Disease-causing pathogens are known dangerous enemies and have developed many tricks to thwart the body’s immune system. Among the most terrifying things are those that can infiltrate the nervous system, even infecting the brain.
Now, a new study by researchers in the UK, Australia and Singapore has unearthed a time series of devastation in lab-grown zebrafish, showing how the fungus that causes a rare type of meningitis spreads from the bloodstream to the brain.
As if the pressure between tightly stacked cells in the blood-brain barrier or the ride inside the brain-associated immune cells (like many other pathogens) weren’t enough, it seems that one of the microbes that causes meningitis is called a Modern Undercover He has another trick in the bag: blocking and bursting the tiny blood vessels in the zebrafish’s brain.
“The brain has very complex and effective defenses against microbes,” says senior author Simon Johnston, an infectious disease researcher at the University of Sheffield, UK.
“But we have identified a simple and effective method that microbes may use to escape from the blood and enter the brain.”
Meningitis is a life-threatening disease caused by bacterial or fungal infections of the brain and spinal cord that leads to swelling and inflammation of the meninges, the protective membrane that blocks the central nervous system.
Meningitis can be fatal if not recognized and treated quickly; A problem exacerbated by the growing threat of antimicrobial resistance, which is now the third leading cause of death worldwide.
Organ transplant recipients, people with HIV/AIDS, and other people with weakened immune systems are most likely to contract fungal meningitis, which does not spread directly between people and can only be caught from the environment.
While there can be many microscopic causes of meningitis, many of which are found in soil infested with insects, C. neoformans It causes fungal meningitis, a rare form of the disease that can be prevented by vaccination. The pathogen is known to damage blood vessels, but exactly how has remained unclear.
“We started this research because we learned of unexplained blood vessel damage in some meningitis patients,” says Johnston, who in his previous work revealed how C. neoformans It treats immune cells.
In this study, Johnston and colleagues used fast-growing zebrafish that can be seen by watching how this happens C. neoformans It behaves in the purple-stained blood vessels in the image below. The C. neoformans Fungal spores are shown in fluorescent yellow.
Using high-resolution imaging techniques and live cells, the researchers visualized the fluorescently-tagged blood-borne fungal invaders over several days. Microbes settled in the blood vessels, which limits blood flow and blocks the blood supply. As the infectious microbes multiply, blood vessels dilate and rupture, and are spurred out C. neoformans in zebrafish brain tissue.
even one C. neoformans Cells can become trapped in small blood vessels, seeding fungal masses that clog blood vessels; These looked frighteningly similar to the fungal or bacterial masses found next to capillaries in the brain in postmortem reports of people who died of the disease.
In zebrafish, the obstruction not only increased local blood pressure but also increased blood flow, and the innate obstruction increased the tension of nearby blood vessel walls, making them more susceptible to rupture.
“Previous research has focused on how microbes break down the brain’s defenses or use immune cells as a pathway into the brain,” Johnston says. “We can show how damaging the blood vessels, for some microbes, is a very effective method of invasion.”
Moreover – and this is the most insightful – the team also found that C. neoformans Lumps accumulated on average two days before a blood vessel burst, a narrow window in which doctors may intervene to stop an infection before damage occurs.
“Infections causing meningitis can be treated with antimicrobials, but patients are often very sick and a lot of damage can be done before treatment is effective,” Johnston says.
Hopefully, understanding how fungal meningitis spreads in the brain will lead to new treatments that help limit damage to the brain’s blood vessels while antifungal treatments clear up the infection.
Any of these treatments are just a dream at this point, as imaging experiments have been conducted on very young zebrafish.
However, Johnston and colleagues believe that their findings may be relevant to other types of infections that damage or rupture blood vessels, although they note that these mechanisms may differ between microbial species.
The study was published in Pathogens PLOS.