Mechanical Forces Govern Interactions of Host Cells with Intracellular Bacterial Pathogens

Bastounis, Effie; Radhakrishnan, Prathima; Prinz, Christopher K.; Theriot, Julie A.

doi:10.1128/mmbr.00094-20

Cited by 10 publications

(5 citation statements)

References 272 publications

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“…These indicated that specific binding of the bacterial collagen adhesin to collagen IV might be a key factor leading to the formation of spatially heterogeneous bacteria-cell adhesion. With the Kyoto Encyclopedia of Genes and Genomes (KEGG) results from the scRNA-seq, we further checked the focal adhesion pathway and its associated genes (e.g., vinculin) that were normally closely related to cellular traction forces, ECM stiffness and even bacterial infection 15 , 26 , 50 (Supplementary Fig. 5b ).…”

Section: Resultsmentioning

confidence: 99%

“…For example, the virulence factor Sca4 secreted by Rickettsia parkeri specifically binds to vinculin to reduce intercellular tension, allowing bacteria to spread more easily by manipulating cytoskeletal forces 25 . In contrast, collective responses of epithelial monolayers to bacterial invasion can trigger the extrusion of infected cells to limit local spread of infection 23 , 26 . Furthermore, gasdermin- d (GSDMD) pore-forming protein mediates the efflux of secretory vesicles from intestinal goblet cells in a nonpyroptotic manner to resist the invasion of pathogenic microorganisms, playing an important physiological role in intestinal barrier homeostasis 27 .…”

Section: Introductionmentioning

confidence: 99%

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Geometric constraint-triggered collagen expression mediates bacterial-host adhesion

Feng,

Wang,

Liu

et al. 2023

Nat Commun

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Cells living in geometrically confined microenvironments are ubiquitous in various physiological processes, e.g., wound closure. However, it remains unclear whether and how spatially geometric constraints on host cells regulate bacteria-host interactions. Here, we reveal that interactions between bacteria and spatially constrained cell monolayers exhibit strong spatial heterogeneity, and that bacteria tend to adhere to these cells near the outer edges of confined monolayers. The bacterial adhesion force near the edges of the micropatterned monolayers is up to 75 nN, which is ~3 times higher than that at the centers, depending on the underlying substrate rigidities. Single-cell RNA sequencing experiments indicate that spatially heterogeneous expression of collagen IV with significant edge effects is responsible for the location-dependent bacterial adhesion. Finally, we show that collagen IV inhibitors can potentially be utilized as adjuvants to reduce bacterial adhesion and thus markedly enhance the efficacy of antibiotics, as demonstrated in animal experiments.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Geometric constraint-triggered collagen expression mediates bacterial-host adhesion

Feng,

Wang,

Liu

et al. 2023

Nat Commun

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“…Finally, to estimate changes in inter- and intra-cellular stresses here we used MSM. 18 , 25 MSM though represents an indirect way of measuring cell monolayer tension, similar to other indirect ways such as laser ablation 26 and relies on several simplifications in terms of boundary conditions, mechanical properties, and the dimensionality of the system. 17 , 18 2D MSM assumes that the intra- and inter- cellular stress components along the normal direction to the plane of the monolayer are negligible, and moreover, MSM considers perfect cell-cell and cell-ECM adhesions.…”

Section: Limitationsmentioning

confidence: 99%

Spatiotemporal characterization of endothelial cell motility and physical forces during exposure to Borrelia burgdorferi

Muenkel¹,

Aparicio-Yuste²,

Tal³

et al. 2022

STAR Protocols

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“…Interestingly, this competition that leads to infected cell elimination is mechanical in nature, and depends on: 1) a decrease in contractility (i.e., traction stresses exerted by the cells on their matrix) of infected as opposed to uninfected neighbors; 2) a lowering in the passive stiffness of infected as opposed to uninfected neighbors, and 3) the presence of cell-cell adhesions since lack of those completely stalls mound formation. Thus, it appears that cell-matrix and cell-cell force transduction as well as cellular stiffness are crucial determinants in driving the mechanical competition that emerges during infection ( Bastounis et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

A Stiff Extracellular Matrix Favors the Mechanical Cell Competition that Leads to Extrusion of Bacterially-Infected Epithelial Cells

Aparicio-Yuste

Muenkel

Clark

et al. 2022

Front. Cell Dev. Biol.

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Cell competition refers to the mechanism whereby less fit cells (“losers”) are sensed and eliminated by more fit neighboring cells (“winners”) and arises during many processes including intracellular bacterial infection. Extracellular matrix (ECM) stiffness can regulate important cellular functions, such as motility, by modulating the physical forces that cells transduce and could thus modulate the output of cellular competitions. Herein, we employ a computational model to investigate the previously overlooked role of ECM stiffness in modulating the forceful extrusion of infected “loser” cells by uninfected “winner” cells. We find that increasing ECM stiffness promotes the collective squeezing and subsequent extrusion of infected cells due to differential cell displacements and cellular force generation. Moreover, we discover that an increase in the ratio of uninfected to infected cell stiffness as well as a smaller infection focus size, independently promote squeezing of infected cells, and this phenomenon is more prominent on stiffer compared to softer matrices. Our experimental findings validate the computational predictions by demonstrating increased collective cell extrusion on stiff matrices and glass as opposed to softer matrices, which is associated with decreased bacterial spread in the basal cell monolayer in vitro. Collectively, our results suggest that ECM stiffness plays a major role in modulating the competition between infected and uninfected cells, with stiffer matrices promoting this battle through differential modulation of cell mechanics between the two cell populations.

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Mechanical Forces Govern Interactions of Host Cells with Intracellular Bacterial Pathogens

Abstract: To combat infectious diseases, it is important to understand how host cells interact with bacterial pathogens. Signals conveyed from pathogen to host, and vice versa, may be either chemical or mechanical.

Cited by 10 publications

References 272 publications

Geometric constraint-triggered collagen expression mediates bacterial-host adhesion

Geometric constraint-triggered collagen expression mediates bacterial-host adhesion

Spatiotemporal characterization of endothelial cell motility and physical forces during exposure to Borrelia burgdorferi

A Stiff Extracellular Matrix Favors the Mechanical Cell Competition that Leads to Extrusion of Bacterially-Infected Epithelial Cells

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