In this study, the authors demonstrate that ORF8 SARS-CoV-2 is uniquely capable of forming aggregates when expressed in lung epithelial cells. This aggregation potently inhibits anti-viral protein expression in response to IFNγ, which could contribute to SARS-Co-V2 escape from the host antiviral immune response. DOI: 10.3389/fimmu.2021.679482

However, it has recently been shown that decreased CD4 expression by monocytes correlated with disease severity suggesting SARS-Co-V2 infection could potentially affect function. DOI: 10.1089/vim.2020.0166

Recent clinical data suggest that KIM-1 can also be used as a biomarker for individuals that will go on to develop acute kidney injury following SARS-Co-V2 infection. DOI: 10.1007/s40620-021-01079-x

Indeed this distinction between the immune systems of males and females is to be considered when developing vaccines against SARS-Co-V2. (DOI: 10.1021/acs.molpharmaceut.1c00291)

The inhibitor of TMPRSS2, N-0385, administered intranasally, has recently been shown to improve clinical outcomes in the severe K18-human ACE2 transgenic mouse model of SARS-CoV-2 disease. This is another potential novel therapeutic for patients suffering with COVID-19 (DOI: 10.1101/2021.05.03.442520).

Indeed, a recent paper has shown that an inihibitor of HMGB1, glycyrrhizin, can simultaneously stop virus replication and suppress proinflammatory mediators. This evidence provides a potential new therapeutic option for COVID-19 patients (DOI: 10.1016/j.cyto.2021.155496).

ORF8 appears to have originated from ORF7a https://doi.org/10.1128/mBio.03014-20 and the crystal structure of both proteins reveals a very similar core structure https://doi.org/10.1073/pnas.2021785118 , which may suggest that some of the functions for these accessory proteins could be similar or redundant.

and to inhibit the production of INFß https://doi.org/10.1016/j.virusres.2021.198350

SARS-CoV-2 ORF9b facilitates viral replication by targeting multiple innate sensing pathways depleting type I and III IFN signalling. ORF9b interacts with RIG-I, MDA-5, MAVS, TRIF, STING and TBK1 and blocks IRF3 phosphorylation and nuclear translocation. https://doi.org/10.1002/jmv.27050

Published now in J. Virol:

Rebendenne A, Valadão ALC, Tauziet M, Maarifi G, Bonaventure B, McKellar J, Planès R, Nisole S, Arnaud-Arnould M, Moncorgé O, Goujon C. SARS-CoV-2 triggers an MDA-5-dependent interferon response which is unable to control replication in lung epithelial cells. J Virol. 2021 Jan 29:JVI.02415-20. doi: http://doi.org/10.1128/JVI.02415-20 Epub ahead of print. PMID: 33514628.

ORF3 directly impairs DNA sensing by binding to STING and blocking nuclear accumulation of p65 to inhibit NF-kB signalling. Also, the main viral protease of SARS-CoV-2 can inhibit RIG-I receptor (RLR) and STING. https://doi.org/10.1038/s41392-021-00515-5

The IFN response is activated by SARS-CoV-2 viral intermediates through MDA5-mediated sensing. In lung epithelial cells, MDA5 and LGP2 govern the innate immune response with transcription factors IRF3, IRF5, and NF-κB/p65 regulating IFN pathways in SARS-CoV-2 infection. https://doi.org/10.1016/j.celrep.2020.108628

Lipid metabolism can also influence infection as HDL-scavenger receptor B type 1 (SR-B1) facilitates entry into ACE2-expressing cells.The mechanism involve SARS-CoV-2 S1 subunit binding to cholesterol and to HDL components to enhance viral uptake. SR-B1 is co-expressed with ACE2 in different tissues including the human lung. http://doi.org/10.1038/s42255-020-00324-0

TMPRSS4 has also been reported to facilitate virus entry by enhancing SARS-CoV-2 spike fusogenic activity. https://doi.org/10.1126/sciimmunol.abc3582

A Genome-wide CRISPR screen identified lysosomal protein TMEM106B as a host factor to facilitate infection uniquely to SARS-CoV-2, and not involved in other coronavirus infections. http://doi.org/10.1016/j.cell.2020.12.004