Dual input control: activation of the B artonella henselae VirB / D 4 type IV secretion system by the stringent sigma factor RpoH 1 and the BatR / BatS two‐component system

Summary The co‐ordinated expression of virulence factors is a critical process for any bacterial pathogen to colonize its host. Here we investigated the mechanisms of niche adaptation of the zoonotic pathogen B artonella henselae by combining genetic approaches and shotgun proteomics. We demonstrated that expression of the VirB / D 4 type IV secretion system ( T 4 SS ) and its secreted effector proteins require the alternative sigma factor RpoH 1, which levels are controlled by the stringent response ( SR ) components DksA and SpoT . The RpoH 1‐dependent activation requires an active BatR / BatS two‐component system ( TCS ) while BatR expression is controlled by RpoH 1 and the SR components. Deletion of spoT results in a strong attenuation of VirB / D 4 T 4 SS expression whereas dksA , rpoH1 or batR deletion fully abolishes its activity. In contrast to their activating effect on the VirB / D 4 T 4 SS , which is critical at the early stage of host infection, SpoT and DksA negatively regulate the Trw T 4 SS , which mediates host‐specific erythrocyte infection at a later stage of the colonization process. Our findings support a model where the SR signalling and the physiological pH ‐induced BatR / BatS TCS conjointly control the spatiotemporal expression of B . henselae adaptation factors during host infection.