MyD88-Dependent IFN-γ Production by NK Cells Is Key for Control ofLegionella pneumophilaInfection

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-γ 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.

Antibodies protect against intracellular bacteria by Fc receptor-mediated lysosomal targeting

“…Lpn strains used in this study were JR32 (wt Philadelphia-1) (38), GS3011 (icmT deletion mutant lacking a functional Icm/Dot T4SS; ΔT) (39), thymidine-auxotroph derivatives of Lpn ΔT, and Corby (wt or flaA deletion mutant). Where indicated, Lpn constitutively expressed GFP from plasmid pMMB207-Km14-GFPc (8) or DsRed from plasmid pSW001 (40). Before infections, Lpn was grown for 3 d at 37°C on charcoal yeast-extract agar (CYE) plates.…”

“…Although primary infection of Lpn is largely controlled by innate immune mechanisms, particularly, natural killer cell-derived IFNγ (8,9), early reports also documented adaptive cell-mediated and humoral immune responses upon Lpn infection (10). We have previously analyzed the Lpn-specific humoral response in detail and documented that Lpn-specific Abs can mediate protection against Lpn challenge (11).…”

Evolutionary struggles between NK cells and viruses

“…Although natural killer (NK) cells have been studied most extensively in terms of viral and tumour immunity, there is an increasing awareness that NK cells are activated, and in some situations potentially have a protective role, in immune responses to certain microorganisms, including Legionella pneumophila 109 122 and Plasmodium falciparum (reviewed in REF. 123 ).…”

Nonhematopoietic Cells Are Key Players in Innate Control of Bacterial Airway Infection

“…We have used an airway infection model with the Gram-negative bacterium Legionella pneumophila, the causative agent of Legionnaire's disease, to assess in vivo the importance of nonhematopoietic cells in the lung and their communication with AMs to initiate an inflammatory response, which, in turn, is critical for rapid control of L. pneumophila infection (5)(6)(7)(8)(9). On airway infection, L. pneumophila infect AMs, and in contrast to extracellular bacteria, L. pneumophila resist intracellular lysosomal degradation by means of their icm/dot type IV secretion system (T4SS) (10).…”