Engineered vesicles protect brain from bacterial toxin

Bacterial meningitis can cause severe brain damage even when patients receive antibiotic treatment promptly. Researchers at Karolinska Institutet have developed tiny biological vesicles that, in animal studies, were able to capture bacterial toxins, protect neurons, reduce inflammation and delay disease progression. The findings are published in the journal Journal of Extracellular Vesicles.

Pneumococcal meningitis is a life-threatening infectious disease of the central nervous system caused by the bacterium Streptococcus pneumoniae. Despite treatment with antibiotics and anti-inflammatory drugs, around one in three patients are left with long-term neurological complications. According to the researchers, one reason is that antibiotics may take time to reach the brain and do not neutralize pneumolysin, a toxin released by the bacteria that contributes to neuronal damage and inflammation.

In the new study, researchers investigated whether extracellular vesicles, small membrane-bound particles naturally produced by cells, could be used to protect the brain during infection. The vesicles were engineered in different ways, including a version designed to target neurons more efficiently and suppress severe neuroinflammation. They were then tested in laboratory-grown neuronal and brain immune cells, as well as in a preclinical meningitis mouse model.

Extracellular vesicles acting as decoys

The experiments showed that all types of vesicles could bind to and sequester pneumolysin before it damaged neurons. They also reduced the ability of the bacteria to attach to neurons and lowered harmful inflammatory signals in both cell-based experiments and in vivo.

When given through the bloodstream, the vesicles were able to reach the brain in infected mice. Treatment delayed the onset of severe disease and increased survival compared with untreated animals.

The vesicle variant engineered with RVG peptides, which help target neurons in the nervous system, and an IL6-decoy designed to selectively inhibit IL-6 trans-signaling had the strongest neuroprotective and anti-inflammatory effects in both the brain and the rest of the body.

“Our results suggest that the extracellular vesicles act as decoys, capturing pneumolysin before the toxin can reach and damage neurons. Importantly, the same biomaterial also acts as a suppressor of severe and harmful inflammation,” says associate professor Federico Iovino, group leader at the Department of Neuroscience at Karolinska Institutet and last author of the study.

Further studies required

The treatment has not yet been tested together with antibiotics, which are the standard treatment for patients. The researchers therefore stress that further studies are needed before the method can be evaluated in humans.

“We hope that extracellular vesicles could eventually become a complement to current treatments for pneumococcal meningitis, but more research is required before any clinical application can be considered, and this is what my lab is currently working on,” says Iovino.

“These results were possible thanks to the strong collaboration my lab established with the research groups of assistant professor Oscar Wiklander and professor Samir El Andaloussi at the Department of Laboratory Medicine, Karolinska Institutet,” he continues.

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