A recent study published on the Research Square * prepress server showed that 7DW8-5, an immunostimulatory glycolipid, prevented three respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vivo.
Study: An immunostimulatory glycolipid that blocks infections by SARS-CoV-2, RSV, and influenza in vivo. Image credit: Nhemz / Shutterstock
Fund
Over the past two and a half years, the SARS-CoV-2 pandemic has affected populations around the world. The successful discovery and use of preventive vaccines that significantly reduced deaths, symptomatic infections, and hospitalizations helped reduce the impact of the 2019 coronavirus disease pandemic (COVID-19).
However, the frequency of innovative vaccine infections has increased, especially after the emergence of viral variants that are antigenically different from the ancestral strain used in existing COVID-19 vaccines, as SARS-CoV-2 it continues to spread and mutate globally. Therefore, the preventive arsenal should include more strategies, such as those that exploit the innate immune system of the host and allow rapid control of infection.
Natural killer T cells (NKT), a crucial component of innate immunity, are implicated in autoimmune diseases, cancer, and infection prevention. Invariant NKT cells (iNKT) are NKT cells that have a semi-invariant T cell receptor (iTCR), which identify particular glycolipids bound to CD1d molecules in antigen-presenting cells and trigger a reaction in chain of cytokines and chemokines. Α-galactosylceramide (α-GalCer), a glycolipid, was the first CD1d ligand to be discovered.
The authors of the present work have identified an α-GalCer analogue, 7DW8-5, from a well-targeted collection of synthetic glycolipids that demonstrates a much more robust immunostimulatory action in human and human iNKT cells. in vitro mice.
About the study
In the present study, the scientists described the specific role of the 7DW8-5 mechanism in protecting animal models from infection with influenza virus, SARS-CoV-2, and respiratory syncytial virus (RSV).
The team evaluated the hypothesis that the immunostimulatory impact of 7DW8-5 could hinder SARS-CoV-2 infection in mice. In addition, they examined whether 7DW8-5 could lose its antiviral efficacy due to repeated dosing, possibly leading to NKT cell anergy.
The researchers explored the antiviral impact of 7DW8-5 in other variants of SARS-CoV-2, starting with B.1.1.529, that is, the Omicron BA.1 variant, infecting wild-type mice without prior adaptation. A comparable assay was performed using B.1.617.2, i.e., the Delta variant, which may infect transgenic mice of the 18-human keratin angiotensin 2 converting enzyme (K18-hACE2), as well as hamsters and not wild-type mice. The scientists then investigated whether the defense of 7DW8-5 could be extended to other clinically significant viral infections, such as influenza virus and RSV, since it lacked direct antiviral efficacy against SARS-CoV-2. in vitro and was probably stimulating a component of innate immunity. .
One day after giving six BALB / c 2 µg mice of 7DW8-5 IN or saline, the authors examined the pattern of chemokines / cytokines in bronchoalveolar lavage (BAL), serums, and homogeneities of lungs or nasal horns. Finally, they investigated the protection mechanism of the 7DW8-5.
Results and conclusions
The team found that intranasal delivery of the 7DW8-5 immunostimulatory glycolipid prevented SARS-CoV-2 infection in wild-type mice. This was demonstrated with stable body weight and a reduction in viral replication in the lung by> 2 records.
In addition, the viral titer in the nasal horn was reduced by about 50-fold, which was greater than the blockade exhibited by monoclonal antibodies in this tissue compartment. However, administration of 7DW8-5 after exposure to SARS-CoV-2 was ineffective, indicating that this glycolipid will not be beneficial as a treatment. This is probably because its immunostimulatory properties require a significant advantage in suppressing a virus that replicates rapidly.
The authors also demonstrated that 7DW8-5 protected against two variants of SARS-CoV-2, namely Omicron BA.1 in wild-type mice and Delta in hamsters and K18-hACE2 transgenic mice. In addition, equivalent antiviral activity was observed in mice in the face of RSV or influenza virus challenges. These results illustrate the range of immunity offered by 7DW8-5 against three relevant respiratory viral families (CoV, orthomyxovirus, and paramyxovirus) with pandemic potential.
The results of the study also showed that 7DW8-5 has a host-directed and mechanism-specific activity. Although this glycolipid produced several chemokines / cytokines, its antiviral activity was eliminated in CD1d-knockout (KO) mice.
In addition, interferon γ (IFN-γ), a proven innate immune system element that exhibits broad antimicrobial properties, was shown to be another key part of the protective role of 7DW8-5. In fact, pretreatment with an anti-IFN-γ inhibitory monoclonal antibody caused the protective effect of 7DW8-5 in wild-type mice to be drastically ineffective. In addition, it did not demonstrate any protection among IFN-γ-KO mice.
Therefore, IFN-γ and CD1d were needed for the in vivo activity of 7DW8-5; however, it is still unknown whether these two factors alone are adequate, as there may be significant mediators operating downstream of IFN-γ.
The researchers noted that a chemical like 7DW8-5, which is easy to administer and low-cost to produce, can help contain the COVID-19 pandemic and respond to future respiratory virus pandemics before the development of vaccines or drugs.
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Research Square publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guided by clinical practice or health-related behavior, or treated as established information.