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Preferential invasion of mitotic cells by Salmonella reveals that cell surface cholesterol is maximal during metaphase

Significance Statement

Salmonellac auses typhoid fever (a disease mostly present in developing countries) and is the culprit behind most cases of gastroenteritis.  This bacteriumuses a molecular needle to inject very active proteins into human cells, thereby forcing them to absorb the bacteria. To attach itself to a targeted cell, the molecular needle relies on cholesterol present at the surface of the cell.

The study – a collaboration between University College London and Imperial College – reveals that human cells are about 100 times more sensitive to Salmonella infection when they are dividing than at any other time in their life cycle. “We were absolutely astonished when we saw the pictures for the first time”, said Dr Boucrot; “we had rare dividing cells (~1% of the cell population in the study) packed with bacteria just next to non-dividing ones with just one or no bacterium at all”.

As this targeting of dividing cells was dependent on cholesterol, this prompted the authors to measure the levels of cell surface cholesterol along the entire life cycle of human cells. Consistently, they found that dividing cells had much more cholesterol at their surface. “This has profound implications”, said Dr Boucrot;“there are many other life-threatening bacteria as well as viruses (including the AIDS causative virus HIV-1) that rely on cell surface cholesterol to infect human cells. Cells might be more sensitive to infection by allof these pathogenswhile they are dividing.”

“This increase of cell surface cholesterol during cell division might also have some role in cholesterol homeostasisand thus cardiovascular diseases” added Dr Boucrot; “this phenomenon might make dividing cells more sensitive to lipoproteins such as HDL (the so-called ‘good cholesterol’) that extract cell surface cholesterol. This would be a fascinating future direction for this line of research”.

 

Preferential invasion of mitotic cells by Salmonella reveals that cell surface cholesterol is maximal during metaphase- Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

Journal Reference

Santos AJ, Meinecke M, Fessler MB, Holden DW, Boucrot E.

J Cell Sci. 2013 ;126(Pt 14):2990-6.

Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.

 Abstract

 Cell surface-exposed cholesterol is crucial for cell attachment and invasion of many viruses and bacteria, including the bacterium  Salmonella, which causes typhoid fever and gastroenteritis. Using flow cytometry and 3D confocal fluorescence microscopy, we found that mitotic cells, although representing only 1-4% of an exponentially growing population, were much more efficiently targeted for invasion by Salmonella. This targeting was not dependent on the spherical shape of mitotic cells, but was instead SipB and cholesterol  dependent. Thus, we measured the levels of plasma membrane and cell surface cholesterol throughout the cell cycle using, respectively, brief staining with filipin and a fluorescent ester of polyethylene glycol-cholesterol that cannot flip through the plasma membrane, and found that both were maximal during mitosis. This increase was due not only to the rise in global cell cholesterol levels along the cell cycle but also to a transient loss in cholesterol asymmetry at the plasma membrane during mitosis. We measured that cholesterol, but not phosphatidylserine, changed from a ∼2080 outerinner leaflet repartition during interphase to ∼5050 during metaphase, suggesting this was specific to cholesterol and not due to a broad change of lipid asymmetry during metaphase. This explains the increase in outer surface levels that make dividing cells more susceptible to Salmonella invasion and perhaps to other viruses and bacteria enteringcells in a cholesterol-dependent manner. The change in cholesterol partitioning also favoured the recruitment of activated ERM (Ezrin, Radixin, Moesin) proteins at the plasma membrane and thus supported mitotic cell rounding.

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