Does an infection also affect the immunisation of subsequent generations? Researchers at Radboud University (Netherlands) have investigated this together with the Universities of Bonn, Saarland, Lausanne (Switzerland) and Athens (Greece). Mouse sires that 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 offspring. The study has now been published in the renowned journal "Nature Immunology".
It is not only what is written in the DNA sequence that is inherited. 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, for example.
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 from 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), the University of Bonn, Saarland University, the University of Lausanne (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 trains the immune system of mice
The scientists infected male mice with thrush fungi (Candida albicans). After overcoming the infection, the animals were mated with completely healthy females. The researchers compared the resulting children with the offspring of mice pairs 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 E. coli. "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 of the Radboud Centre for Infectious Diseases. This effect was also seen 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 Candida-infected male mice and the non-infected 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, the offspring of Candida-infected fathers were also found to upregulate the activity of genes involved in inflammation. Offspring of male mice previously infected with thrush fungi were found to have better readout of inflammation-associated genes in monocyte precursors than in sons of uninfected fathers. "This shows that the monocyte precursors of the immune system are epigenetically reprogrammed if the fathers have previously undergone an infection with Candida albicans," Schlitzer concludes.
Shift in gene activity is detectable in sperm
How does this information get passed on to the next generation? In cooperation with Saarland University, the researchers investigated the gene activity of the sperm of mouse fathers infected with Candida. They analyzed the extent to which methyl groups blocked access to the genes. "Here, a shift in gene markers was evident," said Prof. Dr. Jörn Walter of Saarland University. Offspring of Candida-infected male mice showed fewer gene blockades in gene regions that are important for inflammatory processes and the maturation of monocytes. How the sperm marker information gets to the bone marrow, the birthplace of many immune cells, remains to be explored in further studies.
"The results have been made possible by the very good and close cooperation of researchers from different disciplines and institutions," emphasizes Prof. Netea. Together with Prof. Schlitzer, the scientist is also a member of the Cluster of Excellence ImmunoSensation2 and the Life & Medical Sciences Institute (LIMES) of the University of Bonn.
"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," says Schlitzer. "The mechanisms and cells of the immune system involved are very similar in mice and humans."