Viruses and the human cell: The evolutionary arms race

Researchers at the Technion-Israel Institute of Technology Faculty of Biology have discovered a unique genetic mechanism that provides cells with rapid and efficient protection against viruses. The findings could lead to the development of new therapeutic strategies.

The research group led by Prof. Yael Mandel-Gutfreund from the Faculty of Biology presents new findings related to the immune system's activity against viral infections. The study, published in Nature Communications, was led by Prof. Mandel-Gutfreund and Dr. Amir Argoetti as part of the latter’s doctoral research.

The Technion researchers focused on the interaction between two molecules that play significant roles in genetic processes:

NORAD is a unique molecule from the lncRNA group, a group of non-coding RNA molecules. While many RNA molecules serve as intermediates in the protein synthesis pathway based on genetic code, lncRNAs do not take part in this process. Instead, they play essential roles in genetic regulation, cell differentiation, and embryonic development – critical processes for organism development and health. In embryonic stem cells, these molecules influence differentiation toward becoming specific mature cell types (muscle, skeleton, fat, cornea, etc.) and reprogramming processes, artificially directing mature cells back into a stem cell-like state.

STAT3 is a protein that belongs to a large family of proteins crucial for controlling transcription – the process of copying genes into RNA to build proteins. STAT3 is essential for embryonic development and is also involved in inflammatory processes, immune system activation, and other biological processes.

The Technion researchers discovered that in a healthy state (without viral infection), the interaction between NORAD and STAT3 prevents the immune system from producing a virus-targeted immune response. However, when a viral attack occurs, the cell responds by cutting and digesting NORAD molecules. The lack of NORAD suppresses STAT3 activity, thereby releasing the brakes on the immune system and triggering a rapid and efficient immune response that halts the viral infection. This response neutralizes the virus's ability to replicate within the human cell.

The researchers demonstrated this mechanism through both laboratory experiments and analyses of human cell samples. To support their conclusions, they examined the immune activity of cells lacking NORAD and found these cells exhibited heightened antiviral activity. This suggests that under normal conditions, NORAD molecules are abundant in the cell, "guarding" the immune system against false activation. However, in response to a viral attack, their frequency decreases, activating the immune system to combat the virus.

The researchers also analyzed the evolutionary history of this mechanism, showing that although both molecules are highly conserved (ancient in evolution), the specific interaction and mechanism discovered are unique to humans and closely related primates and do not exist in most other mammals. This represents a case of species-specific evolution.

Prof. Mandel-Gutfreund and Dr. Argoetti speculate this mechanism evolved during human evolution in response to viruses that learned to manipulate infected cells to prevent immune responses. The unique mechanism presented in the study provides a rapid and efficient response, bypassing slower and more cumbersome immune mechanisms that viruses can manipulate, thus creating an immediate defense.

Beyond the scientific value of the discovery, the researchers at the Faculty of Biology hope and believe that the study’s findings will eventually lead to the development of new strategies for correcting immune system "malfunctions" and better combating viral infections.

The research was supported by the Israel Science Foundation (ISF).