PROJECT SUMMARY Environmental sensing is at the basis of an organism’s ability to adapt its physiology to respond to changes in its niche. Over the past years, it has emerged that bacteria not only perceive and respond to chemical stimuli, but are capable of sensing and processing physical forces as an environmental cue. In the case of bacterial pathogens, we and others have shown that mechanical stimuli can act as a hallmark of host colonization and lead to activation of virulence genes. Despite this realisation, our mechanistic understanding of pathways and systems involved in mechanosensing, transduction and processing of physical forces is currently limited, as is our knowledge regarding the role of mechanoregulation within the host environment. The objective here is to understand how enterohemorrhagic E. coli, an important human pathogen, responds to physical force. In the human host, ingestion of EHEC can lead to enterocolitis and severe complications such as haemolytic uremic syndrome. These hallmarks of infection are caused by the concerted action of virulence factors, including colonization factors and Shiga-like toxins. Here, we will (a) characterize how virulence gene induction responds to physical forces, (b) determine the biochemical basis of signal transduction between membrane and transcriptional regulator, and (c) define the role of mechanosensing during the transitions between environmental and host-associated lifestyles. This work will reveal how EHEC perceive and process physical forces, and integrate these cues to coordinate their infection cycle. Such knowledge may highlight new targets for the development of anti-infective strategies that disable the pathogen by rendering it ‘numb’ to the host.