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Chickenpox Virus Fatal in Newly Discovered Immunodeficiency

Summary: Researchers at Aarhus University have identified a mutation in an immune system sensor that can result in chicken pox infection becoming fatal. According to the study, immune cells in those with extreme reaction to VZV neither detected the virus nor activated the immune system. The findings shed light on why some people are more susceptible to infections than others.

Source: Aarhus University.

A new study has identified an immunodeficiency which leads to some people becoming seriously ill from the chickenpox virus. The discovery of the gene mutation may help to improve prevention and treatment of the disease. It also contributes with fundamental new knowledge about the immune system.

A mutation in one of the sensors that the immune system uses to detect viruses can, in rare cases, turn infections with the chickenpox virus into a life-threatening matter. For two out of every 10,000 people, it can lead to inflammation of the brain, and for twenty out of 10,000, to severe pneumonia, which can be particularly dangerous for pregnant women. The cause of these rare but serious diseases has thus far been unknown, and it has not been possible to predict who was in the danger zone.

A mapping of the genome in patients who have been very severely affected by these infections has now shown that they have mutations in what is known as the POL III sensor. This is the sensor which the immune system uses to recognise the genome of varicella zoster virus (VZV), which normally simply leads to chicken pox.

The immune system fails to activate

Analyses of cells from the affected patients showed that their cells did not detect the infection and consequently neither did they activate the immune system’s defensive responses. This allowed the virus to spread to the brain, for example. If the mutated gene was repaired, the cells were able to fight the infection. This suggests that individuals with mutations in POL III have an increased risk of developing serious illness with the VZV infection.

“We cannot yet put an exact figure on how much the risk of complications is increased when you have this new immunodeficiency, since we have looked at relatively few patients in our study. Neither do we know how large a proportion of all those who have inflammation of the brain and pneumonia have the defect. But we do know that this applies to both children and adults,” says one of the driving forces behind the study, Professor with special responsibilities (MSO) Trine Hyrup Mogensen from the Department of Clinical Medicine and the Department of Biomedicine at Aarhus University.

The results have just been published in the scientific journal The Journal of Clinical Investigation.

Paves the way for personalised medicine

The results contribute with a genetic explanation of why some individuals are extremely susceptible to certain infections in contrast to others, and it is an important contribution to an emerging field of research. With the combination of clinical research and basic research, the researchers have succeeded in producing fundamental new knowledge about the immune system, and at the same time, provided a tool that can be used directly in clinical practice.

Image shows a small child with chickenpox.

In rare cases chickenpox virus can lead to inflammation of the brain and servere pneumonia. NeuroscienceNews.com image is adapted from the Aarhus University news release.

“Today it is possible to map the entire genomic composition of an individual. At the same time the last few decades have seen an explosion in our knowledge of the immune system. Together this means we are now slowly becoming able to understand the individual differences in susceptibility to infections at both the genetic and molecular level,” says Søren Riis Paludan, who is professor at the Department of Biomedicine at Aarhus University and also one of the researchers behind the research project.

“In general terms, it opens up new possibilities with more individualised diagnosis and treatment of patients. Our study is an important contribution to this,” adds Trine Hyrup Mogensen, who also works as a medical specialist in infectious diseases at Aarhus University Hospital.

About this neuroscience research article

Source: Mette Louise Ohana – Aarhus University
Image Source: NeuroscienceNews.com image is adapted from the Aarhus University news release.
Original Research: Full open access research for “Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections” by Benson Ogunjimi, Shen-Ying Zhang, Katrine B. Sørensen, Kristian A. Skipper, Madalina Carter-Timofte, Gaspard Kerner, Stefanie Luecke, Thaneas Prabakaran, Yujia Cai, Josephina Meester, Esther Bartholomeus, Nikhita Ajit Bolar, Geert Vandeweyer, Charlotte Claes, Yasmine Sillis, Lazaro Lorenzo, Raffaele A. Fiorenza, Soraya Boucherit, Charlotte Dielman, Steven Heynderickx, George Elias, Andrea Kurotova, Ann Vander Auwera, Lieve Verstraete, Lieven Lagae, Helene Verhelst, Anna Jansen, Jose Ramet, Arvid Suls, Evelien Smits, Berten Ceulemans, Lut Van Laer, Genevieve Plat Wilson, Jonas Kreth, Capucine Picard, Horst Von Bernuth, Joël Fluss, Stephane Chabrier, Laurent Abel, Geert Mortier, Sebastien Fribourg, Jacob Giehm Mikkelsen, Jean-Laurent Casanova, Søren R. Paludan, and Trine H. Mogensen in Journal of Clinical Investigation. Published online August 7 2017 doi:10.1172/JCI92280

Cite This NeuroscienceNews.com Article
Aarhus University “Chickenpox Virus Fatal in Newly Discovered Immunodeficiency.” NeuroscienceNews. NeuroscienceNews, 13 August 2017.
<http://neurosciencenews.com/chickenpox-virus-fatal-7292/>.
Aarhus University (2017, August 13). Chickenpox Virus Fatal in Newly Discovered Immunodeficiency. NeuroscienceNew. Retrieved August 13, 2017 from http://neurosciencenews.com/chickenpox-virus-fatal-7292/
Aarhus University “Chickenpox Virus Fatal in Newly Discovered Immunodeficiency.” http://neurosciencenews.com/chickenpox-virus-fatal-7292/ (accessed August 13, 2017).

Abstract

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.

“Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections” by Benson Ogunjimi, Shen-Ying Zhang, Katrine B. Sørensen, Kristian A. Skipper, Madalina Carter-Timofte, Gaspard Kerner, Stefanie Luecke, Thaneas Prabakaran, Yujia Cai, Josephina Meester, Esther Bartholomeus, Nikhita Ajit Bolar, Geert Vandeweyer, Charlotte Claes, Yasmine Sillis, Lazaro Lorenzo, Raffaele A. Fiorenza, Soraya Boucherit, Charlotte Dielman, Steven Heynderickx, George Elias, Andrea Kurotova, Ann Vander Auwera, Lieve Verstraete, Lieven Lagae, Helene Verhelst, Anna Jansen, Jose Ramet, Arvid Suls, Evelien Smits, Berten Ceulemans, Lut Van Laer, Genevieve Plat Wilson, Jonas Kreth, Capucine Picard, Horst Von Bernuth, Joël Fluss, Stephane Chabrier, Laurent Abel, Geert Mortier, Sebastien Fribourg, Jacob Giehm Mikkelsen, Jean-Laurent Casanova, Søren R. Paludan, and Trine H. Mogensen in Journal of Clinical Investigation. Published online August 7 2017 doi:10.1172/JCI92280

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