Meningitis is a life-threatening form of infection in the brain that is difficult to treat. How infection spreads from the blood to cause meningitis is not well understood. Now, researchers from the University of Sheffield report their new study in zebrafish gives a better understanding of how meningitis spreads. Their findings reveal that Cryptococcus neoformans microbes aid meningitis spread from the blood by blocking and bursting blood vessels. Their study may pave the way for understanding other blood vessel-related diseases.

Their findings are published in the journal PLoS Pathogens, in a paper titled, “Blood vessel occlusion by Cryptococcus neoformans is a mechanism for hemorrhagic dissemination of infection.”

“Meningitis caused by infectious pathogens is associated with vessel damage and infarct formation, however, the physiological cause is often unknown,” the researchers wrote. “Cryptococcus neoformans is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of patients, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model that permitted noninvasive in vivo imaging.”

“The brain has very complex and effective defenses against microbes, but we have identified a simple and effective method that microbes may use to escape the blood and enter the brain,” explained Simon Johnston, PhD, senior research fellow in the department of infection, immunity, and cardiovascular disease at the University of Sheffield.

“Previous research has focused on how microbes can break down the defenses of the brain or use immune cells as a route into the brain. We can demonstrate how, for some microbes, damaging blood vessels is a very effective method of invasion.

“Our immune system is very effective at recognizing and destroying microbes, including in the blood. However, some microbes can escape the immune cells and it is these microbes that would be most effective at using blood vessels bursting as a way into the brain.”

The research was carried out in collaboration with the Agency of Science, Technology, and Research (A-Star), Singapore, and the University of Queensland, Australia.

The research team investigated zebrafish larvae to understand how the meningitis infection behaves in blood vessels. The researchers found that the fungal cells become stuck within blood vessels depending on their size. The cells grew within the blood vessels, suggesting that with the blockage and widening of vessels, there was increased local blood pressure. They found that vessel blockage was associated with their rupture and spreading of fungus into the surrounding tissue.

“We started this research because we knew there was unexplained blood vessel damage in some meningitis patients,” added Johnston. “We are now working to find new treatments for these patients.”

The infections causing meningitis can be treated with antimicrobials but patients are often very ill and a lot of damage can be caused before treatment is effective. This will be made worse by the ongoing global increase in antimicrobial-resistant infections.

The researchers found that their data suggest that global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. “Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction during cryptococcal meningitis,” noted the researchers.

“We are using the knowledge we have gained from studying how meningitis can spread to understand how to reduce the damage caused to the brain while treatment takes place,” concluded Johnston.


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