Epigenetics: Immunization is passed on to offspring

October 18, 2021

left: Prof. Dr. Mihai G. Netea; right: Prof. Dr. Andreas Schlitzer (picture: Prof. Netea/Universität Bonn)


Adaptations to infection shown to be passed on over several generations in mice


Does an infection affect the immunity of subsequent generations? Prof. Andeas Schlitzer, member of the Cluster of Excellence ImmunoSensation2 and the Life & Medical Sciences Institute (LIMES) at the University of Bonn, Prof. Dr. Mihai G. Netea

from Radboud University (Netherlands), together with researchers from Saarland University, Lausanne (Switzerland) and Athens (Greece), have investigated this. Mouse sires that either had previously overcome infection with fungi or were stimulated with fungal substances, passed on their improved protection over several generations. The team simultaneously demonstrated an improved immune response that was passed on to the offspring. The study has now been published in Nature Immunology.



It is not only inherited what is written in the DNA sequence: Scientific studies show that environmental influences are also passed on to the next generation. One example: children who grew up in their mothers' wombs during the famine winter of 1944/45 show typical changes in their metabolism. This is apparently an adaptation to food shortages during development and is associated with a higher risk of diabetes and obesity.


Epigenetic research investigates such relationships at the molecular level. It analyzes changes in gene function. "Not all areas of DNA are equally accessible for reading out genetic information," explains Prof. Dr. Andreas Schlitzer of the LIMES Institute at the University of Bonn. For example, if methyl groups block access, the gene cannot be read out properly. These relationships have been researched for decades. The transfer of infection resistance to the next generation has already been demonstrated in plants and invertebrates. A research team from Radboud University Nijmegen (Netherlands), Bonn University, Saarland University, Lausanne University (Switzerland) and the National and Kapodistrian University of Athens (Greece) has now for the first time intensively investigated whether effects of the innate immune system are also passed on to the next generations in mammals.


Infection with thrush fungi trains the immune system of mice


The scientists infected male mice with thrush fungi (Candida albicans). After surviving the infection, the animals were mated with completely healthy females. The researchers compared the resulting children with offspring from pairs of mice that had not previously been infected with Candida. To experimentally examine the status of the immune system, the team infected the males of the subsequent generation of mice with coliform bacteria. "The offspring of the male mice previously exposed to Candida were significantly better protected from subsequent E. coli infection than the offspring of the uninfected male mice," reported Prof. Mihai G. Netea, M.D., of the Radboud Center for Infectious Diseases. This effect was still evident in the next generation.


How does this transmission of immunization to subsequent generations work? The team studied typical immune cells such as monocytes or neutrophils. No differences were found between the offspring of male mice infected with Candida and the uninfected control group. However, in the offspring of the previously infected mouse fathers, the MHC class II complex was upregulated, which activates parts of the immune system. In addition, offspring of Candida-infected fathers were also found to have upregulated activity of genes involved in inflammation. In the offspring of male mice previously infected with thrush fungi, monocyte precursors were found to have better readout of inflammation-associated genes than sons of uninfected fathers. "This shows that the monocyte precursors of the immune system are epigenetically reprogrammed if the fathers have previously undergone infection with Candida albicans," Prof. Schlitzer summarizes.


Shift in gene activity is detectable in sperm


How does the transmission of this information to the next generation take place? Together with the Saarland University, the researchers investigated the gene activity of sperm of mouse fathers infected with Candida. They analyzed the extent to which methyl groups blocked access to the genes. "A shift in gene markers was evident here," says Prof. Dr. Jörn Walter of Saarland University. Offspring of Candida-infected male mice showed fewer gene blockages in gene regions that are important for inflammatory processes and the maturation of monocytes. How sperm marker information gets to the bone marrow, the birthplace of many immune cells, remains to be explored in further studies.



"The study shows for the first time in mammals that adaptations to infectious diseases are also passed on to offspring," says Netea. In contrast to classical evolutionary theory, which assumes slow adaptation through changes in genetic material, these are very rapid changes via the regulation of gene activities, regardless of the genetic code, he said. The researchers do not yet know whether the findings obtained in mice can also be applied to humans. "However, we assume so," Schlitzer says. "The mechanisms and cells of the immune system involved are very similar in mice and humans."


Participating institutions and funding:


In addition to the universities of Bonn, Saarland, Athens and Radboud, the University Hospital of Lausanne (CHUV) and the German Center for Neurodegenerative Diseases (DZNE) were involved. The study was mainly funded by the European Research Council (ERC), the Spinoza Grant of the Netherlands Organization for Scientific Research, the German Research Foundation (DFG) and the Swiss National Science Foundation (SNF).


Publication: Natalie Katzmarski, Jorge Domínguez-Andrés, Branko Cirovic, Georgios Renieris, Eleonora Ciarlo, Didier Le Roy, Konstantin Lepikhov, Kathrin Kattler, Gilles Gasparoni, Kristian Händler, Heidi Theis, Marc Beyer, Jos W. M. van der Meer, Leo A. B. Joosten, Jörn Walter, Joachim L. Schultze, Thierry Roger, Evangelos J. Giamarellos-Bourboulis, Andreas Schlitzer, Mihai G. Netea: Transmission of trained immunity and heterologous resistance to infections across generations, Nature Immunology, DOI: 10.1038/s41590-021-01052-7.




Prof. Dr. Andreas Schlitzer
Quantitative Systembiologie
LIMES-Institut (Life and Medical Sciences Bonn)
Universität Bonn
Tel. +49 2287362847
E-Mail: andreas.schlitzer(at)uni-bonn.de

 Prof. Dr. Mihai G. Netea
Radboud university medical center und
LIMES-Institut der Universität Bonn
Tel. +31 243618819
E-Mail: Mihai.Netea(at)radboudumc.nl