Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially infected epithelial cells.

Intracellular pathogens alter their host cells' mechanics to promote dissemination through tissues. Conversely, host cells may respond to the presence of pathogens by altering their mechanics to limit infection. Here, we monitored epithelial cell monolayers infected with intracellular bacterial pathogens, Listeria monocytogenes or Rickettsia parkeri, over days. Under conditions in which these pathogens trigger innate immune signaling through NF-κB and use actin-based motility to spread non-lytically intercellularly, we found that infected cell domains formed three-dimensional mounds. These mounds resulted from uninfected cells moving toward the infection site, collectively squeezing the softer and less contractile infected cells upward and ejecting them from the monolayer. Bacteria in mounds were less able to spread laterally in the monolayer, limiting the growth of the infection focus, while extruded infected cells underwent cell death. Thus, the coordinated forceful action of uninfected cells actively eliminates large domains of infected cells, consistent with this collective cell response representing an innate immunity-driven process.

Cell biophysical stimuli in lobopodium formation: a computer based approach.

Different cell migration modes have been identified in 3D environments, e.g., modes incorporating lamellopodia or blebs. Recently, a new type of cellular migration has been investigated: lobopodia-based migration, which appears only in three-dimensional matrices under certain conditions. The cell creates a protrusion through which the nucleus slips, dividing the cell into two parts (front and rear) with different hydrostatic pressures. In this work, we elucidate the mechanical conditions that favour this type of migration.One of the hypotheses about this type of migration is that it depends on the mechanical properties of the extracellular matrix. That is, lobopodia-based migration is dependent on whether the extracellular matrix is linearly elastic or non-linearly elastic.To determine whether the mechanical properties of the extracellular matrix are crucial in the choice of cell migration mode and which mechanotransduction mechanism the cell might use, we develop a finite element model. From our simulations, we identify two different possible mechanotransduction mechanisms that could regulate the cell to switch from a lobopodial to a lamellipodial migration mode. The first relies on a differential pressure increase inside the cytoplasm while the cell contracts, and the second relies on a change in the fluid flow direction in non-linearly elastic extracellular matrices but not in linearly elastic matrices. The biphasic nature of the cell has been determined to mediate this mechanism and the different behaviours of cells in linearly elastic and non-linearly elastic matrices.

The role of nuclear mechanics in cell deformation under creeping flows.

Despite the relevant regulatory role that nuclear deformation plays in cell behaviour, a thorough understanding of how fluid flow modulates the deformation of the cell nucleus in non-confined environments is lacking. In this work, we investigated the dynamics of cell deformation under different creeping flows as a general simulation tool for predicting nuclear stresses and strains. Using this solid-fluid modelling interaction framework, we assessed the stress and strain levels that the cell nucleus experiences as a function of different microenvironmental conditions, such as physical constraints, fluid flows, cytosol properties, and nucleus properties and size. Therefore, the simulation methodology proposed here allows the design of deformability-based experiments involving fluid flow, such as real-time deformability cytometry and dynamic cell culture in bioreactors or microfluidic devices.