Running Interference in COVID-19: Regulating interferon responses via STING

The best weapon in our arsenal against the COVID-19 pandemic are vaccines. Vaccines, however, are only a preventative measure intended for the protection of healthy individuals from acquiring the disease and help curb its spread. Unfortunately, there are people who are unable to take vaccines due to pre-existing medical conditions (i.e. immunocompromised individuals), or others who contract a mild form of the disease as a breakthrough infection despite having the vaccine’s protection. Hence, it is imperative to think about treatments to combat an existing infection.

Beyond chemically synthesized antivirals that directly interfere with the virus’ ability to replicate, another strategy against viral infection includes boosting the patient’s own immune system to make it do what it does best – beat the virus!

Antiviral role of interferons in COVID-19

The most effective antivirals produced by an activated immune system are the interferons (IFNs). Interferons are naturally occurring molecules in the body that are part of the primary immune response and are essential for defense against viruses and cancer. Several studies on SARS-CoV-2 have demonstrated the correlation between weakened IFN responses and severity of the disease, showing that lack of a robust IFN response could lead to a greater viral burden in the lungs, which affects patient health and recovery [1] [2]. But what truly makes SARS-CoV-2 a dangerous adversary is that the tissue damage incurred during the infection is often a result of a runaway host immune response and not just the virus. For example, unchecked IFN responses during infection in the lungs can cause delayed recovery and increase vulnerability to co-infections [3] [4]. The takeaway from these observations is that while IFNs are great and absolutely required for controlling and clearing the virus – too much of a good thing may have an opposite effect on the patient’s health. 

So, the important question here is: can IFNs be truly considered as a viable treatment option? And the answer is, it all depends on the timing and intensity! Too little IFNs allow the virus to replicate rapidly and without oversight. However, too many IFNs arriving at the site of infection too late can cause irreparable tissue damage.

Several ongoing clinical trials are exploiting the antiviral properties of IFNs as a treatment for SARS-CoV-2 infection in patients. Two families of IFNs, specifically Type I and Type III IFNs, are being used in multiple trials where IFNs are administered through the nose in patients who have tested positive for COVID-19 within 72 hours. Generally, an IFN response  during viral infection tends to predict a positive outcome for patients. However, the side effects from administered IFNs can often be far-reaching and less favorable. 
Instead of directly administering IFNs, a substitute method for boosting antiviral responses in patients would be to stimulate the patients’ own IFN response. This method would add a layer of control — ideally an “on-off switch” — for activating IFNs in a time-dependent manner while also regulating the strength of the response.

Inducing an endogenous interferon response using a STING-activating molecule

Two back-to-back, independent studies by Humphries, Shmuel-Galia et al and Li et al tested out such an idea by pharmacologically activating an immune pathway called STING (Stimulator of Interferon Genes) to initiate host IFN production. Normally, activation of the STING pathway is achieved through cyclic dinucleotides, which are components of genomic material generated by the host as messengers to alert the cell of foreign invaders. STING activation then leads to the stimulation of Type I IFN production in cells infected with intracellular pathogens such as viruses. In order to activate the STING pathway pharmacologically, both of these studies used a molecule called diABZI (a diamidobenzimidazole compound), which induces clustering of STING to initiate the expression of Type I IFN as well as other antiviral IFN-stimulated genes (ISGs) that are integral to launching an antiviral defense (Figure 1).

Figure 1: An intricate balance of IFN responses leads to a successful antiviral response against a SARS-CoV-2 infection. Transient activation of the STING immune pathway using a synthetic molecule called diABZI presents an “On/Off switch” that may effectively regulate a patient’s IFN production against the viral infection. Created using

These studies show that SARS-CoV-2 replication in lung epithelial cells (the cells lining the surface of the lungs) cultured in a dish is strongly limited when the cells are pre-treated with diABZl. In an air-liquid interface culture system, a cell system that mimics the structure of a functioning lung, diABZl had similar efficacy in blocking viral replication and spread. Further testing of diABZI as an effective antiviral compound was carried out in an animal model, specifically a transgenic mouse model that was engineered to express the human receptor for SARS-CoV-2 cell entry and infection. Intranasal treatment with diABZI either before or shortly after SARS-CoV-2 inoculation showed decreased weight loss and significantly better survival in the infected mice. Li et al further alludes that IFN production via STING activation may be broadly effective against all evolving variants of SARS-CoV-2. 

Mechanistically, Li et al showed that Type I IFN production via diABZI is directly responsible for blocking SARS-CoV-2. Additionally, Humphries et al inspected the immune cell profile in mice treated with diABZI, which showed increased presence and activation of immune cells required for an effective antiviral defense. Reassuringly, the single treatment with diABZI did not cause excessive damage to lung tissue, but was enough to eradicate the virus from the system. Taken together, a controlled IFN production through pharmacological stimulation of STING presents an attractive method of activating antiviral responses in SARS-CoV-2-infected individuals that can translate into a viable treatment option upon early detection of the disease.

Interferons are majestic molecules – indispensable for launching an impregnable defense against viruses such as SARS-CoV-2. They are not only important for clearing a viral infection, but also in preventing infections especially in individuals who are unable to take advantage of vaccines. But like all weapons, their efficacy relies on proper implementation, which in this case is accurate timing and dosing. As antivirals, Type I and Type III IFNs work best when stimulated early and transiently – therefore inducing host IFNs via controlled, temporary STING activation could become an effective route that will allow IFNs to battle SARS-CoV-2 infections while causing minimal lasting damage to the patient’s respiratory system.

This article summarizes work from Humphries, F. et al. A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection. Science Immunology (2021) and Li, M. et al. Pharmacological activation of STING blocks SARS-CoV-2 infection. Science Immunology (2021)

Cover image courtesy of mcmurryjulie from Pixabay

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