Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin
We previously published about this research in a story titled “Understanding Neuronal Cell Death in Bacterial Meningitis” which can be found here. The study was originally published in the research journal PloS Pathogens. You can view the full text of the study here.
This research team was associated with the Karolinska Institutet, Karolinska University Hospital along with The Wenner-Gren Institute at Stockholm University.
One of the most dangerous consequences of bacterial meningitis is the potential for neuronal damage. However, the manner in which the pathogenic bacteria interact with these cells in order to trigger cell death has never been fully understood. The goal of this study was to get a better idea of how this process occurs by studying bacterial meningitis triggered by Streptococcus pneumoniae. This species is one of the leading causes of the disease.
Many survivors are left with residual neurological symptoms as a result of neuron damage and death. This study, which began in 2019, was conducted using a bacterial meningitis mouse model and human primary neurons. The researchers found that the cell death mechanism involved β-actin, a cytoskeleton protein. The bacteria interact with this protein through pilus-1 adhesin RrgA and a cytotoxin called pneumolysin (Ply). This promotes the bacteria to adhere to and subsequently invade the neurons, ultimately leading to their death.
The mouse model further demonstrated how pneumococci expressing RrgA and Ply co-localized with β-actin. Ply contributes to the mechanism of adhesion by interacting with the neuronal plasma membrane using cholesterol-binding domain 4. This boosts the exposure of the outer surface of β-actin, therefore allowing RrgA to bind to a greater number of sites.
When infected, the β-actin filaments in neurons were disrupted. This infection promotes neuron death most likely due to an increase in Ca2+ levels intracellularly. This depends on the presence of Ply and disassembly of the actin cytoskeleton. The researchers found that death of the neurons could be inhibited when an antibody that targeted β-actin was introduced.
About Bacterial Meningitis
Bacterial meningitis is a disease in which the protective membranes around the spinal cord and brain, known as the meninges, become inflamed. Because of how close the inflammation is to the spine and brain, meningitis constitutes a medical emergency that must be addressed in a timely fashion. Bacterial meningitis is the result of an infection with a pathogenic bacteria. Characteristic symptoms of the disease include headaches, stiff neck, and an altered state of consciousness. Other symptoms include fever, intolerance of loud noises and light, and vomiting. Without prompt treatment, bacterial meningitis can inflict long-term problems such as cognitive disability, deafness, and epilepsy. Treatment depends on the cause, but if the disease is suspected, antibiotics are recommended as soon as possible, even if the definite diagnosis hasn’t been confirmed. In the Western world, bacterial meningitis is rare. To learn more about meningitis, click here.
Why Does it Matter?
The findings from this study could help provide a path forward that could ultimately lead to better outcomes for patients once the acute infection has been eradicated:
“We believe this study represents an important step forward in the field of bacterial meningitis, a life-threatening inflammation of the meninges occurring as a consequence of a bacterial infection of the brain. A major issue of bacterial meningitis is the poor life quality post-disease; in fact, even if the bacterial infection in the brain is adequately cured, 50% of the survivors suffer from brain damages caused by the bacterial infection, such as cognitive and motor disabilities, hearing loss, or other neurological deficiencies.” – Federico Iovino, research group leader of the Iovino Laboratory at the Department of Neuroscience and corresponding author
Bacterial infection still remains a serious medical concern around the world despite the widespread use of antibiotics. Treating bacterial meningitis in particular, which affects the brain, is even more difficult because any therapy must pass the blood-brain barrier. The findings from this study should lead to the development of therapies that block the interactions between bacteria and neurons. By blocking these interactions, neurons can avoid damage and death.
This is vital because unlike some other cells, neurons are not often repaired or replaced once they die. The next step will be developing the possible intervention explored in this study, which consisted of β-actin antibodies.