Effie Efthimia Bastounis: Listeria-infected macrophages promote biomechanical alterations in endothelial monolayers for transmigration

Infectious diseases pose a global health concern, which is further exacerbated by the steady emergence of antibiotic-resistant bacterial strains. A better mechanistic understanding of the processes that drive the onset and progression of infection could inform innovative therapeutic strategies to fight pathogens. Intracellular bacterial pathogens like food-borne Listeria monocytogenes (LM) have developed strategies to manipulate the biomechanics of host cells without disrupting cell integrity, as they rely on it. 

One way LM can achieve systemic dissemination is by being carried within immune cells like macrophages (ΜΦ), which are able to transverse the vasculature and reach distant organs such as the brain, further spreading infection and causing devastating fatalities. How do infected ΜΦ manage to transverse vascular endothelial linings breaching their barrier integrity? Have ΜΦ developed mechanisms to (in)directly manipulate endothelial cells (EC)? We discovered that the biomechanical responses of EC to ΜΦ differ markedly with infection, decisively impacting ΜΦ transmigration through the EC monolayer. 

Using long-term videomicroscopy, we find that MΦ exposure, irrespective of their infection status, increases EC polarization and alignment while reducing EC migration speed. However, only EC exposed to uninfected MΦ increase their traction forces, monolayer stresses, and barrier integrity. These EC biomechanical responses are significantly attenuated during exposure to infected MΦ. 

We show that TNF-α secretion during infection compromises EC barrier integrity and, combined with increased MΦ-EC adhesion, facilitates MΦ transmigration. Using zebrafish, we find that infection increases endothelial permeability, enhancing phagocyte extravasation in vivo. Thus, our findings support a model whereby infection overrides MΦ-induced strengthening of the endothelial barrier, promoting pathogen spread, a remarkable feature that could be harnessed for infection control. 

By continuing this line of research, we hope to shed critical light into the physical and chemical alterations that allow ΜΦ carrying bacteria to breach EC barriers like the blood-brain barrier.

You are cordially invited to attend in person or via Zoom.

Meeting-ID: 681 3924 5622

Kenncode: 244911

If you are interested in meeting her for lunch at 12 PM, please contact 

sabrina.deter@mdc-berlin.de