New strategy for COVID-19 prophylaxis
Researchers specifically stimulate the RNA receptor RIG-I
Date:
March 8, 2022
Source:
University of Bonn
Summary:
SARS-CoV-2 viruses can hide from recognition by the immune system.
However, the antiviral immune receptor RIG-I can be
stimulated, which improves protection against lethal SARS-CoV-2
infections. Researchers have shown this in mice. Also, the incidence
of severe disease progression was observed to be significantly
reduced.
FULL STORY ========================================================================== SARS-CoV-2 viruses can hide from recognition by the immune
system. However, the antiviral immune receptor RIG-I can be
stimulated, which improves protection against lethal SARS-CoV-2
infections. Researchers led by Prof. Dr. Gunther Hartmann from
the Institute of 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, have shown this
in mice. Also, the incidence of severe disease progression was observed
to be significantly reduced. The study was published online in advance
in the journal Molecular Therapy -- Nucleic Acids and is now available
in the final version.
==========================================================================
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, I.e.
camouflaged from the immune system, 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.
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 genetic material (here: Ribonucleic acids/RNAs) and sound the alarm. Proteins of SARS-CoV-2 can alter viral ribonucleic acids in a way, that they become indistinguishable from
endogenous RNA.
Camouflage protects virus from immune system For example, viral RNAs
are masked by the addition of a methyl group. In this way, the viral
RNA escapes early recognition by the central antiviral immune- receptor
RIG-I. This receptor normally induces a so called innate immune response
in which antiviral active proteins, cell signals and messenger substances
-- such as type I interferon (IFN) -- are generated.
"A robust, early type I IFN production is key to clearing SARS-CoV-2
infection.
Its absence is associated with disease progression and the development
of severe COVID-19," Prof. Dr. Eva Bartok from the Institute of Clinical Chemistry and Clinical Pharmacology at the University Hospital Bonn
(UKB) explained. The PhD Student and first author 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. "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. Dr. Martin Schlee
from the Institute of Clinical Chemistry and Clinical Pharmacology. In
the present study, the scientists analyzed the effect of synthetic 5'triphopsphorylated dsRNA (3pRNA) on the course of infection with
SARS-CoV-2 in a mouse model.
Mouse model to resemble human COVID-19 infection 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," added Prof. Hiroki Kato from
the Institute of Cardiovascular Immunology at the UKB.
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. However, prior to application in
humans, further studies need to be conducted," summarized Prof. Gunther Hartmann from the Institute of Clinical Chemistry and Clinical
Pharmacology and speaker of the Cluster of Excellence ImmunoSensation2.
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 Hospital 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).
========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. Samira Marx, Beate M. Ku"mmerer, Christian Gru"tzner, Hiroki
Kato, Martin
Schlee, Marcel Renn, Eva Bartok, Gunther Hartmann. RIG-I-induced
innate antiviral immunity protects mice from lethal SARS-CoV-2
infection.
Molecular Therapy - Nucleic Acids, 2022; 27: 1225 DOI: 10.1016/
j.omtn.2022.02.008 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220308102740.htm
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