Mechanotransduction in bacteria: how mechanical forces trigger virulence in Pseudomonas aeruginosa

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Pseudomonas aeruginosa (PA) is a bacterial pathogen that infects a wide variety of host animals including humans. PA is a significant public health concern as a leading cause of hospital acquired infections, burn-wound infections, and cystic fibrosis pathology. PA exhibits high tolerance for many commonly-used antibiotics, raising a clear need for a better understanding of PA virulence regulation. Historically, the field has focused on PAs response to chemical cues such as nutrients or signaling molecules. However, it has recently been demonstrated that PA also regulates virulence in response to mechanical cues in its environment and that the ability to respond to mechanical forces may underlie PAs ability to target a broad range of hosts. The expression of virulence factors is induced by the retraction of pili through the Chp system which resembles the flagellar chemotaxis system. However, there is nothing known about how mechanical forces from retraction are transmitted to this system. With the present proposal, I would like to fill this void and determine the physical mechanism of this mechanotransduction pathway, i.e., how PA senses mechanical forces and translates them to a change in gene expression.In the first step, I will extend an existing combined optical-trapping and fluorescence microscope to several position- and force-feedback modalities. In the second step, I will apply controlled optical forces on single pili over the course of an hour, while monitoring virulence factors as a function of retraction force using fluorescence. In a third step, I will use PA deletion mutants to determine if motor driven retraction or tension within the pilus triggers virulence by activating the Chp system.The information gained by these studies will substantially further our understanding of PA as an opportunistic pathogen and of how PA senses solid surfaces as a way of identifying hosts.