When herpes simplex virus (HSV) infects neurons in the brain, they can self-destruct in some cases, thereby preventing the virus from spreading to the rest of the brain. Now researchers have determined how this happens. This could pave the way for developing drugs to combat brain damage in connection with infections and diseases such as dementia, Alzheimer’s and Parkinson’s.
We should take extra care of our brain’s neurons because, unlike most other cells, they cannot be replaced.
Similarly, we need to avoid viruses infecting the neurons – such as HSV.
When HSV infects the brain’s neurons, it can drive them to self-destruct, thus preventing the virus from spreading. But this process increases the risk of developing brain damage – and potentially also applies to other diseases such as dementia, Alzheimer’s and Parkinson’s.
New research has now characterised how neurons self-destruct. The discovery could pave the way for the development of drugs to prevent this from happening, so that the neurons’ self-defence mechanism does not damage the brain.
“When a virus infects the body, the cells initially try to ensure that the virus does not spread and then to eliminate the virus and prevent damage. One mechanism to achieve this is by eliminating the infected cells. This works very well in most of the body but is a problem in the brain, because the neurons cannot be replaced once they have been destroyed,” explains a researcher behind the study, Søren Riis Paludan, Professor, Department of Biomedicine, Aarhus University.
The research has been published in The EMBO Journal.
Most people harbour HSV
HSV is a very widespread virus that most of us harbour in our bodies, but it is nevertheless under control.
About 60% of all adults are latently infected with HSV type 1, and about 25% are latently infected with HSV type 2.
However, in rare instances, HSV can get out of control and cause trouble, such as among people who are immunosuppressed for various reasons, such as autoimmune disease, old age or cancer treatment.
HSV thus has free rein to spread when a person’s immune system is suppressed.
HSV can destroy the brain
The idea behind the new study comes from observations from autopsies of people who died from viral encephalitis that often involved massive death of neurons.
To understand how a viral infection can lead to programmed cell death, Søren Riis Paludan and colleagues infected neurons in cell culture and examined the cellular response using advanced analysis.
The researchers characterised the differences in how proteins were expressed between healthy and infected cells. The expressed proteins inform the researchers about which signalling pathways a viral infection activates in the cells.
Signal cascade results in apoptosis
The results showed that HSV infection of neurons leads to stress in the endoplasmic reticulum, which has an important role in folding new proteins.
Similarly, the endoplasmic reticulum has a system to prevent errors in folding proteins, which are frequent in infections, cancer and other diseases.
In this scenario, the endoplasmic reticulum shuts down so that no more proteins and enzymes with unwanted functions are produced.
The experiments also showed that the endoplasmic reticulum emits a distress signal when it is stressed.
The cell’s mitochondria pick up this distress signal and activate a signal to begin executing cell death. This leads to a protein cascade resulting in the cleavage of the protein gasdermin E (GSDME). Once cleaved, GSDME attaches to the cell membrane and makes holes.
“GSDME making holes in the cell membrane is like popping a balloon. The cell’s contents flow out into the environment, and the immune system collects and destroys them. Under normal circumstances, stress in the endoplasmic reticulum is a cellular defence mechanism to stabilise the cell, but in HSV infection, the defence mechanism can be overactivated and can induce cell death,” says Søren Riis Paludan, adding that the researchers have studied this mechanism in neurons but the mechanism is similar in many other types of cells.
“Cell death is a last resort. This is only a problem for the brain and not the rest of the body. In this study, we characterised the signalling pathway leading from HSV infection to programmed cell death in neurons for the first time,” explains Søren Paludan.
Relevant target for treating brain disease
In one experiment, the researchers inhibited the signalling molecules involved in endoplasmic reticulum stress response, and the cells survived, since neither the distress signal nor the self-destruct signal was activated.
This discovery opens up an interesting perspective: that drugs could prevent neurons in the brain from self-destructing and thereby slow the progress of diseases such as dementia, Alzheimer’s and Parkinson’s.
Søren Riis Paludan says that another study published at the same time identified the same programmed cell death mechanism in neurons, not related to infection but to amyotrophic lateral sclerosis (ALS).
This indicates that this mechanism of neuronal death is relevant for several brain diseases.
“The obvious perspective is that we now have a molecular basis for targeting brain diseases. Inhibiting the function of GSDME could prevent the cells from self-destructing, and this may be a common denominator in various brain diseases. There is now a good rationale for doing experiments to investigate inhibiting GSDME in various animal models of brain diseases,” concludes Søren Riis Paludan.