by Gertrud U. Rey
There is currently no vaccine that is effective against all viruses and it is unlikely that one will ever exist. But what about a universal antiviral drug? A recent study out of Columbia University suggests that it might be possible to develop effective broad-spectrum antivirals against known, emerging, and unknown viruses.
The idea is based on a rare genetic disorder that causes affected individuals to be in a persistent state of low-grade immunological inflammation, which appears to protect them from developing symptoms of a range of viral infections. The disorder is known as ISG15 deficiency because affected individuals lack both copies of the gene that codes for the immune protein ISG15. ISGs, or “interferon-stimulated genes” are commonly expressed in response to viral infection. As their name implies, they are activated by interferons, which are molecules that prompt downstream immune signaling complexes to elicit a general antiviral state. When immune cells detect a virus, interferons trigger ISGs to make proteins that limit viral replication and degrade viral RNA.
ISG15 regulates the activity of interferon by interacting with another immune protein called ubiquitin-specific peptidase 18 (USP18), an inhibitor of interferon signaling. ISG15 binds to and stabilizes USP18, thereby increasing its abundance and allowing it to dampen the effects of interferon. If there is no ISG15 (as is the case in ISG15-deficient individuals), USP18 becomes unstable and undergoes rapid degradation, leading to a prolonged and hyperactive interferon response. The degradation and absence of USP18 that results from ISG15 deficiency leads to persistent expression of other ISGs and associated inflammation, ultimately causing comprehensive antiviral resistance.
Inspired by this scenario and the apparent immune protection of ISG15-deficient individuals against various viruses, the authors of the study screened and identified 10 ISGs that collectively appeared to increase resistance to Zika virus, vesicular stomatitis virus, influenza virus, West Nile virus, and SARS-CoV-2 (the virus that causes COVID-19) in cell culture. To see whether this effect also occurs in animals, the authors generated a nanoparticle-encapsulated messenger RNA encoding the 10 ISGs. They then administered it to mice intranasally and infected them with influenza virus. Samples collected from the lungs of the mice showed that recipients of the nanoparticle-mRNA drug had reduced replication of influenza virus compared to recipients of placebo control. Moreover, when the investigators administered the drug to hamsters and then infected them with a lethal dose of SARS-CoV-2, the hamsters survived. These results suggested that the combination of the 10 ISGs may have a synergistic effect in restricting infection with various viruses when administered prophylactically (i.e., prior to infection).
A universal antiviral that is effective against a wide variety of viruses, including emerging viral pathogens, would be invaluable for the purpose of pandemic preparedness. Antiviral drugs are often effective in ways vaccines are not – they are useful for protecting vulnerable individuals who can’t be vaccinated, addressing emerging or chronic viruses for which there are no vaccines available, and they may be more likely to be accepted by vaccine-hesitant individuals.
Although the findings from the Columbia study are promising, it is important to note that they are very preliminary and have multiple limitations. The study was only done in rodents, and it is currently unknown if similar results would be obtained in human subjects. The nanoparticle/mRNA drug was only administered prophylactically, and it is not clear if it would be effective in treating an established infection. Based on the study design in the animal model, one wouldn’t know when to administer the drug, or how far in advance of a possible exposure. The protective effect also appears to be transient and it is uncertain how long it would last in humans. It is also unknown what kind of adverse effects the inflammation resulting from the drug would have on a patient. Despite these challenges, more research in this field is warranted, particularly when considering the potential for broad-spectrum antiviral protection.
Interesting. I worked on siglecs in context of sepsis. Rodent siglecs are evolved quite far from humans. Rodent immune systems have been subjected to extreme pressures diverging 80-90 mya. Humans, because of having no functioning siglec for TLR4 easily become hyper-inflammatory already. In COVID-19 and the 1917 flu pandemic, it was the over expression of an inflammatory cascade that was a problem later in the infection. But it’s possible that inflammation early that counteracts the immune modulation genes of COVID-19 may help. I would guess transience is a good feature for humans.
Unfortunately, there is no accurate animal model of the human immune system. Even monkeys and chimpanzees don’t share our unique vulnerability to sepsis. This has repeatedly tripped up researchers. It’s why Jesse Gelsinger died.
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