Research

All living cells are dependent on functional biological membranes for their survival. Cell membranes are essential structural elements in all kingdoms of life. The cell membrane separates the extracellular environment from the intracellular space, where biochemical processes important for cellular life occur. The eukaryotic cell membrane is a highly dynamic barrier between the cell and its surroundings, responsible for a variety of biological functions, including molecular transport and activation of intracellular signaling cascades important to cell proliferation.

Lipids in the cell membrane are of particular importance as they have a critical role in membrane microdomain architecture and membrane trafficking. These properties make lipids an appealing target for bacterial pathogens attempting to modulate host cell activities to survive and thrive. Several lines of evidence suggest that lipids have a crucial role in different phases of host–pathogen interactions. Microbial proteins, including bacterial toxins and viral components such as the SARS-CoV-2 spike protein, bind to the host cell membrane and introduce lipid membrane perturbations that contribute to the severity of the infection process.

Pore-forming protein toxins (PFTs) secreted by a wide range of bacterial pathogens represent a special class of membrane-damaging proteins. They exert their cytolytic effects by punching 'holes' into the target cell membrane, thus destroying the cell membrane. This process causes lysis, and killing of the target cell. PFTs are mainly synthesized as water-soluble monomeric molecules, and in contact with target cell membranes, they undergo conformational change and form membrane-inserted oligomeric pores. Interestingly, we recently discovered a previously unknown phenomenon of cell membrane tubulation by an α-PFT MakA (motility-associated killing factor A), secreted by Vibrio cholerae (Fig. 1).

In my lab, we aim to better understand the molecular mechanisms through which microbial proteins affect lipid membranes.

Specific aims:

1) To investigate the mechanisms involved in the tubulation of lipid membranes by α-PFTs.

2) Mechanism(s) associated with the cellular responses triggered by α-PFTs.

3) To understand the role of microbial protein-lipid interactions in host cell pathogenesis.

4) Biotechnological applications of bacterial α-PFTs.