K lebsiella pneumoniae targets an EGF receptor‐dependent pathway to subvert inflammation

Summary The NF‐κB transcriptional factor plays a key role governing the activation of immune responses. K lebsiella pneumoniae is an important cause of community‐acquired and nosocomial pneumonia. Evidence indicates that K . pneumoniae infections are characterized by lacking an early inflammatory response. Recently, we have demonstrated that K lebsiella antagonizes the activation of NF‐κB via the deubiquitinase CYLD . In this work, by applying a high‐throughput siRNA gain‐of‐function screen interrogating the human kinome, we identified 17 kinases that when targeted by siRNA restored IL‐1β ‐dependent NF‐κB translocation in infected cells. Further characterization revealed that K . pneumoniae activates an EGF receptor ( EGFR )‐phosphatidylinositol 3‐ OH kinase ( PI3K )– AKT – PAK4 – ERK – GSK3β signalling pathway to attenuate the cytokine‐dependent nuclear translocation of NF‐κB . Our data also revealed that CYLD is a downstream effector of K . pneumoniae ‐induced EGFR – PI3K – AKT – PAK4 – ERK – GSK3β signalling pathway. Our efforts to identify the bacterial factor(s)responsible for EGFR activation demonstrate that a capsule ( CPS ) mutant did not activate EGFR hence suggesting that CPS could mediate the activation of EGFR . Supporting this notion, purified CPS did activate EGFR as well as the EGFR ‐dependent PI3K – AKT – PAK4 – ERK – GSK3β signalling pathway. CPS ‐mediated EGFR activation was dependent on a TLR4 – MyD88 – c‐SRC ‐dependent pathway. Several promising drugs have been developed to antagonize this cascade. We propose that agents targeting this signalling pathway might provide selective alternatives for the management of K . pneumoniae pneumonias.