Keynote Speaker: Andrea Puhar

PIEZO1 acts as an immune sensor for invasive infection

Tight regulation of the immune response is crucial to establish protective immunity against pathogens, while tolerating commensals and avoiding autoimmunity. The detection of microbes is the first step of the immune response to infection. Incoming microorganisms are generally sensed by Pattern Recognition Receptors (PRRs) binding characteristic microbial molecules, which evokes anti-microbial defences through changes in cellular activities and gene expression. Intestinal epithelial cells (IECs) are a barrier to gut microbes and important immune sentinels. Several Gram-negative intestinal pathogens induce secretion of the pro-inflammatory danger signal ATP as a rapid alert response of IECs, resulting in overt intestinal inflammation. However, what triggers ATP secretion during infection is unknown. We show that the formation of plasma membrane ruffles accompanying the invasion of Gram-negative or Gram-positive bacteria is a physical immune signal of infection, which is detected by the mechanosensor PIEZO1. PIEZO1 activation is necessary and sufficient to trigger mechanically-induced ATP secretion via Ca²⁺ influx and also reprogrammes inflammatory gene expression in IECs. Thus, mechanosensation of invasion-induced plasma membrane distortion initiates immune signaling upon infection, independently of detection of microbial molecules. Given that formation of plasma membrane ruffles is a characteristic and unifying feature of invasive bacteria, our results indicate that, unlike PRRs which are driven by ligand binding, PIEZO1 acts as a mechanically driven immune sensor for invasive infection.