Periodic Reporting for period 2 - BacForce (Quantifying minute forces: How mechanoregulation determines the behavior of pathogenic bacteria)
Reporting period: 2022-02-01 to 2023-07-31
A central challenge of modern-day biology is to understand how cells control their mechanical behavior to develop multicellular life and also the pertaining diseases. For example, many bacterial pathogens can generate mechanical forces that are important for the colonization of surfaces, formation of antibiotic-resistant biofilms, and infection of host cells. BacForce addresses the fundamental question of how bacteria can control their force generation to robustly colonize complex surfaces. The objectives are to (A) gain access to nanoscopic mechanical phenomena through the development of cutting-edge microscopy, (B) employ the methods to characterize how the human pathogen Pseudomonas aeruginosa controls pilusgenerated forces, and (C) establish how surface properties affects force generation by P. aeruginosa during biofilm formation. In an interdisciplinary approach, BacForce will combine mechanical measurements with genetic perturbations, molecule labeling, and computer simulations to produce functional models of the mechanocontrol strategies. Through these advances, behavioral strategies will be uncovered that are paradigmatic for diverse Gram-negative pathogens. Broadly, such pathogen behaviors have a generic, minimal nature and can appear as basic motives in different organisms throughout nature.
During the first reporting period, BacForce focused on understanding the molecular machinery that drives the migration of the Gram-negative human pathogen Pseudomonas aeruginosa. Employing fluorescent labeling of the molecular driving machinery, a comprehensive numerical model of motility individual bacteria was constructed that fully predicts experimental data. This development led to the discovery of a behavioral strategy that this bacterium uses to optimize its ability to colonize surfaces.
To further understand the biophysical principles behind formation of antibiotic-resistant cell colonies, a comprehensive simulation framework for modeling the microscopic behavior of thousands of bacteria was developed. This simulation framework, together with experiments based on high-resolution microscopy and pharmacological inhibition, revealed how bacterial pathogens tune the mechanical properties of their colonies to invade host organisms.
To further understand the biophysical principles behind formation of antibiotic-resistant cell colonies, a comprehensive simulation framework for modeling the microscopic behavior of thousands of bacteria was developed. This simulation framework, together with experiments based on high-resolution microscopy and pharmacological inhibition, revealed how bacterial pathogens tune the mechanical properties of their colonies to invade host organisms.
The project BacForce uniquely combines sophisticated numerical modeling with beyond state-of-the-art microscopy methods for discovering the behavior of bacterial pathogens. The project has already produced a significant number of scientific discoveries regarding foundational micromechanics of cells and bacteria. Furthermore, new simulation tools, machine-learning procedures, and experimental approaches were developed and will find application in basic science beyond this project. In BacForce, the coming years will see a continuation of the effort to understand the fundamental micromechanics of bacterial infection.