When COVID-19 develops and becomes severe with the new coronavirus, cytokines such as IL-6, IL-18, IFN-γ, IL-15, TNF-α, IL-1α, IL-1β are upregulated, and fall into the so-called cytokine storm state. It is widely known that acute respiratory distress syndrome (ARDS) in COVID-19 is directly correlated with this cytokine storm.
In the expression of such various cytokines, it has been pointed out by the following group that the synergetic effects of TNF-α and IFN-γ in particular may be causing severe disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605562/
Here is an example of in vivo experiment using a mouse that the synergetic effect of TNF-α and IFN-γ mimics the symptoms of COVID-19.
It has also verified in vivo that applying TNF-α and IFN-γ neutralizing antibodies to hACE2 transgenic mice infected with SARS-CoV-2 increases survival rates significantly.
So, inhibitors for accurate points in the downstream signal path of including TNF-α and IFN-γ will lead to development of effective drugs for ADRS of COVID-19.