The COVID-19 pandemic has posed unprecedented challenges to global health, but the scientific community has responded with remarkable speed and innovation in developing countermeasures against the causative agent, SARS-CoV-2. While vaccines and antiviral drugs have played a critical role in mitigating the impact of the virus, the ability of SARS-CoV-2 and other viruses to evolve into new variants resulting in vaccine breakthrough infections necessitate the exploration of novel prevention strategies. In this article, we delve into a potential game-changer in the fight against respiratory viral infections: the stimulation of Natural Killer T (NKT) cells through a novel glycolipid, 7DW8-5. Our two groups of immunologists and virologists with decades of experience in their disciplines, came together to demonstrate hand-in-hand, the ability of 7DW8-5 to prevent infections by SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus in animal models.
The Power of NKT Cells:
NKT cells are a unique subset of lymphocytes with characteristics of both natural killer (NK) cells and αβ T cells. They are crucial components of the innate immune system, playing a role in cancer, autoimmune diseases, and protection against infections. These cells recognize specific glycolipids presented by CD1d molecules on antigen-presenting cells, leading to their activation. These activated NKT cells release antiviral cytokines, such as interferon-gamma (IFN-γ), which play a protective role against various viral infections.
The Discovery of 7DW8-5:
From a library of synthetic glycolipids, our group previously discovered an α-GalCer analogue called 7DW8-5 that exhibited potent immunostimulatory activity in both mouse and human NKT cells in vitro. When stimulated, NKT cells secrete Th1 cytokines and activate populations of NK cells and CD8+ T cells, which release multiple cytokines, including IFN-γ. We hypothesized that the immunostimulatory effect of 7DW8-5 could inhibit viral infections in vivo.
Protection against SARS-CoV-2:
In animal models, intranasal administration of 7DW8-5 before or soon after infection with the mouse-adapted MA10 strain of SARS-CoV-2 led to significant protection against infection. The glycolipid treatment preserved body weight and reduced infectious virus levels in lung and nasal tissues significantly. Furthermore, the timing and dose of 7DW8-5 administration demonstrated its efficacy, with repeated dosing showing no signs of anergy. Histopathological analysis revealed a reduction in lung tissue damage and viral load, validating the protective effects of 7DW8-5 against SARS-CoV-2 (Figure 1).
Figure 1: Representative images of lung tissue treated with saline or 7DW8-5 prior to challenge with SARS-CoV-2 (MA10) virus. Bottom panels were stained for SARS-CoV-2 nucleocapsid and counterstained with hematoxylin (100x magnification).
Mechanism of Protection:
7DW8-5 induced the upregulation of various cytokines and chemokines associated with antiviral responses. IFN-γ was particularly prominent, suggesting its central role in mediating the antiviral activity of 7DW8-5 (Figure 2a,2c,2d). Single-cell RNA-sequence analysis further revealed a shift toward IFN-γ production in specific immune cell populations, including NKT cells and antigen-presenting cells, reinforcing the hypothesis that 7DW8-5 harnesses the innate immune response to combat viral infections (Figure 2b).
Figure 2: Interferon gamma plays a major role in antiviral response mediated by 7DW8-5. (a) Heatmap showing the differential expression of the genes (as indicated) in nasal turbinates 24 h after intranasal 7DW8-5 (2 μg) or saline administration. (b) Single-cell analysis of lung mononuclear cells from 7DW8-5-treated mice showed a shift in cellular population toward those with IFN-γ production, as shown by Uniform Manifold Approximation and Projection (UMAP) of single CD45+ cells at 24 h post treatment. (c-d) The protective effect of 7DW8-5 observed in wild-type mice is lost in IFN-γ KO mice or in BALB/c mice upon pre-treatment with a blocking anti-mouse-IFN-γ monoclonal antibody.
Breadth of Protection:
The study expanded its efficacy measurements to variants of SARS-CoV-2 and against other respiratory viruses. In animal models, 7DW8-5 demonstrated significant protection against Omicron subvariants BA.1 (Figure 3a) and BA.5 (Figure 3b), as well as the Delta variant of SARS-CoV-2 (Figure 3c-d). Additionally, the glycolipid showed substantial protective activity against respiratory syncytial virus (RSV) (Figure 3e) and influenza virus (Figure 3f-g), further highlighting its broad antiviral potential.
Figure 3: 7DW8-5 demonstrates broad antiviral potential against viruses of pandemic potential. Protective efficacy as measured by lack of weight loss and determination of endpoint titers of viral load in either lungs or nasal turbinates of mice or hamsters was shown against (a-d) multiple variants of SARS-CoV-2, (e) respiratory syncytial virus (RSV) and (f) influenza virus isolates. (g) Mice that received 7DW8-5 48h prior were protected against lethal dose challenge of influenza PR8/A/34.
Conclusion:
The discovery of 7DW8-5 and its ability to stimulate NKT cells opens up exciting possibilities for preventive strategies against respiratory viral infections. By activating the innate immune system, we can harness the body's natural defenses to ward off viral pathogens, including SARS-CoV-2, RSV, and influenza virus. The broad protection offered by 7DW8-5, in a mechanism-specific manner, along with its demonstrated efficacy against different viral strains, underscores its potential as a game-changing preventive approach. Further research and clinical trials will be necessary to validate these findings and explore the translational possibilities of 7DW8-5 in human populations. Nonetheless, 7DW8-5 defines a landmark in the innovative immunotherapeutic interventions that leverage the power of the innate immune system to combat respiratory viral infections.
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