A Legionella pneumophila effector impedes host gene silencing to promote virulence

RNA silencing is a gene silencing mechanism directed by siRNAs and miRNAs. Human miRNAs act as central regulators of host-bacteria interactions. However, it is unknown whether human pathogenic bacteria could impede RNA silencing to promote virulence. Here, we show that the Legionella pneumophila type IV-secreted effector LegK1 suppresses siRNA- and miRNA-activities in human cells. This ability depends on its kinase activity and on a functional tryptophan-dependent Argonaute (Ago)-binding platform. We further show that the capacity of LegK1 to activate NF-kB signaling contributes to silencing suppression, demonstrating a link between effector-mediated NF-kB signaling activation and silencing suppression. LegK1 also promotes L. pneumophila growth in both amoeba and human macrophages, supporting a key role of this effector in virulence. In infected macrophages, the latter activity relies on the genetic targeting of human Ago4, highlighting a novel function of this host factor in antibacterial resistance. ### Competing Interest Statement M.R, M.C., D.F., L.S., K.A.S, H.C.V, S.G-M., B. L., D.L., C.B. and L.N declare no competing interests. J.T. is a recipient of an EVOTEC funded PhD fellowship in the context of the French private-public partnership CIFRE program from the ANRT. A.A. is an EVOTEC employee.