Scientists at the BRIC–Rajiv Gandhi Centre for Biotechnology (RGCB) have uncovered a previously unknown mechanism that may help a pneumonia-causing bacterium spread its toxin between neighbouring cells. The discovery reveals how a cellular defence mechanism designed to repair damage can inadvertently extend the harmful effects of a bacterial toxin. Published in the Journal of Extracellular Vesicles, the study identifies an unexpected pathway through which pneumolysin, a major toxin produced by Streptococcus pneumoniae, can move from one cell to another and cause further damage.
How Cells May Help Spread the Toxin
Pneumolysin is a pore-forming toxin that damages host cells by binding to cholesterol in their membranes and creating destructive pores. When exposed to sub-lethal levels of the toxin, cells attempt to protect themselves by removing damaged portions of their plasma membrane. During this repair process, cells release tiny membrane-bound structures called extracellular vesicles. However, the RGCB researchers found that these vesicles can carry biologically active pneumolysin instead of simply disposing of damaged cellular material. Specifically, the toxin becomes concentrated in plasma membrane-derived microvesicles. These toxin-bearing vesicles can then interact with neighbouring cells, creating an additional route for pneumolysin to spread its damaging effects.
Molecular Simulations Reveal a New Mechanism
To understand how the toxin-bearing vesicles damage other cells, the researchers conducted molecular simulations in collaboration with Dr Jagannath Mondal and colleagues at the Tata Institute of Fundamental Research (TIFR), Hyderabad. The simulations revealed a previously unrecognised mechanism in which an exposed region of vesicle-bound pneumolysin directly interacts with lipids in the recipient cell’s membrane. This interaction causes the membrane to bend and thin, while also promoting water penetration into the membrane. Furthermore, when the researchers altered key amino acids involved in this interaction, membrane deformation decreased substantially. These findings suggest that pneumolysin can damage cell membranes through mechanisms beyond its conventional pore-forming activity.
Experiments Confirm Toxin Transfer Between Human Cells
The team subsequently tested the mechanism using human cells. Microvesicles released by monocytes exposed to pneumolysin transferred the toxin to human peripheral blood immune cells, compromised their membrane integrity and increased cell death. In addition, cryo-electron microscopy (cryo-EM) analysis, conducted in collaboration with Dr Somnath Dutta and colleagues at the Indian Institute of Science (IISc), Bengaluru, revealed the localisation of pneumolysin (PLY) at sites of membrane interaction. Together, these experiments provided further evidence that toxin-bearing microvesicles can facilitate membrane damage in neighbouring cells.
Cellular Repair Machinery May Extend Tissue Damage
Senior researcher Dr Karthik Subramanian said the study highlights an unexpected consequence of the host cell’s own repair machinery. He explained that the process intended to protect cells can repackage pneumolysin into a new membrane-active form. Rather than merely transporting the toxin, these microvesicles help it interact with neighbouring cells and extend damage beyond the initially affected cell. Consequently, the findings reveal a previously overlooked connection between the body’s cellular repair mechanisms and bacterial virulence.
Implications for Pneumonia Research
The discovery could improve scientists’ understanding of how pneumococcal infections cause cellular and tissue damage. It also identifies vesicle-mediated toxin transfer as a potential area for future therapeutic research. However, further studies, particularly investigations in living organisms, are necessary to establish how significantly this mechanism contributes to disease progression. As per the press release, researchers must also determine whether blocking toxin transfer through extracellular vesicles could help limit tissue damage and support the development of new treatment strategies.