Bonn – SARS-CoV-2 viruses can camouflage themselves to such an extent that they are not recognized by the immune system. However, the antiviral immune receptor RIG-I can be stimulated, which improves protection against deadly SARS-CoV-2 infections. Researchers led by Prof. Dr. Gunther Hartmann from the Institute for Clinical Chemistry and Clinical Pharmacology at the University Hospital Bonn in cooperation with other members of the Cluster of Excellence ImmunoSensation2 at the University of Bonn. The frequency of serious illnesses is also significantly reduced. The study was previously published online in the journal “Molecular Therapy – Nucleic Acids” and is now available in its final version.
The SARS-CoV-2 pandemic has revealed an urgent need for antiviral drugs and vaccines. While vaccines have been available after a remarkably short period of time, the development of direct antiviral treatments has been comparatively slow. However, given the risk of future pandemics, there is still a great need for drugs and treatments that act directly against viral infection. In addition, emerging SARS-CoV-2 variants camouflaging themselves from the immune system are of concern. Because they can cause high numbers of infections even in a vaccine-immunized population, antiviral drugs are urgently needed to treat COVID-19.
SARS-CoV-2 belongs to the betacoronavirus genus. Like other members of this genus, SARS-CoV-2 is equipped with several molecular tools that allow the pathogen to evade detection by the immune system. The virus carries with it the information to produce a number of proteins capable of inhibiting antiviral recognition systems of the infected cell. The immune system can actually identify viral genetic material (here: ribonucleic acids/RNA) and sound the alarm. However, SARS-CoV-2 proteins can change the viral ribonucleic acids in such a way that they can no longer be distinguished from the body’s own RNA.
Camouflage protects the virus from the immune system
For example, viral RNAs are camouflaged by attaching a methyl residue. In this way, the viral RNA escapes early detection by the central antiviral immune receptor RIG-I. The receptor triggers what is known as an innate immune response, in which antiviral proteins, cell signals and messenger substances – such as type I interferon (IFN) – are produced.
“Robust, early Type I IFN production is key to eradicating SARS-CoV-2 infection. If it does not occur, the disease progresses and can take a serious course,” explained Prof. Dr. Eva Bartok from the Institute for Clinical Chemistry and Clinical Pharmacology at the University Hospital Bonn (UKB). Adds graduate student and first author Samira Marx: “Furthermore, activation of the innate antiviral response, including the release of type I and type III IFNs, is extremely important for the development of an appropriate antiviral adaptive immune response.” The immune system’s adapted response takes place only a few days after infection and includes the activation of further immune cells and finally the formation of antibodies.
The immune receptor RIG-I has previously been recognized as a suitable target for the prophylactic induction of antiviral effects. It was shown in mouse models that prophylactic stimulation of RIG-I mice can protect against a fatal influenza virus infection. “Such RIG-I stimulating RNAs that mimic viral RNA can be chemically synthesized and used as therapeutics to activate the innate immune response against numerous diseases including cancer and viral infections,” says Prof. Dr. Martin Schlee from the Institute for Clinical Chemistry and Clinical Pharmacology. In the present study, the researchers investigated the effect of synthetic 5’triphosphorylated dsRNA (3pRNA) on the course of infection with SARS-CoV-2 in a mouse model.
Mouse model replicates human COVID-19 disease
Since mice are generally not susceptible to SARS-CoV-2, genetically modified mice that produce the SARS-CoV2 binding protein ACE2 had to be used. “The mouse model we used recreates important aspects of the human COVID-19 disease,” says Prof. Dr. Hiroki Kato from the Institute for Cardiovascular Immunology at the UKB.
Using this model, the researchers were able to show that systemic application of 3pRNA one to seven days before infection with SARS-CoV-2 drastically reduced the proportion of fatal infections. A similar observation was made with the therapeutic application of 3pRNA one day after infection. “Our results clearly show that targeting RIG-I, both prophylactically and therapeutically, is a promising approach to treat COVID-19. However, further studies must be carried out before it can be used on humans,” summarizes Prof. Dr. Gunther Hartmann from the Institute for Clinical Chemistry and Clinical Pharmacology and spokesman for the Cluster of Excellence ImmunoSensation2 at the University of Bonn.
Participating institutions and funding:
In addition to the Institute for Clinical Chemistry and Clinical Pharmacology, the Institute for Virology, the Institute for Cardiovascular Immunology and the Mildred Scheel School of Oncology at the University Hospital Bonn, the German Center for Infection Research and the Institute for Tropical Medicine Antwerp (Belgium) were involved. The study was mainly funded by the German Research Foundation (DFG).
Publikation: Samira Marx, Beate M. Kümmerer, Christian Grützner, Hiroki Kato, Martin Schlee, Marcel Renn, Eva Bartok and Gunther Hartmann: RIG-I-induced innate antiviral immunity protects mice from lethal SARS-CoV-2 infection, Molecular Therapy – Nucleic Acids, DOI: 10.1016/j.omtn.2022.02.008
(J.S.)