Typhoid fever is an infection caused by a bacteria called Salmonella enterica typhi which, according to the CDC, affects about 22 million people every year. Many of those affected by the disease come from developing countries where there is poor sanitation and a lack of access to clean water.
Symptoms of typhoid fever include headaches, stomach pain, and high fever. On rare occasions, these infections can affect the brain resulting in serious neurological symptoms such as slurred speech and lack of muscle control. Treatment success rates are still poor in these cases. Worryingly, even when the initial infection is cleared, doctors have seen cases of relapses with survivors suffering from various mental disorders including cerebral palsy and even mental retardation.
Despite the severity of the disease, scientists are still unsure of how exactly Salmonella causes these neurological symptoms. Many previous studies involving the bacteria have focused on how it spreads in the bloodstream rather than how it affects the brain.
In this study, a team of Indian scientists sought to better understand how Salmonella causes these brain infections using laboratory mice. The team also wanted to know whether treatment with antibiotics could help alleviate some of these neurological impairments.
The team first wanted to determine whether Salmonella could enter the brain and how it could do so. Entering into the brain is not an easy task, be it in mice or humans. Most of the brain is protected by a wall of cells called the blood brain barrier that normally prevents the movement of bacteria and many other molecules into the brain tissue. When the team harvested the brains of mice infected with Salmonella, they found the bacteria growing in various parts of the brains. This finding strongly suggests that the bacteria was able to bypass the blood-brain barrier. The researchers also found that Salmonella produces specific proteins to ‘trick’ the cells on the blood-brain barrier to allow this crossing to take place. Further genetic experiments revealed that specific Salmonella proteins (OmpA and SPI-1) seem to play a role in this “breaking and entering”. The team thinks that some of these bacterial proteins could be binding to host proteins present on the barrier and “convincing” the cells on the barrier to allow it safe passage across.
When the researchers looked at the brains of the infected mice, they also noticed that the surrounding tissue of some of the midbrains showed signs of inflammation. Inflammation can damage brain cells, which might explain the neurological symptoms seen in human infections. This finding would have to be verified in human tissue. To see if Salmonella also affected brain function in mice, the researchers conducted water-maze tests by measuring how long it takes for healthy and infected mice to swim through the maze to a platform. Indeed, infected mice took considerably longer to swim to the platform or did not reach the platform at all. This finding strongly suggests that tissue damage from Salmonella infections likely contributes to a decline in brain function.
The scientists then wondered whether antibiotic treatment could help treat the neurological symptoms associated with Salmonella infection. After infecting mice with Salmonella, the researchers administered an antibiotic which would kill the bacteria and then observed whether the performance of the mice in the water-maze challenge was improved. Surprisingly, they found that antibiotic treatment could not completely clear the infections. Some mice were still unable to swim to the platform. Even in the mice that showed improvement in swimming time, the researchers still found traces of bacteria in their brains. The team suspects that the residual bacteria in the brain may explain why humans who have been “cured” from typhoid fever sometimes relapse.
The findings in this study have shed new light on how Salmonella enterica typhi infects the brain and causes a decline in brain function. The worrying observation that traces of bacteria are still present in the brain even after antibiotic treatment suggests that the brain might be acting as a reservoir for future re-infections. If confirmed in humans, these observations will be a big step towards finding better treatment for this devastating infection.