From herpesvirus in oysters to cancer in humans: the discovery of shared mechanisms opens up new avenues of research

Scientists from the Ifremer reveal in the journal Science Advances that, as with most species, the age of oysters influences the survival of their offspring: the older the oysters, the higher the mortality of their larvae. More surprisingly, young oysters from older parents were found to be more susceptible to infection by the herpesvirus OsHV-1, responsible for high mortality rates among young oysters worldwide. To explain this sensitivity, the scientists studied two biomarkers involved in aging in most species: telomeres (protective ends of chromosomes) and the associated repairing enzyme telomerase. They have demonstrated in vivo at the whole organism level that telomerase is activated during viral infection by OsHV-1, a phenomenon already observed in vitro in human cells in contact with oncogenic viruses capable of rendering cells cancerous. Ifremer will continue its work to find a way of limiting telomerase activation in oysters, and hopes to contribute to the advancement of cancer research in humans.

In humans, as in most animals, the age of the parents at conception has negative effects on the offspring: the survival and performance of the offspring of older parents are lower. This process is known as reproductive aging. Scientists have suspected for several years that telomeres, the repetitive DNA sequences located at the ends of chromosomes, are one of the markers that integrate the age of parents, since they are transmitted to offspring through germlines and can predicts their survival. We know that telomeres - whose role is to preserve genetic information as cells divide - inexorably shorten over the course of a lifetime. Telomere shrinking may be compensated by the action of the enzyme telomerase, which repairs telomeres by lengthening them during gamete production, so that offspring may start life with viable aging capital. Telomere shortening is viewed as a hallmark of aging in most species. Nevertheless, the precise role of telomeres and telomerase in the process of reproductive aging remains poorly understood in vertebrates, and even more in invertebrates such as shellfishes. Are telomeres a mechanism of reproductive aging in the Pacific oyster Magallana gigas previously known as Crassostrea gigas?

The pacific oyster, a biological model for exploring intergenerational transmission mechanisms

As a starting point, scientists from Ifremer, in collaboration with the University of Caen, the Institut de Systématique, Évolution, Biodiversité and the Institut Universitaire de France, crossed 12 males with 12 oyster females of three age classes ("young" 2 or 3 years old, "medium" 6 years old or "old" 8 to 10 years old) and produced 36 full-sibling families. They explored two phenomena: firstly, the developmental success of the offspring, including survival and growth of larvae, the resistance of young oysters (called spats) to viral infection by the ostreid herpesvirus type 1, and the survival of oysters once adults. In parallel, they explore the dynamic of telomere length at these multiple life stages and the activity levels of telomerase, which repairs telomeres.

“By choosing the Pacific oyster as our biological model, we were able to overcome most of the methodological biases that usually hinder this type of evolutionary study. This is because this animal has a simple and well controlled reproductive strategy; at each reproduction, it produces new gametes whose quality depends directly on the age of the parents; and lastly, this species does not provide any parental care to its offspring, thus avoiding experimental bias from one family to another.”

Andréaz Dupoué, researcher in evolutionary ecophysiology at Ifremer

First result: older parents produce offspring that survive and grow at lower rates, and are more susceptible to infection by OsHV-1, responsible for episodes of high mortality in young hollow oysters worldwide.

Second result: telomeres erode faster in spat from older parents. This reduction in telomere length may explain their increased susceptibility to infection by the OsHV-1 virus.

Following Exposition to the virus, the telomerase enzyme is stimulated, as in 90% of human cancers.

“This is the first time we have demonstrated in vivo that telomerase is activated during herpesvirus infection. This had already been demonstrated on human cells exposed in vitro to oncogenic viruses, i.e. viruses capable of inducing cancer, such as papillomaviruses for example, but never at whole animal level in a natural environment, i.e. under such realistic conditions”.

Andréaz Dupoué, researcher in evolutionary ecophysiology at Ifremer

Telomerase activation is a prerequisite for the development of human tumors, identified in 90% of cancers. It acts by rendering cancer cells immortal, thereby enabling tumors to grow.

Ifremer scientists have also shown that although telomerase action is essential for young oysters to resist viral infection, it becomes deleterious when overactive. Under the effect of the virus, a telomerase that is too active may elongate telomeres and lead to genetic disorders, predictive of greater oyster deathas an adult.

“Our in vivo demonstration of this telomerase runaway reaction caused by the herpes virus opens the way to new avenues of understanding and to the search of solutions to inhibit telomerase activity during viral infection first in oysters, then in other species including humans”, hopes the scientist.