A cellular defence mechanism intended to repair damage may inadvertently help a pneumonia-causing bacterium spread its deadly toxin to adjacent cells, according to the findings of a new study by scientists at RGCB here.
The study, published in the prestigious Journal of Extracellular Vesicles, has uncovered an unexpected route by which pneumolysin, a major toxin produced by ‘Streptococcus pneumoniae’ that causes pneumonia and other serious infections, can move from one cell to another.
The researchers found that when cells attempt to repair damage caused by the toxin, they shed tiny membrane-bound vesicles that remain loaded with biologically active pneumolysin and can pass that toxin to other cells, a Rajiv Gandhi Centre for Biotechnology (RGCB) release said.
The finding reveals a previously overlooked link between the host cell’s membrane-repair machinery and bacterial virulence, suggesting that a process designed to protect cells can, under certain circumstances, unwittingly extend toxin-mediated damage.
Pneumolysin is a pore-forming toxin that damages host cells by binding to cholesterol in their membranes and creating destructive pores. At sub-lethal levels, cells respond by removing damaged portions of their plasma membrane through the release of extracellular vesicles.
The RGCB team found that pneumolysin is enriched in plasma membrane-derived microvesicles.
Rather than being discarded as cellular waste, the toxin remains attached to the vesicle membrane and retains its biological activity.
When the vesicles subsequently interact with neighbouring cells, they provide an additional route for toxin activity, leading to further membrane damage.
“Molecular simulations carried out in collaboration with Dr Jagannath Mondal and colleagues at TIFR Hyderabad revealed a previously unrecognised mechanism in which an exposed region of vesicle-bound pneumolysin directly engages lipids in a recipient membrane.
“This interaction causes membrane bending and thinning and promotes water penetration into the membrane. When key amino acids involved in the interaction were altered, membrane deformation was substantially reduced, supporting a mechanism of membrane engagement that goes beyond the toxin’s conventional pore-forming activity,” the release said.
The researchers also demonstrated the phenomenon using human cells.
Cryogenic electron microscopy (Cryo-EM) analysis in collaboration with Dr Somnath Dutta and colleagues at IISc Bengaluru revealed the localisation of pneumolysin at the sites of membrane interaction, the release said.
Senior researcher Dr Karthik Subramanian said the study highlights that a process meant to protect the cell can effectively repackage pneumolysin into a new membrane-active form.
“These toxin-bearing microvesicles do more than carry the toxin — they help it engage neighbouring cells and extend damage beyond the cell that was initially attacked,” he explained.
The findings can have implications for understanding how pneumococcal infections cause tissue damage, the release said.
(PTI)
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