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Disease and treatment

Virus researchers discover why chickenpox can be fatal

Nearly every Dane has chickenpox as a child, and most have no long-term problems. However, one person in 10,000 develops encephalitis, resulting in serious complications, including death. Researchers have now discovered that the immune system of these children fails to recognize the virus and therefore does not eliminate it. A simple genetic test can reveal who is in danger so that they can choose to be vaccinated against chickenpox.

A slight temperature and headache and then, a few days later, a rash on the face and chest. This spreads, accompanied by a very high body temperature. Although the fluid-filled spots that often result are extremely itchy, chickenpox does not cause long-term problems for most children. However, one in 10,000 children develops a serious lung infection or encephalitis, and half of these children have severe long-term health problems or, in the worst case, die from it. Now researchers have discovered the reason why some children develop severe and long-term complications.

“When we examined children who had severe complications from chickenpox, we discovered a surprising mechanism that explains why some become seriously ill. They have a mutation in one enzyme: RNA polymerase III. This means that their immune system does not initially recognize the chickenpox virus. The virus can therefore multiply and thereby severely threaten these children’s health and lives,” explains Trine Mogensen, specialist in infectious diseases at Aarhus University Hospital and Professor at Aarhus University.

Immune system fails to recognize the threat

This research is part of a Danish-led worldwide collaboration. The aim is to build bridges between clinical discoveries related to viral infections and basic research, in which researchers try to discover the genetic and molecular mechanisms of these diseases. The comparison across borders and disciplines in the chickenpox study produced a surprising discovery.

“We often see viruses mutating, thereby avoiding being recognized by the host immune system. However, the varicella-zoster virus that causes chickenpox mutates very little. So the defects in the immune system of these children must be the reason why they become seriously ill. We found that their immune system simply fails to recognize the virus, allowing it to propagate unhindered in their cells.”

The immune system of most individuals easily detects varicella-zoster virus because its DNA has many adenine and thymine base pairs. The immune system has DNA sensors that ensure this recognition, and RNA polymerase III plays a key role in this process. However, this does not apply to the people who develop serious complications as a result of chickenpox.

“Among most children, the RNA polymerase recognizes and binds to the DNA of the virus genome, thereby inducing the immune system to generate an immediate antiviral response through interferon, which activates the primary immune response. Among these children, the RNA polymerase fails to recognize the virus DNA and therefore does not induce any primary immune response. The virus therefore establishes itself and spreads before the secondary response kicks in.”

One in 10,000 have long-term health problems

Chickenpox is very contagious, and people can only get chickenpox once in their life. However, the chickenpox virus remains latent in the body and can later be reactivated in the form of shingles. Because this is generally much more painful for adults, the practice in Denmark has been to ensure that children have chickenpox while young. In contrast, the United States and Germany have chosen to vaccinate against chickenpox.

“Only very few people have serious complications from chickenpox, and the decision not to use chickenpox vaccine as part of the Danish immunization programme is presumably therefore based on economic priorities, even though the vaccine is very safe and well tested."

There has been discussion on the extent to which immunizing against chickenpox, instead of experiencing the real infection, may result in reduced immunity and protection in the long term and therefore may result in a higher incidence of shingles among adults. The consequences for the five children in Denmark who develop the dangerous complications each year can be very serious.

"About 1–3 in 10,000 children develop the disease so severely that they have long-term disabilities or die. As we now understand the genetic basis for the individuals experiencing the serious complications, one could consider vaccinating those in the high-risk group. These genetic changes are hereditary, so the people in the high-risk group can be identified, screened and vaccinated."

Nevertheless, the new discovery will presumably enable the most serious complications of the disease to be treated more specifically in the long term. Of the 21 people in the studies who had the genetic basis of their disease examined, four had genetic mutations in their RNA polymerase III. The remaining cases, which the researchers are examining further, may have other defects in recognizing the virus and activating the immune system.

“So far, we have shown that, if we express the normal form of the gene encoding the mutated RNA polymerase III subunit in cells from the patients, their immune system can suddenly fight the varicella-zoster virus again. We may therefore be able to treat individuals with the defective genes by using gene therapy, perhaps including gene editing tools such as the CRISPR-Cas technique in the future,” concludes Trine Mogensen.

“Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections” has been published in the Journal of Clinical Investigation. The Novo Nordisk Foundation awarded grants in 2015 and 2016 to the two senior authors, Trine Mogensen and Søren Paludan, for research on viral infections.

Trine Mogensen
Professor MSO
The aim of my research is to understand basic mechanisms in innate immunology relevant to infectious diseases and immunodeficiencies in humans. One part of the research is focused on pathogen sensing and innate immune activation during HIV infection, i.e how HIV infection is sensed/recognized by pattern recognition receptors, the outcome of virus-cell interactions on antiviral activities, activation of chronic inflammation, and viral immune evasion strategies. The other part of the research deals with immunodeficiencies in innate immunity with particular focus on herpes encephalitis and other viral CNS infections and in particular the involvement of deficiencies in production of IFNs due to mutations in the TLR3 signaling pathway.