About two in three people become infected sometime during their life with the herpes simplex virus type 1 (HSV1), which is best known for cold sores on the lips that plague those who have it. However, this is mild compared with the harmful effects of HSV1 on the brain of a very few people. Now researchers have shown that microglia form the first line of defence against virus attacks on the brain. This discovery is essential to avoid and rehabilitate the damage that occurs when the herpesvirus and other viruses penetrate the brain.
Most people are never aware that they are being attacked by HSV1. The only evidence is a tiny blister. However, it also spreads to the peripheral nervous system of many people, appearing sporadically as irritating cold sores. Very few herpesviruses migrate to the central nervous system and the brain because they are effectively stopped by microglia, one of the immune system’s most important cells, which sense tiny changes and send signals that render potential enemies harmless.
“In 2016, we showed that infection with HSV1 causes these microglia to emit interferon signals, and a few years later we showed that viruses have mechanisms to inhibit the signals, so we had an idea that viruses were battling the immune system. In our new study, we can now finally show that, without the microglia, stemming virus attacks is incredibly difficult because the brain has to launch a far more violent defence against viruses that can ultimately lead to serious brain damage,” explains a researcher behind the discovery, Søren Riis Paludan, Professor, Department of Biomedicine, Aarhus University.
Life-threatening brain damage
Herpes simplex encephalitis is an extremely rare but often fatal condition in which HSV1 spreads from the peripheral nervous system to the central nervous system, leading to extensive infection and pathological inflammation in the brain. Left untreated, 70% of people die and about half of those who survive the acute phase have severe brain damage. The new research found that microglia cells play a critical role in the first-line defence against herpes simplex encephalitis.
“Our research tested the effect of removing the microglia in mice. Their absence led to greatly increased levels of HSV1 and very severe illness, so microglia are clearly involved in detecting viruses and initiating antiviral defence responses. Without microglia, the viruses appear to have free rein, enabling them to move from the peripheral neurons and reach the central nervous system,” says Søren Riis Paludan.
Shortly after the virus enters the brain, other immune cells are activated to combat the invader. However, these immune cells apparently combat the viruses so strongly that they also provoke a strong inflammatory response, and this can induce life-threatening brain damage caused by nerve cells dying.
“Our research provided solid evidence that the microglia carried out the initial defence. When the microglia are not present, type I interferon neurotransmitters are not secreted early enough in the brain, and then control is lost so that the herpesvirus can copy itself uninhibited. However, the effect of microglia appears to be limited to the very early stage of HSV1 entry into the central nervous system. We do not yet know which immune cells take over then,” explains Søren Riis Paludan.
Swatting a fly without breaking the china
The new research demonstrates the critical role of microglia in the early sensing of whether viruses can establish themselves in the central nervous system and thus produce life-threatening neural infections and damage. At least in mice, the battle against the virus is lost when microglia are not present.
“This highlights the importance of a rapid antiviral immune response to reduce the risk of developing herpes simplex encephalitis but also other neurodegenerative disorders. As seen recently with COVID-19 and other viral infections, this requires finding the right balance between eliminating the virus without making the immune system react so strongly that it causes more damage than the virus itself – a bit like swatting a fly without breaking the china,” says Søren Riis Paludan.
The long-term goal of the research is therefore not only understanding the mechanisms behind the brain’s defence against viral attacks but also learning how to arrest the development of disease and reduce the damage following attacks. These include HSV1 infections but also the side-effects of COVID-19 and mosquito-borne viruses such as Zika and West Nile, which are a rapidly growing problem in some parts of the world.
“If we can elucidate the mechanisms of the immune response, we can also learn to attenuate and treat the response and avoid late side-effects. For example, people with HSV1 have an increased incidence of Alzheimer’s disease. This understanding will also make it easier for us to identify whether people with special genetic profiles are hit harder than others, so we can improve prevention, for example by strengthening the immune system in these groups,” concludes Søren Riis Paludan.