II-R-deficient mice carried severely increased bacterial burdens or failed to control Lpn infection, respectively. Besides the dependence of inflammatory cytokine induction on Lpn virulence, we also demonstrate a strict requirement of MyD88 for this process, suggesting the involvement of TLRs in the recognition of Lpn. However, screening of several TLR-deficient hosts did not reveal a master TLR responsible for the sensing of an Lpn infection, but provided evidence for either redundancy of individual TLRs in Lpn recognition or TLR-independent induction of inflammatory responses. more...
- Published
- 2006
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