PT  - JOURNAL ARTICLE
AU  - Anna Lena Jung
AU  - Cornelia Stoiber
AU  - Christina Herkt
AU  - Christine Schulz
AU  - Wilhelm Bertrams
AU  - Bernd Schmeck
TI  - <em>Legionella pneumophila</em>-derived outer membrane vesicles promote bacterial replication in macrophages
AID  - 10.1183/13993003.congress-2016.PA4648
DP  - 2016 Sep 01
TA  - European Respiratory Journal
PG  - PA4648
VI  - 48
IP  - suppl 60
4099  - http://erj.ersjournals.com/content/48/suppl_60/PA4648.short
4100  - http://erj.ersjournals.com/content/48/suppl_60/PA4648.full
SO  - Eur Respir J2016 Sep 01; 48
AB  - Legionella pneumophila, a causative agent of severe pneumonia, primarily infects and replicates within macrophages. We and others have shown that they release outer membrane vesicles (OMVs).Here, we analyzed the influence of L. pneumophila OMVs on macrophages. Differentiated THP-1 cells were incubated with increasing doses of Legionella OMVs, leading to a TLR2-dependent classical activation of macrophages with the release of pro-inflammatory cytokines. Inhibition of NF-κB signaling reduced the induction pro-inflammatory cytokines. Furthermore, treatment of THP-1 cells with OMVs prior to infection reduced replication of L. pneumophila in THP-1 cells. Blocking of TLR2 activation or heat denaturation of OMVs restored bacterial replication in the first 24 h of infection. With prolonged infection-time, OMV pre-treated macrophages became more permissive for bacterial replication than untreated cells, dependent on NF-κB signaling, and showed increased numbers of Legionella-containing vacuoles and reduced pro-inflammatory cytokine induction. Additionally, miRNA-146a was found to be transcriptionally induced by OMVs and to facilitate bacterial replication. Accordingly, IRAK-1, one of miRNA-146a's targets, showed prolonged activation-dependent degradation, which rendered THP-1 cells more permissive for Legionella replication.In conclusion, L. pneumophila OMVs are initially potent pro-inflammatory stimulators of macrophages, acting via TLRs, IRAK-1, and NF-κB, while at later time points, OMVs facilitate L. pneumophila replication by miR-146a-dependent IRAK-1 suppression. OMVs might thereby promote spreading of L. pneumophila in the host.