Champagne in The Center of Excellence when the article was accepted by Nature
Only one year after it was established, the Center of Excellence CiViA has made it into the journal Nature with an article that Professor Søren Riis Paludan calls the biggest achievement of his career.
More than half of us are carriers of herpesviruses. But even though this virus can infect our neuronal cells, it rarely causes serious infection of the brain. Now Professor Søren Riis Paludan and his research group at the Department of Biomedicine have discovered a key element of the explanation.
Their study has just been published in the scientific journal Nature, and staff at the Center of Excellence CiViA (Center for Immunology of Viral Infections) have already celebrated the good news with champagne.
One of the most important unanswered questions in immunology is how the body fights infection without doing harm to itself at the same time, and this is precisely what CiViA was established to answer. So, there is every reason to now celebrate that the researchers have discovered a previously unknown defence mechanism forming a central part of the explanation of why herpesvirus infection causes serious and potentially fatal brain inflammation only in one out of 250,000 individuals.
The study has uncovered important new information on how the brain defends itself against viral infections, says Søren Riis Paludan. He is the article’s last author, a Lundbeck Foundation Professor and centre director of CiViA. The people behind the study comprises a large group of people, including first author Assistant Professor Manja Idorn, and CiViA group leaders Professor Trine Hyrup Mogensen and Professor Jacob Giehm Mikkelsen from the Department of Biomedicine.
Manja Idorn explains that the study is particularly interesting because the brain is very sensitive to inflammatory reactions:
"We’ve discovered how our body prevents herpesvirus from entering the brain, even though 50-80% of us are chronically infected with this particular virus. The mechanism we’ve discovered fights the virus without causing inflammatory reactions," she explains.
The answer lies in the protective TMEFF1 gene.
Two children with brain inflammation caused by herpes
Many years of experimenting with the genome-wide CRISPR screening technology and development of mice that lacked the critical gene have finally convinced the researchers that TMEFF1 encodes a protein that prevents herpesvirus from entering neuronal cells.
The study in Nature will be published back-to-back with an article by Honorary Skou Professor Jean-Laurent Casanova from the Rockefeller University in New York. The article describes two patients with brain inflammation, called encephalitis, caused by herpesvirus infection. In collaboration with the researchers in New York, the research group in Aarhus discovered that two children who developed encephalitis following infection with herpesvirus were carrying genetic defects that disabled the protective TMEFF1 gene.
Jean-Laurent Casanova has visited Aarhus University several times, where he collaborates with Trine Hyrup Mogensen on several projects.
"The collaboration is very fruitful because his genetic study is based on clinical findings and our discovery is based on identification of a cellular and molecular process. Combining these two approaches is extremely powerful," says Trine Hyrup Mogensen, pointing out that together the two articles are an excellent example of biomedical research that covers everything from identification and understanding of molecular mechanisms to description of what causes a human disease.
The idea arose a long time ago
The study itself has taken eight years, and it has been two years since the research group submitted the first version of a manuscript to Nature.
"As far as publications go, it's the biggest achievement of my career. Scientifically, this is also very satisfactory for me because it builds on an idea that I started to develop more than 10 years ago and which turned out to hold water," says Søren Riis Paludan.
"The study supports the idea that our immune system is more complex than previously assumed. Our discovery of a key antiviral defence mechanism that is not associated with potentially harmful inflammatory reactions does not fit into the prevailing immunological theories. This suggests that we still lack a basic understanding of the body's earliest immune responses to infections," he says.
Søren Riis Paludan points out that when researchers try to get they work published, they always try to assess the potential of a given study for being published in one of the highest-ranking journals. This is important because it takes resources on several levels to go through the often very hard and lengthy processes before an article is accepted or rejected.
"However, I nearly always choose to aim high, partly because publications in hop-ranking journals leave clearer marks in the scientific literature, and partly because it gives the young people working on the project the best research training and the best career opportunities," he says.
May provide a better understanding of Alzheimer's
The new study is groundbreaking because it updates the basic understanding of the body's defence mechanism against viral infections, and it illustrates that there is still much to learn about how the body fights infections, explains Søren Riis Paludan:
"The study is also relevant for neuroscience because it sheds light on how the brain, so to say, prevents unwanted visitors from intruding without causing harm to the brain itself."
Søren Riis Paludan hopes that the study is the first step towards revealing a completely new range of brain defence mechanisms. One of the tracks that the group will now investigate is what the discovery may mean for the development of dementia.
Research has already demonstrated a correlation between herpesvirus infection and later development of Alzheimer's disease.
"Perhaps our discovery of a new antiviral mechanism in the brain can help to clarify whether individual differences in this particular mechanism or similar mechanisms can give the virus access to the brain and accelerate neurodegenerative processes," says Søren Riis Paludan.
About CiViA
- The Center for Immunology of Viral infections (CiViA) was established in 2023 and is located at the Department of Biomedicine at Aarhus University.
- The centre consists of research groups based at AU and the Technical University Munich. The research groups aim to uncover novel immune mechanisms that contribute to the early defence against infections – and to decipher how the delicate balance between protective and pathological immune responses are achieved.
- Professor Søren Riis Paludan is the centre director of CiViA, which is funded by the Danish National Research Foundation through their Center of Excellence programme.
- Read more here: https://biomed.au.dk/civia
The research results - more information
- The study is basic research.
- The partners are: Mark Denham, Dandrite University; Poul Nissen, AU; Trine Hyrup Mogensen, AU; Jacob Giehm Mikkelsen, AU; Yujia Cai, Shanghai Jiao Tong University; Shen-Ying Zhang and Jean Laurent Casanova, Rockefeller University.
- External funding: The Lundbeck Foundation, the Danish National Research Foundation and the European Research Council (ERC)
- Direct link to the scientific article on which the media coverage is based: https://www.nature.com/articles/s41586-024-07670-z
Contact
Professor Søren Riis Paludan
Aarhus University, Department of Biomedicine
Telephone: +45 28 99 20 66
Email: srp@biomed.au.dk
[Translate to English:]
[Translate to English:]
Et af de vigtigste ubesvarede spørgsmål inden for immunologien er, hvordan kroppen nedkæmper infektioner uden samtidig at beskadige sig selv, og CiViA er sat i verden for at finde svar på netop det spørgsmål.
Derfor er der grund til fejring, når forskerne nu har opdaget et hidtil ukendt forsvar i kroppen, som gør, at herpesinfektion kun i et ud af 250.000 tilfælde giver en alvorlig og potentielt dødelig hjernebetændelse.
Læs mere om CiViA her: https://biomed.au.dk/civia
[Translate to English:]
[Translate to English:]
Over halvdelen af os bærer rundt på herpesvirus.
Men selv om herpesvirus kan inficere nerveceller, giver det kun sjældent anledning til alvorlig infektion i hjernen. Nu har professor Søren Riis Paludans forskningsgruppe på Institut for Biomedicin fundet en central del af forklaringen.
Studiet er netop udgivet i det videnskabelige tidsskrift Nature, og det har for længst udløst champagne i grundforskningscenteret Center for Immunology of Viral Infections, CiViA.
Studiet kan gøre os klogere på, hvordan hjernen forsvarer sig mod virusinfektioner, fortæller Søren Riis Paludan.
Han er er sidsteforfatter på artiklen, Lundbeck Foundation professor, og centerleder i CiViA. Bag studiet står et stort team, som inkluderer førsteforfatter adjunkt Manja Idorn og CiViA gruppeledere professor Trine Hyrup Mogensen og professor Jacob Giehm Mikkelsen fra Institut for Biomedicin.
Manja Idorn forklarer, at studiet især er interessant, da hjernen er meget følsom for betændelsesreaktioner:
”Vi har fundet ud af, hvordan vores krop hindrer, at herpesvirus kommer ind i hjernen, selvom 50-80% af os er kronisk inficerede med netop det virus. Den mekanisme, vi har fundet, er én, der bekæmper virus uden at give betændelsesreaktioner,” forklarer hun.
Svaret ligger i det beskyttende gen TMEFF1.
To børn med herpes-forårsaget hjernebetændelse
Det har taget mange års forsøg med teknologien genome-wide crispr screening og udviklingen af mus, der manglede det kritiske gen, før forskerne var sikre på, at netop TMEFF1 producerer et protein, der forhindrer herpesvirus i at komme ind i nerveceller.
Studiet i Nature publiceres back-to-back med en artikel af Honorary Skou-professor Jean-Laurent Casanova fra The Rockefeller University i New York. Artiklen beskriver to patienter med herpes-forårsaget hjernebetændelse. I samarbejde med forskerne i New York har forskergruppen i Aarhus nemlig opdaget, at to børn, som fik alvorlig hjernebetændelse efter infektion med herpesvirus, bar på en genetisk defekt, som satte det beskyttende TMEFF1-gen ud af funktion.
Jean-Laurent Casanova har flere gange besøgt Aarhus Universitet, hvor han samarbejder med Trine Hyrup Mogensen om en række projekter.
”Samarbejdet er frugtbart, fordi hans genetiske studium har afsæt i klinikken, og det, vi har lavet, har afsæt i petriskålen. Når de to tilgange mødes, er det enormt stærkt,” siger Trine Hyrup Mogensen og påpeger, at de to artikler tilsammen udgør et fint eksempel på biomedicinsk forskning hele vejen fra identifikation og forståelse af molekylære mekanismer til beskrivelse af årsager til en human sygdom.
Tanken opstod for længe siden
Selve studiet har taget 8 år, og det er 2 år siden, forskergruppen sendte første udgave af et manus til Nature.
”Rent publikationsmæssigt er det det største i min karriere. Det er stort for mig videnskabeligt, fordi det bygger på en idé, jeg begyndte at modne for over 10 år siden, og som viste sig at holde,” siger Søren Riis Paludan.
”Studiet er en understøttelse af ideen om, at vores immunsystem er mere komplekst, end vi tidligere har antaget. Vores fund af en helt central antiviral forsvarsmekanisme, der ikke er forbundet med skadelige betændelsesreaktioner, passer ikke ind i de gængse immunologiske teorier. Det tyder på, at vi stadig mangler grundlæggende forståelse af kroppens tidligste forsvarsreaktioner mod infektioner,” siger han.
Søren Riis Paludan pointerer, at man som forsker altid vurderer, hvor stort potentiale et studium har for at blive publiceret i et af de højest rangerende tidsskrifter - for det koster ressourcer på flere niveauer at gå gennem de ofte meget hårde og lange processer, inden en artikel bliver optaget eller afvist.
”Jeg vælger dog næsten altid at satse højt, dels fordi det efterlader mere klare fodaftryk i den videnskabelige litteratur, hvis det lykkes, dels fordi det giver de unge folk, som arbejder på projektet, den bedste forskningstræning og de bedste karrieremuligheder,” fortæller han.
Kan give bedre forståelse af Alzheimers
Det nye studie er banebrydende, fordi det opdaterer den grundlæggende forståelse af kroppens forsvar imod virusinfektioner, og det illustrerer, at der stadig er så meget, vi ikke ved, om hvordan kroppen bekæmper infektioner, forklarer Søren Riis Paludan:
”Studiet er også relevant for neurovidenskab, fordi det kaster lys over, hvordan hjernen populært sagt holder uønskede gæster ude uden at bruge metoder, der kan beskadige inventaret.”
Søren Riis Paludan håber, studiet er første skridt mod at afsløre en helt ny række af hjernens forsvarsmekanismer. Et af de spor, som gruppen nu vil undersøge, er, hvad opdagelsen kan betyde for udviklingen af demens.
Forskning har nemlig allerede påvist en sammenhæng mellem infektion med herpesvirus og senere udvikling af Alzheimers.
”Måske kan vores opdagelse af en ny antiviral mekanisme i hjernen være med til at opklare, om individuelle forskelle i netop den aktuelle eller lignende mekanismer kan give virus adgang til hjernen og accelerere neuro-degenerative processer,” siger Søren Riis Paludan.
Om CiViA
- The Center for Immunology of Viral infections (CiViA) blev oprettet i 2023 og ligger på Institut for Biomedicin ved Aarhus Universitet.
- Centeret består af forskningsgrupper med base på AU og Det Tekniske Universitet München. Grupperne arbejder bl.a. på at afdække nye immunmekanismer, der bidrager til tidligt forsvar mod infektioner – og de forsker i, hvordan kroppen balancerer mellem beskyttende og sygdomsfremkaldende immunresponser.
- Professor Søren Riis Paludan er centerleder i CiViA, som er finansieret af Danmarks Grundforskningsfond (DNRF) gennem Center of Excellence-programmet.
- Læs mere her: https://biomed.au.dk/civia
Bag om forskningsresultatet
- Studiet er grundforskning.
- Samarbejdspartnere er Mark Denham, Dandrite AU; Poul Nissen, AU; Trine Hyrup Mogensen, AU; Jacob Giehm Mikkelsen, AU; Yujia Cai, Shanghai Jiao Tong University; Shen-Ying Zhang og Jean Laurent Casanova, Rockefeller University.
- Ekstern finansiering: Lundbeck Fonden, Danmarks Grundforskningsfond og Det Europæiske Forskningsråd ERC
- Direkte link til den videnskabelige artikel, som medieomtalen bygger på: https://www.nature.com/articles/s41586-024-07670-z
Kontakt
Professor Søren Riis Paludan
Aarhus Universitet, Institut for Biomedicin
Telefon: 28 99 20 66
Mail: srp@biomed.au.dk