Written by Isobel Young, Science Writer
Around the world, COVID-19 cases are still being reported. This highlights how understanding the mechanisms behind SARS-CoV-2 infection remains an important topic. Now, we are one step closer to this thanks to a recent study from the University of Hong Kong. The team conducting the study investigated the link between the apoptotic protease caspase-6 and coronavirus pathogenesis, in the hopes of identifying a new target for coronavirus therapeutics.
Apoptosis and coronaviruses
Caspase-6 is a cytosine-aspartic proteases in the apoptosis cascade and works via nuclear protein (N) cleavage. Previous research has found that coronaviruses cause apoptosis of host cells, which is believed to aid their pathogenesis. Because of this, the team hypothesized that by inhibiting caspase-6, apoptosis will be prevented and therefore hinder coronavirus pathogenesis.
They first investigated this theory using ex vivo human lung tissue. The tissue samples were infected with the coronavirus MERS-CoV and then were either treated with a caspase-6 inhibitor or were left untreated. The caspase-6 inhibitor used was z-VEID-fmk, which works by preventing N cleavage. It was found that the tissue samples treated with z-VEID-fmk had significantly reduced viral replication. Additionally, the amount of pro-inflammatory cytokines and chemokines were also significantly decreased in the treated group, further strengthening the theory that caspase-6 is involved in coronavirus pathogenesis. This study was repeated on genetically engineered mice and generated the same results.
Reduction in COVID-19 symptoms
Next, the team wanted to see if treatment of z-VEID-fmk would yield the same results in cells infected with SARS-CoV-2. They studied this by infecting golden Syrian hamsters with the virus. As with the previous experiment, half of the hamsters were treated with z-VEID-fmk and half remained untreated. The results demonstrated a significant reduction in viral replication in the treated hamsters compared to the untreated hamsters, suggesting that caspase-6 has a role in SARS-CoV-2 pathogenesis, as well as MERS-CoV.
As well as looking at viral replication, the team investigated histological changes in the lungs of the SARS-CoV-2 infected hamsters. They found significant damage in the untreated lungs; epithelial cell death, pulmonary blood vessel wall inflammation and alveoli hemorrhage were all observed. In contrast, the z-VEID-fmk treated lungs were relatively undamaged, aside from a small amount of alveoli hemorrhage. These results have huge implications for the development of novel therapeutics to treat severe cases of COVID-19.
Importantly, the team also found that the body weights of the treated hamsters stayed consistent throughout the study, which was not seen in the untreated hamsters. The untreated hamsters’ body weights significantly decreased after being infected with the virus, which is homologous to the experience of some humans who contract COVID-19. Moreover, it was found that the hamsters that were treated with z-VEID-fmk had significantly lower mortality rates compared to the untreated hamsters. This begs the question: could z-VEID-fmk also reduce the number of deaths in humans infected with SARS-CoV-2? While the study doesn’t investigate this, it provides rationale for future studies to investigate the effect of z-VEID-fmk on individuals suffering with COVID-19.
IFN Signaling pathway
The interferon (IFN) signaling pathway is involved in cellular resistance to viral expression. An important finding of this study was that in cell cultures that were deficient of the IFN signaling pathway, the results mentioned previously were not found. “Our results demonstrated that the antiviral effect of z-VEID-fmk diminished when the IFN pathway is non-functional,” says the author. They go on to elaborate; “these results hinted that caspase-6-mediated N cleavage might modulate coronavirus replication by regulating IFN signaling.”
Implications for COVID-19 treatment
The findings of this research add another piece to the puzzle of our understanding of how COVID-19 makes people ill. Furthermore, it provides an insight into the mechanisms of the IFN signaling pathway, that was previously missing, highlighting a need for further investigation. Using this knowledge, novel therapeutics could be designed for targets that were not originally known to be involved in the pathogenesis of COVID-19. Future research may choose to focus on creating a drug or vaccine which inhibits caspase-6 in serious cases of COVID-19, giving those affected a better prognosis and a higher chance of survival.
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