Shigella flexneri Disruption of Cellular Tension Promotes Intercellular Spread
This week we profile a recent publication in Cell Reports from the laboratory of Dr. Marcia
Goldberg (pictured, front row, fourth from left) at Massachusetts General Hospital.
Can you provide a brief overview of your lab’s current research focus?
The Goldberg laboratory studies at the molecular level how infectious pathogens interact with and manipulate human hosts. Pathogenic microbes have evolved complex mechanisms to subvert host cell signaling pathways to enhance disease processes. We investigate the molecular mechanisms by which microbial factors modulate host proteins to divert host signaling pathways involved in pathogen restriction and pathogen killing. We are interested not only in the underlying microbial and cell biology, but also the immune response, both at the cellular level and at the systems level. Currently, our work focuses on enteric gram-negative bacteria and COVID-19.
What is the significance of the findings in this publication?
The findings in this publication demonstrate that the gram-negative intracellular bacterial pathogen Shigella flexneri, which is the most common cause of diarrhea and dysentery worldwide, remodels the host cell cytoskeleton during infection. Key to the S. flexneri infectious process is the ability of the bacterium to spread from one infected host cell into adjacent host cells. In this paper, we show that to enable spread between cells, the S. flexneri protein IpaC decreases the tension of the cell’s membrane by disrupting the cellular cortical cytoskeleton, which lies just under the cell’s membrane and is responsible for anchoring the cell against adjacent cells within tissue. These findings are significant because they show that Shigella manipulates the biophysical properties of cells in ways that promote infection.
What are the next steps for this research?
The next steps for this research are to elucidate at the molecular level how IpaC decreases the tension of the cell membrane. Whereas we showed in the current paper that the IpaC protein interacts with the cortical cytoskeletal protein beta-catenin and that this interaction is required for decreasing membrane tension, we now will investigate how this interaction causes decreased membrane tension. These studies will elucidate both how the pathogen alters the host cortical cytoskeleton and more broadly how cortical cytoskeletal factors maintain membrane tension.
This work was funded by:
- American Lung Association
- Massachusetts General Hospital Executive Committee on Research
- Harvard Medical School
- Ellison Foundation
- Kenneth Rainin Foundation