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About viruses and men: the PRRfect steer comes with a STING to RIG 1 answer at a time

COVID-19 vaccines are the most effective way to prevent severe acute respiratory syndrome (SARS-CoV-2) coronavirus 2 infection. For people who are already infected, new research suggests that the small molecule stimulator of the interferon (STING) agonist-1 genes, diABZI, may be effective in controlling SARS-CoV-2 infection, including those caused by variants. Led by Sara Cherry of the University of Pennsylvania, preclinical results showed that administering a dose of the ABZI agonist to the respiratory mucosa 12 hours after SARS-CoV-2 infection in mice was highly protective. The study was published in the journal Science Immunology. The team’s results showed that SARS-CoV-2 produced a delayed innate immune response in respiratory epithelial cells, allowing it to spread and infect more lungs. Given the previous findings, the researchers sought to stimulate other innate immune pathways to allow detection and neutralization of SARS-CoV-2.

They found that SARS-CoV-2 did not alter interferon (IFN) levels as there was no difference between uninfected cells and SARS-CoV-2 infected cells. This suggested that the virus did not block IFN activation, but rather evaded their response, making IFN agonists a viable therapy to consider. Because proteins such as IFNs are difficult to produce on a large scale for therapeutic use, the researchers set out to identify additional drug-like molecules that could activate innate antiviral immunity. The researchers examined a library of 75 agonists targeting different pattern recognition receptor detection pathways in Calu-3 cells, looking for those that could potentially inhibit SARS-CoV-2. They landed on STING agonists due to their ability to cause a 100-fold reduction in viral RNA levels. STING agonists are also effective in stimulating the production of IFN and inflammatory cytokines by activating the TBK1-IRF3 pathway.

At a low dose with a low toxicity rate, administration of the ABZI agonist STING caused a dramatic inhibition of SARS-CoV-2 infection and an approximately 1,000-fold reduction in viral RNA levels in cells. The antiviral effects of diABZI continued to manifest in Calu-3 cells 1 hour before infection or 3 hours after infection. Similar to type I IFN treatment, diABZI helped repress COVID-19 infection in primary and transformed human respiratory epithelial cells, with an approximately 1,000-fold reduction. Further analysis showed that diABZI’s mechanism of action was based on IFN signaling. The researchers stated, “This suggests that diABZI will be active against a wide range of SARS-CoV-2 variants and probable additional coronaviruses. Since diABZI can also inhibit human parainfluenza virus and rhinovirus replication in cultured cells, the STING agonists may be more broadly active against respiratory viruses.

The STING agonist activated 403 genes, 146 that were associated with antiviral IFN pathways. This included increases in type I and III IFNs after treatment. The agonist also lowered the rate of viral infectivity and lung inflammation in hACE2 K18 transgenic mice treated with diABZI expressing human ACE2. After 7 days of infection, mice treated with an intranasal dose of diABZI lost less body weight than their untreated counterparts, who lost 25% of their weight. ABZI treatment stimulated IFNs along with cytokines and chemokines, indicating benefits for protective immunity against SARS-CoV-2. The compound not only controlled SARS-CoV-2 infection, but was also protective against it. Mice given a single intranasal dose of diABZI were protected against variant B.1.351, known for its rapid transmission and ability to evade neutralizing antibodies. Mice treated before or after infection showed decreased viral load in the lung and nasal turbinates.

The treated mice were also less likely to lose weight due to the virus. So this drug could be used as a preventative in the future, similar to some drugs used to prevent flu syndromes. Meanwhile, an independent team of researchers has identified two substances with anti-coronavirus effect, or rather two new broad-spectrum NOD2 blocking antiviral drugs that inhibit the replication of a number of viruses: GSK717 and GSK583. NOD2 is a protein receptor that recognizes the muramyl dipeptide peptidoglycan (MDP) found in some bacteria and RNA viruses. In response to the detection of MDP, NOD2 launches an immune response. GSK717 inhibits replication of flaviviruses (the family that includes Zika and Dengue), alfavirus, enterovirus, and SARS-CoV-2. GSK583, on the other hand, is an inhibitory agent of RIPK2 (a mediator of the NOD2 signal) that has been shown to be particularly effective against enteroviruses, the group that includes the common cold, polio and foot and mouth disease.

GSK717 and GSK583 are primarily anti-inflammatory drugs that may also benefit patients suffering from the inflammatory effects commonly associated with flavi, alpha, entero and coronavirus. The authors of the study, therefore, promote further research on the identification of broad-spectrum antiviral compounds that suppress the actions of the NOD2 receptor. Their study also highlights the potentially novel mechanism of exploitation of NOD2 expression undertaken by new viruses to evade immune responses. Even before the COVID-19 pandemic, parts of the world were prone to local outbreaks of viruses such as yellow fever, foot and mouth disease, and dengue. As SARS-CoV-2 is currently at the forefront of global medical research, the production of compounds that successfully address this and other viral epidemics could end up producing great strides in eradicating decades-long persistent viruses.

Finally, a Japanese team from the University of Hokkaido has discovered a branch of the immune response against SARS-CoV2 infection dependent on the immune receptor RIG-1, which detects RNA viruses. Microbial pathogens in our body are detected by proteins called pattern recognition receptors (PRRs), which also activate immune responses to these pathogens. Viral infections are detected by a subset of PRRs; the scientists focused their attention on the RIG-I protein, which belongs to this subset. RIG-1 is known to be critical for the detection and response to RNA viruses such as the influenza virus. Scientists investigated the role of RIG-1 and found that its deficiency caused increased viral replication. A single previous study has shown that the expression of RIG-1 is downregulated in the lung cells of patients with COPD (chronic pulmonary disease, analogous to pulmonary emphysema).

Using primary lung cells from two COPD patients, the scientists demonstrated that this downregulation of RIG-1 led to detection of viral replication after 5 days. They also showed that treating these COPD cells with all-trans retinoic acid (ATRA), which upregulates RIG-I expression, significantly reduced viral titers in the cells. Furthermore, using RIG-I mutants, they were able to elucidate the mechanisms by which RIG-1 suppressed SARS-CoV-2 replication: the helicase domain, a structural element in RIG-1, interacts with the ‘Viral RNA, blocking a viral enzyme responsible for replication. It is singular that the cellular mechanisms of RIG-1 share proteins already mentioned above such as TBK1 and RIPK2, as certain PRRs pattern receptors also do the same thing to deliver the message from the cell surface to the DNA. Further investigation of these mechanisms could bring the dawn of the birth for new generations of broad-spectrum antivirals with selectivity never achieved before.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Li M et al. Science Immunol 2021 May 18; 6(59):eabi9007.

Limonta D et al. Antimicrob Agents Chemother. 2021 May 17.

Yamada T, Sato S et al. Nature Immunol 2021 May 11.

Liu W, Reyes HM et al. J Virol. 2021 Mar 31:JVI.00490-21.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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