Researchers of the Bonn Cluster of Excellence ImmunoSensation2 observe increased protection against severe COVID-19 courses through targeted stimulation of the RNA receptor RIG-I
The ongoing SARS-CoV-2 pandemic has caused an imminent urge for both antiviral therapeutical drugs and vaccines. While the development of vaccines was accomplished in a remarkably short timeframe, the identification of direct antiviral treatments has progressed comparatively slowly. In the light of the further risk of pandemics in the future, however, there remains need for direct antiviral drugs and treatments. Moreover, emerging immune-evasive SARS-CoV-2 variants are of concern. These cause high numbers of infections even in a highly immunized population, underscoring the continuing need for effective antiviral drugs to treat COVID-19.
PhD student Samira Marx and her advisor Prof. Gunther Hartmann of the Institute of clinical chemistry and clinical pharmacology at the University Hospital Bonn, in collaboration with further members of the Cluster of Excellence ImmunoSensation2 at the University of Bonn Prof. Eva Bartok, Prof. Martin Schlee, Prof. Hiroki Kato, and colleagues have now shown that prophylactic stimulation of the antiviral innate immune receptor RIG-I provides protection against lethal SARS-CoV-2 infections in mice and reduces disease severity. The work has recently been published in the journal Molecular Therapy – Nucleic Acids.
Since its outbreak in 2019, the SARS-CoV-2 virus has caused more than 290 million confirmed infections and more than 5.4 million deaths worldwide. The COVID19 disease caused by SARS-CoV-2 affects the upper and lower respiratory tract and can cause severe pneumonia. In addition, the infection is often accompanied by neurological symptoms such as anosmia (loss of the sense of smell) and can lead to long-term, chronic effects observed after recovery from the acute illness, referred to as "long-term COVID."
SARS-CoV-2 belongs to the genus Betacoronavirus. Like other members of this genus, SARS-CoV-2 is equipped with several molecular tools that allow it to evade recognition by the immune system. The virus carries the information to produce a series of proteins, capable of inhibiting antiviral recognition systems of the infected cell. Actually, these systems could identify viral RNAs and sound the alarm. This recognition is based on small structural subtleties that distinguish a viral from a human RNA. SARS-CoV-2 proteins can alter viral RNA so that it is indistinguishable from endogenous RNA.
For example, viral RNAs are masked by the addition of a methyl group. This process is known as "capping". In this way, the viral RNA escapes early recognition by central antiviral restriction factors such as IFIT1 or the innate immune receptor RIG-I. The latter normally induces a so called immune response in which antiviral active proteins, cell signals and messenger substances, such as type I and type III interferon (IFN) are released. "A robust, early type I IFN production is key to clearing SARS-CoV-2 infection, and its absence is associated with disease progression and the development of severe COVID-19," Prof. Eva Bartok explained. Samira Marx added, "The activation of an innate antiviral response, including the release of type I and type III IFNs, is also extremely important for the development of an appropriate antiviral adaptive immune response." The adaptive immune response occurs only after a few days and involves the activation of further immune cells and ultimately the production of antibodies.
The immune receptor RIG-I has previously been identified as a suitable target for prophylactic triggering of antiviral effects. For example, mouse models have shown that prophylactic stimulation of RIG-I can protect mice from lethal influenza virus infection. RIG-I is activated by double-stranded RNA (dsRNA) containing a 5'-di or triphosphate. A recognition motif found in most viral RNAs. “Such RIG-I stimulating RNAs that mimic viral RNA can be chemically synthesized and used as therapeutics to turn the innate immune response against numerous illnesses including cancer and viral infections” said Prof. Martin Schlee. “In the present study, we analyzed the effect of synthetic 5’triphopsphorylated dsRNA (3pRNA) on the course of infection with SARS-CoV-2 in a mouse model.”
As mice are generally not susceptible to SARS-CoV-2, the researchers had to use genetically adapted mice, able to generate the SARS-CoV-2 binding protein Angiotensin Converting Enzyme 2 (ACE2). “The mouse model we used recapitulates key aspects of the human COVID-19 disease.” Prof. Hiroki Kato added.
Using this model, the researchers of the University Hospital Bonn could show that a systemic application of 3pRNA, one to seven days prior to infection with SARS-CoV-2, drastically reduced the proportion of lethal infections. A similar observation was made for therapeutic application of 3pRNA, one day after infection. “Our findings clearly show that targeting RIG-I, both in a prophylactic and a therapeutical manner, is a promising approach in the treatment of COVID-19” summarized Prof. Gunther Hartmann.
Participating institutions and funding
In addition to the Institute of Clinical Chemistry and Clinical Pharmacology, the Institute of Virology, the Institute of Cardiovascular Immunology and the Mildred Scheel School of Oncology at the University Clinics Bonn, the German Center for Infection Research and the Institute of Tropical Medicine, Antwerpen, Belgium were involved.The study was mainly funded by the German Research Foundation (DFG).
Publikation
Samira Marx, et. al. (2022), RIG-I-induced innate antiviral immunity protects 1 mice from lethal SARS-CoV-2 infection, Molecular Therapy – Nucleic Acids, DOI: 10.1016/j.omtn.2022.02.008
Contact
Institute of Clinical Chemistry & Clinical Pharmacology
Medical Faculty, University of Bonn
University Hospital of Bonn
Venusberg - Campus 1
53127 Bonn
